Researcher Profile and Settings

Master

Affiliation (Master)

• Research Faculty of Agriculture　Fundamental AgriScience Research　Bioscience and Chemistry

Affiliation (Master)

• Research Faculty of Agriculture　Fundamental AgriScience Research　Bioscience and Chemistry

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Profile and Settings

Degree

• Ph.D. in Agricultural Chemistry（Hokkaido University）

Profile and Settings

• Name (Japanese)

  Hira

• Name (Kana)

  Tohru

• Name

  200901025842820520

Achievement

Research Interests

• enteroendocrine cells   gastrointestinal hormone   栄養生理学   消化管生理学   Nutritional physiology   

Research Areas

• Life sciences / Food sciences
• Life sciences / Physiology

Research Experience

• 2020/04 - Today 北海道大学大学院農学研究院 准教授
• 2013/04 - 2020/03 Hokkaido University Graduate School of Agriculture Research Faculty of Agriculture
• 2007/04 - 2013/03 Hokkaido University Graduate School of Agriculture Research Faculty of Agriculture
• 2005/01 - 2007/03 北海道大学大学院農学研究科（院） 助手
• 2003 - 2004 北海道大学大学院農学研究科 研究員
• 2001/11 - 2003/03 University of Manchester (UK), Visiting Research Fellow
• 2000 - 2003 北海道大学大学院農学研究科 日本学術振興会特別研究員
• 1999 - 2000 北海道科学・技術振興財団 研究員

Education

•        - 1999/09  Hokkaido University
•        - 1997/03  Hokkaido University
•        - 1995/03  Hokkaido University  Faculty of Agriculture
•        -   鹿児島県立志布志高等学校 卒業

Awards

• 2024/05 日本栄養・食糧学会 第78回日本栄養・食糧学会大会 優秀発表賞
   ラットにおいて希少糖アルロースにより生じる回腸の伸展がGLP-1 分泌を促進する 

  受賞者: 水間 志織
• 2024/05 日本栄養・食糧学会 第78回日本栄養・食糧学会 トピックス賞
   「ラットにおいて希少糖アルロースにより生じる回腸の伸展がGLP-1 分泌を促進する」 

  受賞者: 水間 志織、比良 徹
• 2023/12 2023年度 日本農芸化学会北海道支部 第二回学術講演会 学生優秀発表賞
   ラットにおけるL-リジンのGLP-1 分泌促進作⽤ 

  受賞者: 入江 明歩;比良 徹
• 2023/11 日本食物繊維学会 日本食物繊維学会第28回学術集会発表賞
   アルロースによる伸展刺激を介したGLP-1分泌機構の解明 

  受賞者: 水間 志織;比良 徹
• 2022/11 日本食物繊維学会 令和4年度 日本食物繊維学会 学会賞
   ルミナコイドによる消化管ホルモン分泌促進作用 

  受賞者: 比良 徹
• 2021/07 日本農芸化学会北海道支部 2021年度日本農芸化学会北海道支部第１回講演会 学生優秀発表賞
   ラットにおけるカルシウムによる食欲抑制に対する食事組成の影響 

  受賞者: 原田 和馬,比良 徹
• 2021/05 日本栄養·食糧学会 令和3年度 日本栄養·食糧学会トピックス賞
   2-モノアシルグリセロールのCCK分泌活性評価およびその作用機構の解明 

  受賞者: 落合 啓太、廣岡 里菜、境野 眞善、竹内 茂雄、比良 徹
• 2020/12 日本栄養・食糧学会北海道支部 2020年度 日本農芸化学会北海道支部／第50回 日本栄養・食糧学会北海道支部 合同学術講演会 若手奨励賞
   ラットにおける伸展刺激負荷による GLP-1 分泌応答の解析 

  受賞者: 木村 夏織;比良 徹
• 2020/03 日本農芸化学会 日本農芸化学会 2020年度大会 優秀発表賞
   食事誘導性肥満ラットにおけるGLP-1分泌応答の増強には回腸部が寄与する 

  受賞者: 佐野 杏莉;比良 徹
• 2019/11 日本食物繊維学会 日本食物繊維学会第 24回学術集会 発表賞
   ラットにおける D- アルロースによる GLP-1 分泌促進機構の解析 

  受賞者: 木村夏織、飯田 哲郎、岸本 由香、原 博;比良 徹
• 2019/11 日本農芸化学会北海道支部 日本農芸化学会 北海道支部第２回講演会 学生優秀発表賞
   食事誘導性肥満ラットにおけるGLP-1の分泌応答と小腸上部および下部での違い 

  受賞者: 佐野 杏莉、比良 徹
• 2019/09 日本栄養・食糧学会北海道支部 第49回 日本栄養・食糧学会北海道支部会 若手奨励賞
   タンパク質投与で生じる高い GLP-1 応答への DPP-4 の関与 

  受賞者: 清水 祐希、原 博、比良 徹
• 2019/07 日本農芸化学会北海道支部 2019年度日本農芸化学会 北海道支部第１回講演会 学生優秀発表賞
   ラットへの食用油経口投与による胃排出への影響 

  受賞者: 李 佳昕;松本 尚二;西村 沙希;境野 眞善;佐野 貴士;原 博;比良 徹
• 2018/05 日本栄養・食糧学会 第 72 回日本栄養・食糧学会大会 トピックス演題
   Zein加水分解物による小腸部位別でのGLP-1分泌応答 

  受賞者: 清水 祐希;比良 徹;原 博
• 2017/11 第24回日本未病システム学会学術総会 優秀演題賞
   ケルセチン配糖体の反復投与は糖負荷後のラットGLP-1分泌能を増強する 

  受賞者: 長瀬 僚介、比良 徹、原 博
• 2017/07 日本農芸化学会北海道支部 平成29年度日本農芸化学会北海道支部第１回講演会
   The role of endogenous GLP-1 against the development of glucose intolerance in rats fed a high fat and high sucrose diet 

  受賞者: Jukkrapong Pinyo;Tohru Hira;Hiroshi Hara
• 2017/05 日本栄養・食糧学会 第 71 回日本栄養・食糧学会大会 学生優秀発表賞
   肥満誘導食摂取ラットにおける食事刺激に対するGLP-1分泌応答の解析 

  受賞者: 柳原 くるみ;比良 徹;原 博
• 2016/11 日本食物繊維学会 日本食物繊維学会 第21回学術集会 発表賞
   D-プシコースによる GLP-1 分泌促進作用における糖輸送担体の関与 

  受賞者: 早川 真輝;比良 徹;飯田 哲郎;岸本 由香;原 博
• 2016/05 日本栄養・食糧学会 第70回日本栄養・食糧学会大会 学生優秀発表賞
   D-プシコースの経口投与はラットにおいてGLP-1分泌を促進する 

  受賞者: 早川 真輝;比良 徹;飯田 哲郎;岸本 由香;原 博
• 2014/09 The XXVIIth International Conference on Polyphenols (ICP 2014) and 8th Tannin Conference The XXVIIth International Conference on Polyphenols (ICP 2014) and 8th Tannin Conference Poster Award
   A non-digestible saccharide, fructooligosaccharide, increases the promotive effect of a flavonoid, α-glucosyl-isoquercetin, on glucagon-like peptide 1 (GLP-1) secretion in rat intestine and enteroendocrine cells. 

  受賞者: Phuwamongkolwiwat P;Hira T;Hara H
• 2013/11 日本アミノ酸学会 2013年度日本アミノ酸学会 科学・技術賞
   

  受賞者: 比良 徹
• 2012/11 日本食物繊維学会 17回学術集会 日本食物繊維学会 17回学術集会 発表賞
   難消化性デキストリンの単回及び長期摂取はラットのGLP-1分泌を促進する 

  受賞者: 池江 明日香;比良 徹;岸本 由香;原 博
• 2012/09 The 25th Anniversary of the Discovery of GLP-1 symposium Young Investigator Abstract Competition Honorable Mention
   

  受賞者: HIRA Tohru
• 2012/05 日本栄養・食糧学会 平成24年度日本栄養・食糧学会奨励賞
   

  受賞者: 比良 徹
• 2011/11 2011 The International Conference on Food Factors 2011 The International Conference on Food Factors, Travel Award
   Fructooligosaccharides enhances beneficial effects of a flavonoid, quercetin-3-β-glucoside, on insulin sensitivity in rats. 

  受賞者: Phuwamongkolwiwat P;Suzuki T;Hira T;Hara H
• 2011/11 日本食物繊維学会 16 回学術集会 日本食物繊維学会 16 回学術集会 発表賞
   トウモロコシたんぱく質 Zein の加水分解物による血糖上昇抑制への GLP-1 の関与 

  受賞者: 樋口 謹行、比良 徹、原 博
• 2010/09 The 18th International Symposium on Regulatory Peptides The 18th International Symposium on Regulatory Peptides, Poster Award
   Calcium-sensing receptor is a sensor for dietary peptides to stimulate cholecystokinin secretion in the enteroendocrine cell line STC-1 

  受賞者: S. Nakajima;T. Hira;M.K.N.B. Sufian;Y. Eto;H. Hara
• 2010/09 日本アミノ酸学会 日本アミノ酸学会第4回学術大会 ポスター賞
   ラットにおけるCalcium-sensing receptorアゴニストによる血糖上昇抑制作用とその作用機構 

  受賞者: 村松 茉耶;比良 徹;江藤 譲;原 博
• 2008/11 日本食物繊維学会 第13回日本食物繊維学会学術集会 奨励賞
   トウモロコシの難消化性たんぱく質Zeinの加水分解物によるラットにおける Glucagon-like peptide-1分泌機構 

  受賞者: 持田 泰佑;比良 徹;原 博

Published Papers

• Targeting intestinal neprilysin to ameliorate glucose homeostasis through insulinotropic effect.

  Shiori Mizuma, Tohru Hira

  Endocrinology 2024/09/27 [Refereed][Invited]
  
• Effect of Single Oral Coingestion of GABA and Malic Acid on Postprandial GLP-1, Glucose, and Insulin Responses in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

  Hiroki Noguchi, Takeshi Ikenaga, Shota Ueno, Chieko Kohashi, Yasuhiro Matsumura, Yusuke Kakumoto, Noriyuki Kohda, Hiroshi Hara, Tohru Hira

  Molecular nutrition & food research 68 (7) e2300610  2024/04 [Refereed][Not invited]
   

  SCOPE: This study examines whether coingestion of γ-aminobutyric acid (GABA) and malic acid (MA) before meals enhances glucagon-like peptide-1 (GLP-1) secretion, and which affects subsequent insulin and glycemic responses in humans. METHODS AND RESULTS: Initially, a murine enteroendocrine STC-1 cell line is used to verify coadministration of GABA and MA synergistically induces GLP-1 secretion. Next, 22 healthy adults are given water (50 mL) containing 400 mg GABA and 400 mg MA (Test), or only 400 mg citric acid (CA) (Placebo) 20 min before meal tolerance test (MTT). Interval blood samples are taken postprandially over 180 min to determine GLP-1, insulin, and glucose responses. By comparison to preload of Placebo, preload of Test significantly increases plasma GLP-1 (total/active) levels (incremental area under the curve by 1.2- and 1.6-fold), respectively. However, there are no significant differences in postprandial blood glucose and insulin. CONCLUSION: Coingestion of GABA and MA before meals enhances postprandial GLP-1 secretion. Future studies should explore optimal dosage regimens to find the efficacy of the mixture on insulin and glycemic response.
• 食品タンパク質・ペプチドによるGLP-1分泌促進とそれによる血糖上昇抑制、体温上昇作用

  比良 徹

  日本栄養・食糧学会誌 77 (1) 2024/02 [Refereed][Invited]
  
• Tunable structure of chimeric isomaltomegalosaccharides with double α-(1 → 4)-glucosyl chains enhances the solubility of water-insoluble bioactive compounds

  Weeranuch Lang, Takayoshi Tagami, Yuya Kumagai, Seiya Tanaka, Hye-Jin Kang, Masayuki Okuyama, Wataru Saburi, Haruhide Mori, Tohru Hira, Chaehun Lee, Takuya Isono, Toshifumi Satoh, Hiroshi Hara, Takayuki Kurokawa, Nobuo Sakairi, Yoshiaki Yuguchi, Atsuo Kimura

  Carbohydrate Polymers 319 121185 - 121185 0144-8617 2023/11 [Refereed][Not invited]
  
• Synergistic enhancement of glucagon-like peptide-1 release by γ-aminobutyric acid and L-phenylalanine in enteroendocrine cells - searching active ingredients in a water extract of Corn Zein protein.

  Hiroki Noguchi, Noriyuki Kohda, Hiroshi Hara, Tohru Hira

  Bioscience, biotechnology, and biochemistry 2023/09/04 [Refereed]
   

  This study investigated the glucagon-like peptide-1 (GLP-1)-releasing activity of an aqueous extract (ZeinS) from corn zein protein, and aimed to identify the active compounds responsible for this activity. GLP-1-releasing activity was evaluated using a murine enteroendocrine cell line (GLUTag). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on purified fractions of ZeinS to identify active molecules. ZeinS stimulated more GLP-1 secretion from GLUTag cells compared to zein hydrolysate. Fractions displaying biological activity were determined by solid phase extraction and high-performance liquid chromatography (HPLC) fractionation. Subsequent LC-MS/MS analysis identified several amino acids in the active fractions of ZeinS. In particular, γ-aminobutyric acid (GABA) exhibited significant GLP-1 releasing activity both alone and synergistically with L-phenylalanine (Phe). Moreover, ZeinS-induced GLP-1 secretion was attenuated by antagonists for the GABA receptor and calcium sensing receptor. These results demonstrate that GABA and Phe identified in ZeinS synergistically stimulate GLP-1 secretion in enteroendocrine cells.
• Trp-Tyr is a dipeptide structure that potently stimulates GLP-1 secretion in a murine enteroendocrine cell model, identified by comprehensive analysis.

  Hayate Taguchi, Kana Murai, Tohru Hira

  Biochemical and biophysical research communications 661 28 - 33 2023/06/18 [Refereed]
   

  Dietary peptides potently stimulate glucagon-like peptide-1 (GLP-1) secretion, however, the underlying molecular mechanisms, such as structure-activity relationships and sensing mechanisms are only partly elucidated. In this study, we used a dipeptide library to identify dipeptides that potently stimulate GLP-1 release and to clarify the underlying structure-activity relationship. Murine enteroendocrine GLUTag cells were exposed to 339 dipeptides for 60 min, and the concentration of GLP-1 released into the supernatant was measured. Subsequently, selected dipeptides were examined for their reproducibility and dose responsiveness. In addition, we investigated the role of constituent amino acids in the secretion of GLP-1, and whether tripeptides containing the active dipeptide structures maintained their activity. In a concentration range of 1-5 mg/mL, twelve dipeptides had reproducible and concentration-dependent GLP-1-releasing activity. Among them, nine dipeptides (FY, KF, NI, PM, QL, QY, WF, WN, WY) were novel, with WY exhibiting the most potent activity. The reverse sequences and most free amino acids did not induce GLP-1 secretion, indicating that GLP-1-producing cells recognize the structure of each peptide to induce GLP-1 secretion. However, no apparent similarities were found between the active peptides. A comparison between the six tripeptides composed of F, W, and Y revealed the further potent tripeptides FWY and WYF, than WY. In the present study, a comprehensive analysis revealed nine novel dipeptides with high potential to stimulate GLP-1 secretion. Furthermore, the results indicate that 'WY' is a specific dipeptide sequence that potently stimulates GLP-1 secretion.
• Glucagon-like peptide-1 is involved in the thermic effects of dietary proteins in male rodents.

  Keita Ochiai, Asuka Muto, Bong Soo Seok, Yuta Doi, Yusaku Iwasaki, Yuko Okamatsu-Ogura, Daniel J Drucker, Tohru Hira

  Endocrinology 2023/05/04 [Refereed]
   

  Protein intake potently increases body temperature and energy expenditure, but the underlying mechanism thereof remains incompletely understood. Simultaneously, protein intake potently stimulates glucagon-like peptide-1 (GLP-1) secretion. Here, we examined the involvement of GLP-1 in the thermic effects of dietary proteins in rodents by measuring rectal temperature and energy expenditure and modulating GLP-1 signaling. Rectal temperature of rats or mice fasted for 4 or 5 h were measured using a thermocouple thermometer before and after an oral administration of nutrients. Oxygen consumption after oral protein administration was also measured in rats. Rectal temperature measurements in rats confirmed an increase in core body temperature after refeeding, and the thermic effect of the oral administration of protein was greater than that of a representative carbohydrate or lipid. Among the five dietary proteins examined (casein, whey, rice, egg, and soy), soy protein had the highest thermic effect. The thermic effect of soy protein was also demonstrated by increased oxygen consumption. Studies using a nonselective β-adrenergic receptor antagonist and thermal camera suggested that brown adipose tissue did not contribute to soy protein-induced increase in rectal temperature. Furthermore, the thermic effect of soy protein was completely abolished by antagonism and knockout of GLP-1 receptor, yet potentiated via augmentation of intact GLP-1 levels through inhibition of dipeptidyl peptidase-4 activity. These results indicate that GLP-1 signaling is essential for the thermic effects of dietary proteins in rats and mice, and extend the metabolic actions of GLP-1 ensuing from nutrient ingestion to encompass the thermic response to ingested protein.
• Formulation and evaluation of a novel megalomeric microemulsion from tamarind seed xyloglucan-megalosaccharides for improved high-dose quercetin delivery

  Weeranuch Lang, Debashish Mondol, Aphichat Trakooncharoenvit, Takayoshi Tagami, Masayuki Okuyama, Tohru Hira, Nobuo Sakairi, Atsuo Kimura

  Food Hydrocolloids 137 0268-005X 2023/04 [Refereed]
   

  Megalomeric microemulsion is a new term referring to lipid-based formulation using amphiphilic megalosaccharide as a coexcipient. Quercetin is a dose-dependent bioactive compound and has promising therapeutic potential, but its low water solubility and permeability restrict its treatment efficacy. We aimed to formulate high-dose quercetin loaded into colloidal micelles by the self-micro emulsifying system (SMES) in combination with Tween 80, isopropyl myristate, and xyloglucan megalosaccharide (X-MS). X-MS is a moderate-size heterologous saccharide obtained from enzymatic cleavage of tamarind seed xyloglucan. X-MSs with an average degree of polymerization of 16 and 56 were investigated to bearing their surface hydrophobic interaction with a fluorescence probe 6-(p-toluidino)-2-naphthalene-6-sulfonate yielded the binding constant values of 127 and 180 M−1, respectively and X-MS itself displayed a slight effect on quercetin binding. However, the implementation of X-MSs toward SMES was highly compatible because X-MS molecules were confined in micellular solutions. Consequently, X-MSs improved the quercetin loading from 1 to 2 to 12.5–17.7 mg/mL based on the composition ratio, X-MS chain lengths, and X-MS concentrations (0.15–3.0%, w/v) and stabilized the quercetin-loaded oil-in-water SMES. The optical appearances were transparent yellow containing uniformly fine droplets with diameters of 11–12 nm. In vitro radical scavenging activity tests with 2,2-diphenyl-1-picrylhydrazyl showed that the megalomeric microemulsions improved the half-maximal inhibitory concentration (IC50 = 22–24 μg/mL) over that of the X-MS-free microemulsion. This study provided a new approach of liquid supplementation from commercially unavailable-size xyloglucan to be a promising added-value agent for oral uptake of quercetin.
• Research on Luminacoids-Indeced Gastrointestinal Hormone Secretion

  比良徹

  ルミナコイド研究 27 (1) 1 - 7 2186-4136 2023 [Refereed][Invited]
  
• Direct visualization of glucagon-like peptide-1 secretion by fluorescent fusion proteins.

  Atsushi Tsuzuki, Yoichiro Fujioka, Aiko Yoshida, Sayaka Kashiwagi, Maho Amano, Tohru Hira, Akinobu Nakamura, Hideaki Miyoshi, Tatsuya Atsumi, Yusuke Ohba

  Journal of diabetes investigation 13 (7) 1134 - 1139 2022/04/04 [Refereed]
   

  Live-cell imaging with fluorescent proteins (FPs) is a powerful tool for investigating the exocytosis processes of hormones. However, the secretion process of glucagon-like peptide-1 (GLP-1) has not been visualized by FPs, which might be because tagging FPs inhibits GLP-1 synthesis through the post-translational processing from proglucagon. Here, we have developed FP-tagged GLP-1 by inserting FPs into the middle of GLP-1 and adding the proglucagon signal peptide. Confocal imaging confirmed that GLP-1 fused to FPs with high folding efficiency showed granular structure, in which secretory vesicle markers colocalized. The fluorescence intensity of FP in the culture supernatant from cells treated with KCl or forskolin was significantly increased compared with those from untreated cells. Furthermore, FP-tagged GLP-1 enables direct visualization of stimulation-dependent exocytosis of GLP-1 at a single granule resolution with total internal reflection fluorescence microscopy. FP-tagged GLP-1 might facilitate the screening of GLP-1 secretagogues and the discovery of new antidiabetic drugs.
• 2-Arachidonoyl glycerol suppresses gastric emptying via the cannabinoid receptor 1-cholecystokinin signaling pathway in mice.

  Keita Ochiai, Rina Hirooka, Masayoshi Sakaino, Shigeo Takeuchi, Tohru Hira

  Lipids 2022/03/10 [Refereed]
   

  2-Monoacylglycerol (2-MAG) is one of the digestion products of dietary lipids. We recently demonstrated that a 2-MAG, 2-arachidonoyl glycerol (2-AG) potently stimulated cholecystokinin (CCK) secretion via cannabinoid receptor 1 (CB1) in a murine CCK-producing cell line, STC-1. CCK plays a crucial role in suppressing postprandial gastric emptying. To examine the effect of 2-AG on gastric emptying, we performed acetaminophen and phenol red recovery tests under oral or intraperitoneal administration of 2-AG in mice. Orally administered 2-AG (25 mg/kg) suppressed the gastric emptying rate in mice, as determined by the acetaminophen absorption test and phenol red recovery test. Intraperitoneal administration of a cholecystokinin A receptor antagonist (0.5 mg/kg) attenuated the gastric inhibitory emptying effect. In addition, both oral (10 mg/kg) and intraperitoneal (0.5 mg/kg) administration of a CB1 antagonist counteracted the 2-AG-induced gastric inhibitory effect. Furthermore, intraperitoneal 2-AG (25 mg/kg) suppressed gastric emptying. These results indicate that 2-AG exhibits an inhibitory effect on gastric emptying in mice, possibly mediated by stimulating both CCK secretion via CB1 expressed in CCK-producing cells and acting on CB1 expressed in the peripheral nerves. Our findings provide novel insights into the 2-MAG-sensing mechanism in enteroendocrine cells and the physiological role of 2-MAG.
• Identification of G protein-coupled receptor 55 (GPR55) as a target of curcumin.

  Naoki Harada, Mai Okuyama, Yoshiaki Teraoka, Yumi Arahori, Yoh Shinmori, Hiroko Horiuchi, Paula B Luis, Akil I Joseph, Tomoya Kitakaze, Shigenobu Matsumura, Tohru Hira, Norio Yamamoto, Takashi Iuni, Naoki Goshima, Claus Schneider, Hiroshi Inui, Ryoichi Yamaji

  NPJ science of food 6 (1) 4 - 4 2022/01/14 [Refereed]
   

  The identification of molecular targets of bioactive food components is important to understand the mechanistic aspect of their physiological functions. Here, we have developed a screening system that enables us to determine the activation of G protein-coupled receptors (GPCRs) by food components and have identified GPR55 as a target for curcumin. Curcumin activated GPR55 and induced serum-response element- and serum-response factor-mediated transcription, which were inhibited by Rho kinase and GPR55 antagonists. Both the methoxy group and the heptadienone moiety of curcumin were required for GPR55 activation. The F1905.47 residue of GPR55 was important for the interaction with curcumin. The curcumin-induced secretion of glucagon-like peptide-1 in GLUTag cells was inhibited by a GPR55 antagonist. These results indicate that expression screening is a useful system to identify GPCRs as targets of food components and strongly suggest that curcumin activates GPR55 as an agonist, which is involved in the physiological function of curcumin.
• Enteroendocrine Systems That Sense Nutrients in the Gut and Control the Body

  Tohru Hira

  Journal of Nutritional Science and Vitaminology 68 S5 - S7 0301-4800 2022 [Not refereed][Invited]
   

  Gut hormones produced and released from enteroendocrine cells have key roles not only in nutrient digestion and absorption, but also in control of appetite, nutrient deposition and storage in the body. Several types of enteroendocrine cells sense nutrients after meal ingestion and release specific gut hormones. Understanding how gut hormone responses are controlled and in turn regulate physiological outcomes is an area of active research. In addition, the role of the endocrine system in human-physiology and in patho-physiology (obesity, diabetes, and gastrointestinal diseases) has begun being investigated. The symposium was organized to present and discuss recent advances in this research field from the aspects of bench to bedside.
• GLP-1 Responses to Oral Administration of a Dietary Peptide in Rats Fed Resistant Maltodextrin or Fructooligosaccharides

  比良徹, 池江明日香, 岸本由香, 原博

  ルミナコイド研究 26 (1) 1 - 8 2186-4136 2022 [Refereed]
  
• 2‐Arachidonoyl glycerol potently induces cholecystokinin secretion in murine enteroendocrine STC ‐1 cells via cannabinoid receptor CB1

  Keita Ochiai, Rina Hirooka, Masayoshi Sakaino, Shigeo Takeuchi, Tohru Hira

  Lipids 0024-4201 2021/09/17 [Refereed]
  
• Diet-induced obesity enhances postprandial glucagon-like peptide-1 secretion in Wistar rats, but not in diabetic Goto-Kakizaki rats.

  Jukkrapong Pinyo, Hiroshi Hara, Tohru Hira

  The British journal of nutrition 126 (4) 518 - 530 2021/08/28 [Refereed]
   

  Glucagon-like peptide-1 (GLP-1) is postprandially secreted from enteroendocrine L-cells and enhances insulin secretion. Currently, it is still controversial whether postprandial GLP-1 responses are altered in obesity and diabetes. To address the issue and to find out possible factors related, we compared postprandial GLP-1 responses in normal rats and in diabetic rats chronically fed an obesogenic diet. Male Wistar rats and diabetic Goto-Kakizaki (GK) rats were fed either a control diet or a high-fat/high-sucrose (HFS, 30 % fat and 40 % sucrose) diet for 26 weeks. Meal tolerance tests were performed for monitoring postprandial responses after a liquid diet administration (62·76 kJ/kg body weight) every 4 or 8 weeks. Postprandial glucose, GLP-1 and insulin responses in Wistar rats fed the HFS diet (WH) were higher than Wistar rats fed the control diet (WC). Although GK rats fed the HFS diet (GH) had higher glycaemic responses than GK rats fed the control diet (GC), these groups had similar postprandial GLP-1 and insulin responses throughout the study. Jejunal and ileal GLP-1 contents were increased by the HFS diet only in Wistar rats. Furthermore, mRNA expression levels of fatty acid receptors (Ffar1) in the jejunum were mildly (P = 0·053) increased by the HFS diet in Wistar rats, but not in GK rats. These results demonstrate that postprandial GLP-1 responses are enhanced under an obesogenic status in normal rats, but not in diabetic rats. Failure of adaptive enhancement of GLP-1 response in GK rats could be partly responsible for the development of glucose intolerance.
• Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity.

  Tohru Hira, Aphichat Trakooncharoenvit, Hayate Taguchi, Hiroshi Hara

  International journal of molecular sciences 22 (12) 2021/06/21 [Refereed][Invited]
   

  Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes.
• Combination of α-Glycosyl-Isoquercitrin and Soybean Fiber Promotes Quercetin Bioavailability and Glucagon-like Peptide-1 Secretion and Improves Glucose Homeostasis in Rats Fed a High-Fat High-Sucrose Diet.

  Aphichat Trakooncharoenvit, Hiroshi Hara, Tohru Hira

  Journal of agricultural and food chemistry 69 (21) 5907 - 5916 2021/06/02 [Refereed]
   

  This study examined the effects of a combination of soybean fiber and α-glycosyl-isoquercitrin (AGIQ) on improving quercetin bioavailability and glucose metabolism in rats fed an obesogenic diet. For 9 weeks, rats were individually fed a control diet, a high-fat high-sucrose (H) diet, H with soybean fiber (HS), or with AGIQ (HQ), or with both (HSQ). Quercetin derivatives in plasma, feces, urine, and cecal content were quantified by high-performance liquid chromatography to assess the bioavailability of quercetin, and meal tolerance tests were performed to assess postprandial glycemia and glucagon-like peptide-1 (GLP-1) responses. The HSQ group had higher plasma quercetin levels than HQ. The postprandial glycemia was attenuated in the HSQ group when compared to the H group. The basal plasma GLP-1 concentrations positively correlated with plasma quercetin derivative concentrations. Hence, the combination of soybean fiber and AGIQ could be beneficial for reducing the risk of glucose intolerance, possibly involving enhanced quercetin bioavailability and GLP-1 secretion.
• Acute Oral Calcium Suppresses Food Intake Through Enhanced Peptide-YY Secretion Mediated by the Calcium-Sensing Receptor in Rats.

  Akiho Igarashi, Shono Ogasawara, Ryo Takagi, Kazufumi Okada, Yoichi M Ito, Hiroshi Hara, Tohru Hira

  The Journal of nutrition 151 (5) 1320 - 1328 2021/05/11 [Refereed]
   

  BACKGROUND: Dietary calcium has been proposed to reduce appetite in human studies. Postprandial satiety is mainly controlled by gut hormones. However, the effect of calcium on appetite and the role of gut hormones remain unclear. OBJECTIVES: We examined whether oral administration of calcium reduces food intake in rats and investigated the underlying mechanism. METHODS: Male Sprague Dawley rats (8-12 wk old) were used after an overnight fastifffng. In a series of 2 trials with 1-wk interval between challenges, food intake was measured 0.5-24 h after oral gavage of a vehicle (saline containing 1.5% carboxymethyl cellulose) as the control treatment, or the vehicle containing various calcium compounds [calcium chloride (CaCl2), calcium carbonate, calcium lactate, in a random order] at 150 mg calcium/kg dose. A conditional taste aversion test was conducted. In separate experiments, plasma calcium and gut hormone concentrations were measured 15 or 30 min after oral administration of the calcium compounds. In anesthetized rats, portal peptide-YY (PYY) concentrations were measured after intraluminal administration of a liquid meal with or without additional calcium. RESULTS: Oral CaCl2 reduced food intake acutely (30 min, ∼20%, P < 0.05) compared with control rats, without taste aversion. Plasma PYY concentration was higher (100%, P < 0.05) in CaCl2-preloaded rats than in control rats, 15 min after administration. In anesthetized rats, luminal meal + CaCl2 induced a 4-fold higher increase in plasma PYY than the control treatment did. Oral administration of a calcium-sensing receptor (CaSR) agonist suppressed food intake (∼30%, P < 0.05), but CaCl2 and CaSR agonist did not suppress food intake under treatment with a PYY receptor antagonist. Furthermore, the CaSR antagonist attenuated the effect of CaCl2 on food intake. CONCLUSIONS: CaCl2 suppresses food intake partly by increasing CaSR-mediated PYY secretion in rats. Our findings could at least partially explain the satiating effect of calcium.
• Glucagon-like peptide-1 response to whey protein is less diminished by dipeptidyl peptidase-4 in comparison with responses to dextrin, a lipid and casein in rats.

  Yuki Shimizu, Hiroshi Hara, Tohru Hira

  The British journal of nutrition 125 (4) 398 - 407 2021/02/28 [Refereed]
   

  Although glucose is the best-known nutrient to stimulate glucagon-like peptide-1 (GLP-1) secretion, dietary peptides also potently stimulate GLP-1 secretion. Certain peptide fragments derived from dietary proteins possess dipeptidyl peptidase-4 (DPP-4) inhibitory activity in vitro. Hence, we hypothesised that dietary peptides protect GLP-1 from degradation through attenuating DPP-4 activity in vivo. Here, we compared GLP-1 responses with dietary proteins, a carbohydrate and a lipid (Intralipos) in rats having or not having plasma DPP-4 activity. Plasma GLP-1 concentrations clearly increased by oral administration of whey protein (2-4 g/kg), but not by that of dextrin (2-4 g/kg), in control rats (untreated Sprague-Dawley rats and F344/Jcl rats), having DPP-4 activity. In contrast, dextrin administration increased the plasma GLP-1 concentrations as the whey protein administration did, in rats having reduced or no DPP-4 activity (a DPP-4 inhibitor, sitagliptin-treated Sprague-Dawley rats or DPP-4-deficient F344/DuCrl/Crlj rats). DPP-4 inhibition by sitagliptin treatment also enhanced GLP-1 response to Intralipos, and casein, but the treatment did not further enhance GLP-1 response to whey protein. Intestinal GLP-1 content and gastric emptying rate were not associated with differences in GLP-1 responses to test nutrients. The luminal contents from rats administered whey protein decreased DPP-4 activity in vitro. These results suggest that GLP-1 released by dextrin, Intralipos and casein was immediately degraded by DPP-4, while GLP-1 released by whey protein was less degraded. Our study provides novel in vivo evidence supporting the hypothesis that dietary peptides not only stimulate GLP-1 secretion but also inhibit DPP-4 activity to potentiate GLP-1 response.
• Blood Sampling From Rat Ileal Mesenteric Vein Revealed a Major Role of Dietary Protein in Meal-Induced GLP-1 Response.

  Tohru Hira, Madoka Sekishita, Hiroshi Hara

  Frontiers in endocrinology 12 689685 - 689685 2021 [Refereed]
   

  The present study was conducted to examine region-dependent glucagon-like peptide-1 (GLP-1) responses to "meal ingestion" under physiological (conscious and unrestrained) conditions using rats with a catheter inserted into either the portal vein (PV) or the ileal mesenteric vein (ILMV). After recovery from the cannulation surgery, blood samples were collected from either PV or ILMV catheter before and after the voluntary ingestion of test diets. After an AIN-93G standard diet ingestion, GLP-1 concentration was higher in ILMV than in PV, and postprandial responses of peptide-YY (PYY) had similar trend, while that of glucose dependent-insulinotropic polypeptide showed an opposite trend to GLP-1/PYY responses. In a separated experiment, a protein-enriched diet containing casein at 25% wt/wt transiently increased GLP-1 concentration only in ILMV; however, a protein-free diet did not increase GLP-1 concentrations in PV or ILMV. These results indicate that postprandial GLP-1 is immediately released from the distal intestine under physiological conditions, and that dietary protein has a critical role in the enhancement of postprandial GLP-1 response.
• Expression of serotonin receptor HTR4 in glucagon-like peptide-1-positive enteroendocrine cells of the murine intestine.

  Motoshi Okumura, Akihiro Hamada, Fumina Ohsaka, Takeshi Tsuruta, Tohru Hira, Kei Sonoyama

  Pflugers Archiv : European journal of physiology 472 (10) 1521 - 1532 0031-6768 2020/10 [Refereed]
   

  Serotonin (5-hydroxytryptamine [5-HT]) synthesized and released in enterochromaffin (EC) cells participates in various functions in the gastrointestinal tract by acting on a diverse range of 5-HT receptors (HTRs) expressed on smooth muscle, enteric neurons, and epithelial cells. We previously observed that genes encoding HTR2A, HTR2B, and HTR4 are expressed in murine intestinal organoids, suggesting the expression of these HTRs in intestinal epithelial cells. The present study investigated the localization of these HTRs in the murine intestine by immunofluorescence staining. HTR2A, HTR2B, and HTR4 localized in individual solitary cells in the epithelium, while HTR2C was observed in the lamina propria. In the epithelium, HTR2A, HTR2B, and HTR4 colocalized with 5-HT, and HTR4 colocalized with glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). Murine intestinal organoids show a colocalization pattern that is similar to in vivo HTR2A and HTR4 with 5-HT, GLP-1, and PYY. Intraperitoneal and intragastric administration of tegaserod, an HTR4 agonist, failed to alter plasma GLP-1 levels in fasted mice. However, intragastric but not intraperitoneal administration of tegaserod reduced dietary lipid-induced increases of plasma GLP-1 levels. This action of tegaserod was inhibited by co-administration of RS39604, an HTR4 antagonist. These results suggest that murine ileal GLP-1/PYY-producing enteroendocrine (EE) cells express HTR4, while 5-HT-producing EC cells express HTR2A, HTR2B, and HTR4. In addition, the observations regarding in vivo GLP-1 secretion suggest that HTR4 signaling in ileal EE cells suppresses dietary lipid-induced GLP-1 secretion. We thus propose that EC and EE cells may interact with each other through paracrine signaling mechanisms.
• Impacts of Low-Digestible Carbohydrates and a Rare Sugar on Enteroendocrine Systems

  比良 徹, 原 博

  ルミナコイド研究 : 日本食物繊維学会会誌 日本食物繊維学会 24 (1) 11 - 18 2186-4136 2020/06 [Refereed][Invited]
  
• Water-soluble dietary fibers enhance bioavailability of quercetin and a fiber derived from soybean is most effective after long-term feeding in rats.

  Aphichat Trakooncharoenvit, Seiya Tanaka, Erika Mizuta, Tohru Hira, Hiroshi Hara

  European journal of nutrition 59 (4) 1389 - 1398 1436-6207 2020/06 [Refereed][Not invited]
   

  PURPOSE: To investigate the effects of water-soluble dietary fibers (pectin, soybean fiber, and guar gum) on the bioavailability of quercetin glucoside mixture (Q3GM) comprising quercetin-3-O-glucoside (Q3G, 31.8%) and its glucose adducts. METHODS: Male Wistar/ST rats were fed test diet containing 0.7% Q3GM with or without 5% of each dietary fiber for 8 weeks. Total quercetin derivatives were evaluated with liquid chromatograph tandem mass spectrometry (LC-MS/MS) as total quercetin derivatives after enzymatic deconjugation in plasma, urine, and fecal samples on week 2, 4, 6 and 8. Quercetin glucuronides excreted in feces were also measured. RESULTS: Fiber feeding elevated cecal weight and reduced cecal pH, indicative of cecal fermentation promotion. Changes in plasma and urinary quercetin levels revealed three phases of quercetin metabolism, including cumulative, transient, and stable phases. On week 2, total quercetin derivatives were higher in plasma samples from three fiber-fed groups than those control groups; however, urinary excretion increased in fiber-fed groups on week 4. Soybean fiber upregulated plasma and urinary quercetin levels on week 6 and 8. Intestinal degradation of quercetin by bacteria, calculated from differences between aglycone ingestion and sum of urinary and fecal excretion, was suppressed after dietary fiber supplementation especially in pectin fiber, which may partly contribute to the increase in quercetin bioavailability. Fecal quercetin glucuronide excretion was high in soybean fiber-fed rats, suggestive of the reduction of β-glucuronidase in colon. CONCLUSION: Water-soluble dietary fibers, especially soybean fiber, enhanced quercetin bioavailability after chronic feeding and may promote beneficial effects of quercetin on disease prevention.
• What Is GLP-1 Really Doing in Obesity?

  Tohru Hira, Jukkrapong Pinyo, Hiroshi Hara

  Trends in endocrinology and metabolism: TEM 31 (2) 71 - 80 1043-2760 2020/02 [Refereed][Not invited]
   

  Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released in response to meal ingestion and enhances insulin secretion from pancreatic β cells. In several human studies, GLP-1 secretory responses to oral glucose load or a meal were decreased in subjects with obesity, glucose intolerance, or diabetes compared with those in healthy subjects. However, the results of meta-analysis and cohort studies do not necessarily support this concept. Results from animal studies are also inconsistent; in multiple studies, GLP-1 secretory responses to a meal were repeatedly higher in diet-induced obese rats than in control rats. Thus, the postprandial GLP-1 response is not necessarily decreased but rather enhanced during obesity development, which is likely to play a protective role against glucose intolerance.
• Correlation between 12α-hydroxylated bile acids and insulin secretion during glucose tolerance tests in rats fed a high-fat and high-sucrose diet.

  Reika Yoshitsugu, Keidai Kikuchi, Shota Hori, Hitoshi Iwaya, Masahito Hagio, Hidehisa Shimizu, Tohru Hira, Satoshi Ishizuka

  Lipids in health and disease 19 (1) 9 - 9 2020/01/15 [Refereed][Not invited]
   

  BACKGROUND: Previously, we found a significant relationship in a rat study between energy intake and bile acid (BA) metabolism especially 12α-hydroxylated (12αOH) BAs. The present study was designed to reveal relationships among BA metabolism, glucose tolerance, and cecal organic acids in rats fed a high-fat and high-sucrose diet (HFS) by using multivariate and multiple regression analyses in two types of glucose tolerance tests (GTTs). METHODS: Male WKAH/HkmSlc rats were fed with a control or a HFS for 13 weeks. Oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were performed at week 9 and 11, respectively. BAs were analyzed by using ultra high-performance liquid chromatography-mass spectrometry. Organic acid concentrations in cecal contents were analyzed by using ultra high-performance liquid chromatography with post-column pH buffered electric conductivity method. RESULTS: A positive correlation of aortic 12αOH BA concentration was observed with energy intake and visceral adipose tissue weight. We found that an increase of 12αOH BAs in enterohepatic circulation, intestinal contents and feces in the HFS-fed rats compared to those in control rats regardless of no significant increase of total BA concentration in the feces in the test period. Fecal 12αOH BA concentration was positively correlated with maximal insulin level in OGTT and area under curve of insulin in IPGTT. There was a positive correlation between aortic 12αOH BAs concentration and changes in plasma glucose level in both OGTT and IPGTT. In contrast, a decrease in the concentration of organic acids was observed in the cecal contents of the HFS-fed rats. Multiple linear regression analysis in the IPGTT revealed that the concentrations of aortic 12αOH BA and cecal acetic acid were the predictors of insulin secretion. Moreover, there was a positive correlation between concentration of portal 12αOH BAs and change in insulin concentration of peripheral blood in the IPGTT. CONCLUSION: The distribution analysis of BA compositions accompanied by GTTs revealed a close relationship between 12αOH BA metabolism and insulin secretion in GTTs in rats.
• Oral preload of calcium reduces food intake via enhanced PYY secretion in rats

  Tohru Hira, Shono Ogasawara, Hiroshi Hara

  PROCEEDINGS OF THE NUTRITION SOCIETY 79 (OCE2) E239 - E239 0029-6651 2020
• Reply to the Letter: Increased bioavailability of plasma polyphenols via the intestinal fermentation of soybean fibers: a role for gut microbiome?

  Aphichat Trakooncharoenvit, Seiya Tanaka, Erika Mizuta, Tohru Hira, Hiroshi Hara

  European journal of nutrition 58 (6) 2563 - 2563 1436-6207 2019/09 [Refereed][Not invited]
  
• Enhanced postprandial glucagon-like peptide-1 secretion during obesity development has a protective role against glucose intolerance induction in rats.

  Jukkrapong Pinyo, Tohru Hira, Hiroshi Hara

  The British journal of nutrition 122 (4) 411 - 422 0007-1145 2019/08/28 [Refereed][Not invited]
   

  Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates postprandial glycaemic response by enhancing insulin secretion. We previously demonstrated that the postprandial GLP-1 response was enhanced during the development of diet-induced obesity in rats. However, the physiological relevance of the enhanced GLP-1 response remained unclear. We aimed to determine the role of endogenous GLP-1 during obesity development. Male Sprague-Dawley rats were given either a control diet or a high-fat/high-sucrose (HFS, 30 % fat and 40 % sucrose, weight basis) diet with or without continuous administration of the GLP-1 receptor antagonist, exendin (9-39) (Ex9, 100 µg/d), for 5 weeks. Meal tolerance tests (MTT) were performed to assess postprandial glucose, insulin and GLP-1 responses to a liquid diet administration (15 kcal (63 kJ)/10 ml per kg body weight) every 2 weeks. The AUC of postprandial glucose in the HFS group was similar to the control group in both MTT (P = 0·9665 and P = 0·3475, respectively), whereas AUC of postprandial GLP-1 (after 4 weeks,P = 0·0457) and of insulin (after 2 and 4 weeks, P = 0·0486 and P = 0·0110) was higher in the HFS group compared with the control group. In the Ex9 group, AUC of postprandial glucose (P = 0·0297 and P = 0·0486) was higher along with a lower insulin response compared with the HFS group (P = 0·0564 and P = 0·0281). These results suggest that enhancement of the postprandial GLP-1 response during obesity development has a role in maintaining a normal postprandial glycaemic response. Hence, enhancing endogenous GLP-1 secretion by certain materials could be a potential target for prevention of glucose intolerance.
• Continuous feeding of a combined high-fat and high-sucrose diet, rather than an individual high-fat or high-sucrose diet, rapidly enhances the glucagon-like peptide-1 secretory response to meal ingestion in diet-induced obese rats.

  Jukkrapong Pinyo, Tohru Hira, Hiroshi Hara

  Nutrition (Burbank, Los Angeles County, Calif.) 62 122 - 130 0899-9007 2019/06 [Refereed][Not invited]
   

  OBJECTIVES: Glucagon-like peptide-1 (GLP-1) is secreted by enteroendocrine L-cells in response to nutrient ingestion. To date, GLP-1 secretion in diet-induced obesity is not well characterized. We aimed to examine GLP-1 secretion in response to meal ingestion during the progression of diet-induced obesity and determinewhether a combined high-fat and high-sucrose (HFS) diet, an individual high-fat (HiFat), or a high-sucrose (HiSuc) diet affect adaptive changes in the postprandial GLP-1 response. METHODS: Rats were fed a control, HiFat diet (30% weight), HiSuc diet (40% weight), or HFS (30% fat and 40% sucrose) diet for 5 wk. Meal tolerance tests were conducted to determine postprandial glucose, insulin, and GLP-1 responses to standard (control) diet ingestion every 2 wk. RESULTS: After 5 wk, body weight gain of the HiFat (232.3 ± 7.8 g; P = 0.021) and HFS groups (228.0 ± 7.8; P = 0.039), but not the HiSuc group (220.3 ± 7.9; P = 0.244), were significantly higher than that of the control group (200.7 ± 5.4 g). In meal tolerance tests after 2 wk, GLP-1 concentration was significantly elevated in the HFS group only (17.2 ± 2.6 pM; P < 0.001) in response to meal ingestions, but the HiFat group (16.6 ± 3.7 pM; P = 0.156) had a similar response as the HFS group. After 4 wk, GLP-1 concentrations were similarly elevated at 15min in the HFS (14.1 ± 4.4; P = 0.010), HiFat (13.2 ± 2.0; P < 0.001), and HiSuc (13.0 ± 3.3; P = 0.016) groups, but the HFS (9.8 ± 1.0; P = 0.019) and HiFat (8.3 ± 1.5; P = 0.010) groups also had significant elevation at 30min. CONCLUSIONS: These results demonstrate that the continuous ingestion of excessive fat and sucrose rapidly enhances the GLP-1 secretory response to luminal nutrients, and the HiFat diet may have a potent effect compared with the HiSuc diet on GLP-1 secretory responses. The increment of postprandial GLP-1 and insulinsecretion may have a role in normalizing postprandial glycaemia and slowing the establishment of glucose intolerance.
• Casein materials show different digestion patterns using an in vitro gastrointestinal model and different release of glucagon-like peptide-1 by enteroendocrine GLUTag cells.

  Yosuke Komatsu, Yasuaki Wada, Hirohisa Izumi, Takashi Shimizu, Yasuhiro Takeda, Tohru Hira, Hiroshi Hara

  Food chemistry 277 423 - 431 0308-8146 2019/03/30 [Refereed][Not invited]
   

  Physicochemical properties of casein (CN) materials manufactured using different processes are well studied; however, data on their bioaccessibility or bioactivity are limited. We compared the digestion patterns and glucagon-like peptide-1 (GLP-1)-releasing activities of micellar CN concentrate (MCC) and sodium caseinate (SCN). MCC and SCN mixed with whey protein isolate (SCN + WPI) were subjected to in vitro gastrointestinal digestion; the digestibility of MCC was higher than that of SCN + WPI, and both CN materials showed different patterns of peptides released after in vitro digestion. A comparison of GLP-1-releasing activities showed that MCC induced GLP-1 secretion to a greater extent than SCN + WPI. Candidate peptides identified from CN digesta were chemically synthesized to test their GLP-1-releasing activity. GPVRGPFPIIV identified only in the MCC digesta, could stimulate GLP-1 release. In conclusion, the digestion patterns and GLP-1-releasing activity of CN materials depend on the production process.
• Wheat gluten hydrolysate potently stimulates peptide-YY secretion and suppresses food intake in rats.

  Wenya Chen, Tohru Hira, Shingo Nakajima, Hiroshi Hara

  Bioscience, biotechnology, and biochemistry 82 (11) 1992 - 1999 0916-8451 2018/11 [Refereed][Not invited]
   

  The study was aimed to compare the satiating effect of various protein hydrolysates in rats and examine the underlying mechanism associated with the satiety hormones. Food intake and portal satiety hormone levels were measured in rats. Enteroendocrine cell-lines were employed to study the direct effect of protein hydrolysates on gut hormone secretions. The results showed that oral preload of wheat gluten hydrolysate (WGH) suppressed food intake greater and longer than other hydrolysates. The portal peptide-YY levels in WGH-treated rats at 2 h and 3 h were higher than those in control- and lactalbumin hydrolysate (LAH)-treated rats. In a distal enteroendocrine cell model, WGH more potently stimulated glucagon-like peptide-1 secretion than LAH, and the effect was largely enhanced by pepsin/pancreatin digestion of WGH. These results suggest WGH is potent in activating enteroendocrine cells to release satiety hormones leading to the prolonged suppression of food intake.
• Novel Mechanism of Fatty Acid Sensing in Enteroendocrine Cells: Specific Structures in Oxo-Fatty Acids Produced by Gut Bacteria Are Responsible for CCK Secretion in STC-1 Cells via GPR40.

  Tohru Hira, Shono Ogasawara, Asuka Yahagi, Minami Kamachi, Jiaxin Li, Saki Nishimura, Masayoshi Sakaino, Takatoshi Yamashita, Shigenobu Kishino, Jun Ogawa, Hiroshi Hara

  Molecular nutrition & food research 62 (19) e1800146  1613-4125 2018/10 [Refereed][Not invited]
   

  SCOPE: The secretion of gut hormones, such as cholecystokinin (CCK) is stimulated by fatty acids. Although a chain length-dependent mechanism has been proposed, other structural relationships to releasing activity remain unclear. We aimed to elucidate specific structures in fatty acids that are responsible for their CCK-releasing activity, and related sensing mechanisms in enteroendocrine cells. METHODS AND RESULTS: CCK secretory activities were examined in a murine CCK-producing cell line STC-1 by exposing the cells to various modified fatty acids produced by gut lactic acid bacteria. The effects of fatty acids on gastric emptying rate as a CCK-mediated function were examined using acetaminophen and phenol red methods in rats. Out of more than 30 octadecanoic-derived fatty acids tested, 5 oxo-fatty acids potently stimulated CCK secretion without cytotoxic effects in STC-1 cells. Three fatty acids had a distinct specific structure containing one double bond, whereas the other two had two double bonds, nearby an oxo residue. CCK secretion induced by representative fatty acids (10-oxo-trans-11-18:1 and 13-oxo-cis-9,cis-15-18:2) was attenuated by a fatty acid receptor G-protein coupled receptor 40 antagonist. Oral administration of 13-oxo-cis-9,cis-15-18:2 lowered the gastric emptying rate in rats in a dose- and structure-dependent manner. CONCLUSION: These results reveal a novel fatty acid-sensing mechanism in enteroendocrine cells.
• Resistant maltodextrin or fructooligosaccharides promotes GLP-1 production in male rats fed a high-fat and high-sucrose diet, and partially reduces energy intake and adiposity

  Tohru Hira, Ryoya Suto, Yuka Kishimoto, Sumiko Kanahori, Hiroshi Hara

  EUROPEAN JOURNAL OF NUTRITION 57 (3) 965 - 979 1436-6207 2018/04 [Refereed][Not invited]
   

  Purpose Increasing secretion and production of glucagon-like peptide-1 (GLP-1) by continuous ingestion of certain food components has been expected to prevent glucose intolerance and obesity. In this study, we examined whether a physiological dose (5% weight in diet) of digestion-resistant maltodextrin (RMD) has a GLP-1-promoting effect in rats fed a high-fat and high-sucrose (HFS) diet. Methods Rats were fed a control diet or the HFS (30% fat, 40% sucrose wt/wt) diet supplemented with 5% RMD or fructooligosaccharides (FOS) for 8 weeks or for 8 days in separated experiments. Glucose tolerance, energy intake, plasma and tissue GLP-1 concentrations, and cecal short-chain fatty acids concentrations were assessed.Results After 4 weeks of feeding, HFS-fed rats had significantly higher glycemic response to oral glucose than control rats, but rats fed HFS + RMD/FOS did not (approx. 50% reduction vs HFS rats). HFS + RMD/FOS-fed rats had higher GLP-1 responses (similar to twofold) to oral glucose, than control rats. After 8 weeks, visceral adipose tissue weight was significantly higher in HFS-fed rats than control rats, while HFS + RMD/FOS rats had a trend of reduced gain (similar to 50%) of the tissue weight. GLP-1 contents and luminal propionate concentrations in the large intestine increased (> twofold) by adding RMD/FOS to HFS. Eight days feeding of RMD/FOS-supplemented diets reduced energy intake (similar to 10%) and enhanced cecal GLP-1 production (similar to twofold), compared to HFS diet.Conclusions The physiological dose of a prebiotic fiber promptly (within 8 days) promotes GLP-1 production in rats fed an obesogenic diet, which would help to prevent excess energy intake and fat accumulation.
• Secretion of GLP-1 but not GIP is potently stimulated by luminal d-Allulose (d-Psicose) in rats.

  Masaki Hayakawa, Tohru Hira, Masako Nakamura, Tetsuo Iida, Yuka Kishimoto, Hiroshi Hara

  Biochemical and biophysical research communications 496 (3) 898 - 903 0006-291X 2018/02/02 [Refereed][Not invited]
   

  Glucagon-like peptide 1 (GLP-1), an incretin gastrointestinal hormone, is secreted when stimulated by nutrients including metabolizable sugars such as glucose and fructose. d-Allulose (allulose), also known as d-psicose, is a C-3 isomer of d-fructose and a rare sugar with anti-diabetic or anti-obese effects in animal models. In the present study, we examined whether an oral administration of allulose could stimulate GLP-1 secretion in rats, and investigated the underlying mechanisms. Oral, but not intraperitoneal, administration of allulose (0.5-2.0 g/kg body weight) elevated plasma GLP-1 levels for more than 2 h in a dose-dependent manner. The effects of allulose on GLP-1 secretion were higher than that of dextrin, fructose, or glucose. In addition, oral allulose increased total and active GLP-1, but not glucose-dependent insulinotropic polypeptide (GIP), levels in the portal vein. In anesthetized rats equipped with a portal catheter, luminal (duodenum and ileum) administration of allulose increased portal GLP-1 levels, indicating the luminal effect of allulose. Allulose-induced GLP-1 secretion was abolished in the presence of xanthohumol (a glucose/fructose transport inhibitor), but not in the presence of inhibitors of the sodium-dependent glucose cotransporter 1 or the sweet taste receptor. These results demonstrate a potent and lasting effect of orally administered allulose on GLP-1 secretion in rats, without affecting GIP secretion. The potent and selective GLP-1-releasing effect of allulose holds promise for the prevention and treatment of glucose intolerance through promoting endogenous GLP-1 secretion.
• GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose.

  Yusaku Iwasaki, Mio Sendo, Katsuya Dezaki, Tohru Hira, Takehiro Sato, Masanori Nakata, Chayon Goswami, Ryohei Aoki, Takeshi Arai, Parmila Kumari, Masaki Hayakawa, Chiaki Masuda, Takashi Okada, Hiroshi Hara, Daniel J Drucker, Yuichiro Yamada, Masaaki Tokuda, Toshihiko Yada

  Nature communications 9 (1) 113 - 113 2041-1723 2018/01/09 [Refereed][Not invited]
   

  Overeating and arrhythmic feeding promote obesity and diabetes. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective anti-obesity drugs but their use is limited by side effects. Here we show that oral administration of the non-calorie sweetener, rare sugar D-allulose (D-psicose), induces GLP-1 release, activates vagal afferent signaling, reduces food intake and promotes glucose tolerance in healthy and obese-diabetic animal models. Subchronic D-allulose administered at the light period (LP) onset ameliorates LP-specific hyperphagia, visceral obesity, and glucose intolerance. These effects are blunted by vagotomy or pharmacological GLP-1R blockade, and by genetic inactivation of GLP-1R signaling in whole body or selectively in vagal afferents. Our results identify D-allulose as prominent GLP-1 releaser that acts via vagal afferents to restrict feeding and hyperglycemia. Furthermore, when administered in a time-specific manner, chronic D-allulose corrects arrhythmic overeating, obesity and diabetes, suggesting that chronotherapeutic modulation of vagal afferent GLP-1R signaling may aid in treating metabolic disorders.
• 消化管ホルモンup to date 食品ペプチドを利用した消化管内分泌系への作用

  比良徹, 中島進吾, 原博

  月刊消化器・肝臓内科 (有)科学評論社 3 (2) 140 - 146 2432-3446 2018 [Not refereed][Invited]
  
• Impact of difructose anhydride III, raffinose, and fructooligosaccharides on energy intake, gut hormones, and cecal fermentation in rats fed a high-fat and high-sucrose diet.

  Tohru Hira, Kurumi Yanagihara, Toshiki Koga, Keisuke Takahashi, Taizo Nagura, Hirokatsu Uchino, Hiroshi Hara

  Bioscience, biotechnology, and biochemistry 81 (11) 2186 - 2194 0916-8451 2017/11 [Refereed][Not invited]
   

  We investigated the effects of dietary supplementation of difructose anhydride III (DFA III), raffinose (Raf), and fructooligosaccharides (FOS) on diet-induced obesity development. Male rats were fed normal or high-fat and high-sucrose (HFS) diet, with or without supplementing (3%) DFA III, Raf, or FOS, for 8 or 5 weeks. Supplementing DFA III to the HFS diet decreased energy intake compared to the non-supplemented HFS diet. Accordingly, body weight gain and fat accumulation reduced in DFA III-fed rats. Cecal acetate production and plasma glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY) were elevated in DFA III-fed rats, while Raf and FOS partially affected these parameters. These results demonstrate that DFA III has suppressive effect on excessive energy intake driven by the palatable obesogenic diet, possibly due to combined effects of increased anorexigenic factors such as cecal acetate production and GLP-1/PYY secretion.
• Canagliflozin potentiates GLP-1 secretion and lowers the peak of GIP secretion in rats fed a high-fat high-sucrose diet.

  Tohru Hira, Toshiki Koga, Kazuyo Sasaki, Hiroshi Hara

  Biochemical and biophysical research communications 492 (2) 161 - 165 0006-291X 2017/10/14 [Refereed][Not invited]
   

  The glucose-induced secretion of incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is dependent on luminal glucose levels and transport of glucose via the sodium-glucose transporter 1 (SGLT1) in the small intestine. Because GLP-1 and GIP function in decreasing and increasing the body weight, respectively, we aimed to analyze the effect of transient inhibition of SGLT1 by canagliflozin on incretin secretion in an obese rat model. Male Sprague-Dawley rats were maintained on a high-fat high-sucrose diet for 6-7 weeks, and plasma GLP-1 and GIP levels were measured during an oral glucose tolerance test (OGTT). In addition, GLP-1 secretion was examined in a murine GLP-1 producing enteroendocrine cell line, GLUTag. Concomitant administration of 10 mg/kg canagliflozin with glucose loading suppressed glucose excursion, increased total GLP-1 levels, and reduced total GIP levels in systemic circulation, as revealed in the OGTT. Total and active GLP-1 levels were increased in portal blood, whereas total and active GIP levels tended to be decreased 15 min after the administration of canagliflozin with glucose. Canagliflozin (at 0.1-30 μM) did not directly affect release of GLP-1 in vitro. These results suggest that the oral administration of canagliflozin suppresses GIP secretion via the inhibition of SGLT1 in the upper part of the intestine and enhances GLP-1 secretion by increasing the glucose delivery to the lower part of the small intestine in an obese rodent model.
• Zinc directly stimulates cholecystokinin secretion from enteroendocrine cells and reduces gastric emptying in rats

  Shingo Nakajima, Tohru Hira, Hitoshi Iwaya, Hiroshi Hara

  MOLECULAR AND CELLULAR ENDOCRINOLOGY 430 (C) 108 - 114 0303-7207 2016/07 [Refereed][Not invited]
   

  Zinc, an essential mineral element, regulates various physiological functions such as immune responses and hormone secretion. Cholecystokinin (CCK), a gut hormone, has a role in protective immunity through the regulation of gastrointestinal motility, appetite, and inflammatory response. Here, we examined the effect of zinc on CCK secretion in STC-1 cells, an enteroendocrine cell line derived from murine duodenum, and in rats. Extracellular zinc triggered CCK secretion accompanied with increased intracellular Ca2+ and Zn2+ mobilization in STC-1 cells. Zinc-induced CCK secretion was abolished in the absence of intracellular Zn2+ or extracellular calcium. Upon inhibition of transient receptor potential ankyrin 1 (TRPA1), extracellular zinc failed to increase intracellular Ca2+ and subsequent CCK secretion. In rats, oral zinc administration decreased gastric emptying through the activation of CCK signaling. These results suggest that zinc is a novel stimulant for CCK secretion through the activation of TRPA1 related to intracellular Zn2+ and Ca2+ mobilization. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
• The calcium-sensing receptor in intestinal cells

  Tohru Hira, Shingo Nakajima, Hiroshi Hara

  Food and Nutritional Components in Focus 2016- (10) 396 - 412 2045-1709 2016 [Not refereed][Invited]
   

  The calcium-sensing receptor (CaSR or CaR) was first identified in the bovine parathyroid gland. Its primary function is to regulate calcium homeostasis in the body. However, CaSR is expressed in a variety of tissues that are not directly related to calcium homeostasis. In addition to calcium ions, various compounds such as l-amino acids, polyamines, basic polypeptides, gamma glutamyl peptides, and other peptides, also activate CaSR in an allosteric manner. Its broad ligands and wide expression profile suggest multiple functions of CaSR in different tissues. This chapter reviews the functions of CaSR in the gastrointestinal tract. Specifically, a role for CaSR in luminal nutrient sensing in the enteroendocrine system is described.
• Diunsaturated Aldehyde, trans,trans-2,4-Decadienal in the Intestinal Lumen Suppresses Gastric Emptying through Serotonin Signaling in Rats

  Tohru Hira, Asuka Yahagi, Said Nishimura, Masayoshi Sakaino, Takatoshi Yamashita, Hiroshi Hara

  JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 63 (37) 8177 - 8181 0021-8561 2015/09 [Refereed][Not invited]
   

  We recently demonstrated that a diunsaturated aldehyde, trans,trans-2,4-decadienal (2,4-decadienal), potently stimulated secretion of cholecystokinin in the enteroendocrine cell line. Gut hormones such as cholecystokinin and serotonin play critical roles in reducing postprandial gastric emptying. In the present study, we first demonstrated that oral administration of 2,4-decadienal (50-100 mg/kg) reduced gastric emptying rate in rats, assessed by both the acetaminophen absorption test and the phenol red recovery method. In contrast, saturated aldehyde, alcohol, and fatty acids having the same chain length as 2,4-decadienal did not affect the gastric emptying rate. Duodenal administration of 2A-decadienal potently reduced gastric emptying rate, but intraperitoneal administration did not. Furthermore, the gastric inhibitory effect of 2,4-decadienal was attenuated by treatment with a serotonin receptor antagonist. These results demonstrated that 2,4-decadienal in the small intestinal lumen has a potent inhibitory effect on gastric emptying, possibly through stimulation of the serotonin-producing enteroendocrine cells.
• Resistant maltodextrin promotes fasting glucagon-like peptide-1 secretion and production together with glucose tolerance in rats

  Tohru Hira, Asuka Ikee, Yuka Kishimoto, Sumiko Kanahori, Hiroshi Hara

  BRITISH JOURNAL OF NUTRITION 114 (1) 34 - 42 0007-1145 2015/07 [Refereed][Not invited]
   

  Glucagon-like peptide-1 (GLP-1), which is produced and released from enteroendocrine L cells, plays pivotal roles in postprandial glycaemia. The ingestion of resistant maltodextrin (RMD), a water-soluble non-digestible saccharide, improves the glycaemic response. In the present study, we examined whether the continuous feeding of RMD to rats affected GLP-1 levels and glycaemic control. Male Sprague-Dawley rats (6 weeks of age) were fed an American Institute of Nutrition (AIN)-93G-based diet containing either cellulose (5 %) as a control, RMD (2.5 or 5 %), or fructo-oligosaccharides (FOS, 2.5 or 5 %) for 7 weeks. During the test period, an intraperitoneal glucose tolerance test (IPGTT) was performed after 6 weeks. Fasting GLP-1 levels were significantly higher in the 5% RMD group than in the control group after 6 weeks. The IPGTT results showed that the glycaemic response was lower in the 5% RMD group than in the control group. Lower caecal pH, higher caecal tissue and content weights were observed in the RMD and FOS groups. Proglucagon mRNA levels were increased in the caecum and colon of both RMD and FOS groups, whereas caecal GLP-1 content was increased in the 5% RMD group. In addition, a 1 h RMD exposure induced GLP-1 secretion in an enteroendocrine L-cell model, and single oral administration of RMD increased plasma GLP-1 levels in conscious rats. The present study demonstrates that continuous ingestion of RMD increased GLP-1 secretion and production in normal rats, which could be stimulated by its direct and indirect (enhanced gut fermentation) effects on GLP-1-producing cells, and contribute to improving glucose tolerance.
• Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats

  Shingo Nakajima, Tohru Hira, Hiroshi Hara

  BRITISH JOURNAL OF NUTRITION 113 (9) 1477 - 1488 0007-1145 2015/05 [Refereed][Not invited]
   

  Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity.
• Rice protein hydrolysates stimulate GLP-1 secretion, reduce GLP-1 degradation, and lower the glycemic response in rats

  Yuki Ishikawa, Tohru Hira, Daisuke Inoue, Yukikazu Harada, Hiroyuki Hashimoto, Mikio Fujii, Motoni Kadowaki, Hiroshi Hara

  FOOD & FUNCTION 6 (8) 2525 - 2534 2042-6496 2015 [Refereed][Not invited]
   

  Rice has historically been consumed in Asia as a major source of carbohydrates, however, little is known regarding the functional roles of rice proteins as dietary factors. In the present study, we investigated whether peptides derived from rice proteins could stimulate GLP-1 secretion, which results in reducing glycemia via the incretin effect in normal rats. Hydrolysates were prepared from the protein fraction of rice endosperm or rice bran, and the effects of these hydrolysates on GLP-1 secretion were examined in a murine enteroendocrine cell line GLUTag. Plasma was collected after oral administration of the rice protein hydrolysates, under anesthesia, or during glucose tolerance tests in rats. In anesthetized rats, plasma dipeptidyl peptidase-IV (DPP-IV) activity was measured after ileal administration of the rice protein hydrolysates. GLP-1 secretion from GLUTag cells was potently stimulated by the rice protein hydrolysates, especially by the peptic digest of rice endosperm protein (REPH) and that of rice bran protein (RBPH). Oral administration of REPH or RBPH elevated plasma GLP-1 concentrations, which resulted in the reduction of glycemia under the intraperitoneal glucose tolerance test. In addition, the plasma DPP-IV activity was attenuated after ileal administration of REPH or RBPH, which resulted in a higher ratio of intact (active) GLP-1 to total GLP-1 in the plasma. These results demonstrate that rice proteins exert potent stimulatory effects on GLP-1 secretion, which could contribute to the reduction of postprandial glycemia. The inhibitory effect of these peptides on the plasma DPP-IV activity may potentiate the incretin effect of GLP-1.
• Dietary sweet potato (Ipomoea batatas L.) leaf extract attenuates hyperglycaemia by enhancing the secretion of glucagon-like peptide-1 (GLP-1)

  Rika Nagamine, Shiori Ueno, Masahito Tsubata, Kazuya Yamaguchi, Kinya Takagaki, Tohru Hira, Hiroshi Hara, Takanori Tsuda

  FOOD & FUNCTION 5 (9) 2309 - 2316 2042-6496 2014/09 [Refereed][Not invited]
   

  'Suioh', a sweet potato (Ipomoea batatas L.) cultivar developed in Japan, has edible leaves and stems. The sweet potato leaves contain polyphenols such as caffeoylquinic acid (CQA) derivatives. It has multiple biological functions and may help to regulate the blood glucose concentration. In this study, we first examined whether sweet potato leaf extract powder (SP) attenuated hyperglycaemia in type 2 diabetic mice. Administration of dietary SP for 5 weeks significantly lowered glycaemia in type 2 diabetic mice. Second, we conducted in vitro experiments, and found that SP and CQA derivatives significantly enhanced glucagon-like peptide-1 (GLP-1) secretion. Third, pre-administration of SP significantly stimulated GLP-1 secretion and was accompanied by enhanced insulin secretion in rats, which resulted in a reduced glycaemic response after glucose injection. These results indicate that oral SP attenuates postprandial hyperglycaemia, possibly through enhancement of GLP-1 secretion.
• A nondigestible saccharide, fructooligosaccharide, increases the promotive effect of a flavonoid, alpha-glucosyl-isoquercitrin, on glucagon-like peptide 1 (GLP-1) secretion in rat intestine and enteroendocrine cells

  Panchita Phuwamongkolwiwat, Tohru Hira, Hiroshi Hara

  MOLECULAR NUTRITION & FOOD RESEARCH 58 (7) 1581 - 1584 1613-4125 2014/07 [Refereed][Not invited]
   

  This study conducted in vivo and in situ experiments with rats to investigate the glucagon-like peptide-1 (GLP-1) secretion in response to oral or ileal administration of alpha-glucosyl-isoquercitrin (20-40 mmol in 2 mL; Q3G), fructooligosaccharides (200 mmol in 2 mL; FOS) and Q3G + FOS. Direct effects on GLP-1-producing L-cells were also examined by an in vitro study using a murine enteroendocrine cell line, GLUTag. To evaluate the plasma GLP-1 level, blood samples from jugular cannula for in vivo and portal cannula for in situ experiments were obtained before and after administration of Q3G, FOS, or Q3G + FOS. We found tendencies for increases but transient stimulation of GLP-1 secretion by Q3G in in vivo and in situ experiments. Although FOS alone did not have any effects, Q3G + FOS enhanced and prolonged high plasma GLP-1 level in both experiments. In addition, application of Q3G on GLUTag cells stimulated GLP-1 secretion while FOS enhanced the effect of Q3G. Our results suggest that Q3G + FOS possess the potential for the management or prevention of Type 2 diabetes mellitus (T2DM) by enhancing and prolonging the GLP-1 secretion via direct stimulation of GLP-1 producing L-cell.
• Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats

  Maya Muramatsu, Tohru Hira, Arimi Mitsunaga, Eri Sato, Shingo Nakajima, Yoshiro Kitahara, Yuzuru Eto, Hiroshi Hara

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 306 (12) C1099 - C1107 0193-1857 2014/06 [Refereed][Not invited]
   

  The calcium-sensing receptor (CaSR) is expressed in various tissues, including the gastrointestinal tract. To investigate the role of gut CaSR on glycemic control, we examined whether single oral administration of CaSR agonist peptides affected the glycemic response in rats. Glucose tolerance tests were performed under oral or duodenal administration of various CaSR agonist peptides (gamma Glu-Cys, protamine, and poly-D-lysine hydrobromide) in conscious rats. Involvement of CaSR was determined by using a CaSR antagonist. Signaling pathways underlying CaSR agonist-modified glycemia were investigated using gut hormone receptor antagonists. The gastric emptying rate after the administration of CaSR agonist peptides was measured by the phenol red recovery method. Oral and duodenal administration of CaSR agonist peptides attenuated glycemic responses under the oral glucose tolerance test, but the administration of casein did not. The promotive effect on glucose tolerance was weakened by luminal pretreatment with a CaSR antagonist. Treatment with a 5-HT3 receptor antagonist partially diminished the glucose-lowering effect of peptides. Furthermore, the gastric emptying rate was decreased by duodenal administration of CaSR agonist peptides. These results demonstrate that activation of the gut CaSR by peptide agonists promotes glucose tolerance in conscious rats. 5-HT3 receptor and the delayed gastric emptying rate appear to be involved in the glucose-lowering effect of CaSR agonist peptides. Thus, activation of gut CaSR by dietary peptides reduces glycemic responses so that gut CaSR may be a potential target for the improvement of postprandial glycemia.
• Unsaturated aldehydes induce CCK secretion via TRPA1 in STC-1 cells

  Shingo Nakajima, Tohru Hira, Asuka Yahagi, Chigusa Nishiyama, Takatoshi Yamashita, Jun Imagi, Hiroshi Hara

  MOLECULAR NUTRITION & FOOD RESEARCH 58 (5) 1042 - 1051 1613-4125 2014/05 [Refereed][Not invited]
   

  ScopeCholecystokinin (CCK) producing cells sense luminal contents to regulate the exocrine pancreas, gastric motility, and appetite. Although long-chain fatty acids (FAs, C12) are well known to stimulate CCK secretion, the CCK-releasing activities of other aliphatic compounds, such as aldehydes (Alds) or alcohols (Alcs), have not been studied.Methods and resultsWe tested the CCK-releasing activities of various aliphatic compounds with various carbon chain lengths (C3-C13) and degrees of unsaturation in the enteroendocrine cell line STC-1. CCK released from the cell was measured using an ELISA, and intracellular calcium concentration was measured using Fura-2. Mono- and di-unsaturated Alds at 100 M, but not saturated Alds, induced CCK secretion in STC-1 cells. Alcs and FAs failed to induce CCK secretion, regardless of carbon chain length or degree of unsaturation. Unsaturated Alds increased intracellular calcium concentration, but saturated Alds, Alcs, and FAs did not. Intracellular calcium mobilization and CCK secretion induced by unsaturated Alds was abolished in the absence of extracellular calcium. In addition, the inhibition of the transient receptor potential ankyrin 1 (TRPA1) channel suppressed unsaturated Ald-induced CCK secretion and intracellular calcium mobilization.ConclusionUnsaturated Alds are potent aliphatic stimulants for CCK secretion through the activation of TRPA1.
• Fructooligosaccharide augments benefits of quercetin-3-O-beta-glucoside on insulin sensitivity and plasma total cholesterol with promotion of flavonoid absorption in sucrose-fed rats

  Panchita Phuwamongkolwiwat, Takuya Suzuki, Tohru Hira, Hiroshi Hara

  EUROPEAN JOURNAL OF NUTRITION 2 53 (2) 457 - 468 1436-6207 2014/03 [Refereed][Not invited]
   

  The aim was to investigate both individual and synergistic effects of quercetin-3-O-beta-glucoside (Q3G) and fructooligosaccharide (FOS) on indices of metabolic syndrome and plasma total cholesterol level with potential mechanisms of action.Five groups of rats were fed a dextrin-based diet as the normal reference group, or sucrose-based (S) diets with 0.3 % Q3G, 5 % FOS, or 0.3 % Q3G + 5 % FOS (Q3G + FOS) for 48 days. Oral glucose tolerance tests (OGTTs) were conducted on days 0, 14, 28, and 45, and adipose tissue and aortic blood were collected on day 48. Effects of Q3G and FOS on portal GLP-1 secretion were separately examined using rats after ileal administration.Abdominal fat weight reduced in FOS-fed groups. Blood glucose levels of the Q3G + FOS group at 60 min in OGTT and HOMA-IR (0.25 +/- A 0.03 vs 0.83 +/- A 0.12 on day 45) were clearly lower in the Q3G + FOS group than in S group throughout the experimental period. Muscle Akt phosphorylation was enhanced only in the Q3G group. The plasma quercetin was largely increased by FOS feeding on day 48 (18.37 +/- A 1.20 with FOS, 2.02 +/- A 0.30 without FOS). Plasma total cholesterol levels in the Q3G + FOS group (3.10 +/- A 0.12, P < 0.05 on day 45) were clearly suppressed compared to the S group (4.03 +/- A 0.18). GLP-1 secretion was enhanced in Q3G + FOS group than in Q3G or FOS group.Q3G + FOS diet improved glucose tolerance, insulin sensitivity, and total cholesterol level with increasing GLP-1 secretion and a higher level of blood quercetin. Q3G + FOS may reduce the risk of T2DM.
• 松田 朋子、神谷 智康、草場 宣延、高野 晃、池口 主弥、高垣 欣也、石橋 千和、比良 徹、原 博

  Effectiveness of Potato Extract in Suppressing Food Intake and Stimulating Satiety

  薬理と治療 42 (3) 211 - 216 2014/03 [Refereed]
  
• Oral Administration of Corn Zein Hydrolysate Stimulates GLP-1 and GIP Secretion and Improves Glucose Tolerance in Male Normal Rats and Goto-Kakizaki Rats

  Noriyuki Higuchi, Tohru Hira, Nao Yamada, Hiroshi Hara

  ENDOCRINOLOGY 154 (9) 3089 - 3098 0013-7227 2013/09 [Refereed][Not invited]
   

  We have previously demonstrated that ileal administration of the dietary protein hydrolysate prepared from corn zein (ZeinH) stimulated glucagon-like peptide-1 (GLP-1) secretion and attenuated hyperglycemia in rats. In this study, to examine whether oral administration of ZeinH improves glucose tolerance by stimulating GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion, glucose tolerance tests were performed in normal Sprague-Dawley male rats and diabetic Goto-Kakizaki (GK) male rats. The test solution was gavaged before ip glucose injection in normal rats or gavaged together with glucose in GK rats. Blood samples were collected from the tail vein or by using the jugular catheter to measure glucose, insulin, GLP-1, and GIP levels. In the ip glucose tolerance test, oral administration of ZeinH (2 g/kg) significantly suppressed the glycemic response accompanied by an immediate increase in plasma GLP-1 and GIP levels in normal rats. In contrast, oral administration of another dietary peptide, meat hydrolysate, did not elicit a similar effect. The glucose-lowering effect of ZeinH was attenuated by a GLP-1 receptor antagonist or by a GIP receptor antagonist. Furthermore, oral ZeinH induced GLP-1 secretion and reduced glycemic response in GK rats under the oral glucose tolerance test. These results indicate that the oral administration of the dietary peptide ZeinH improves glucose tolerance in normal and diabetic rats by its incretin-releasing activity, namely, the incretinotropic effect.
• Activation of gut calcium-sensing receptor by peptide agonists promotes glucose tolerance in rats

  Tohru Hira, Maya Muramatsu, Arimi Mitsunaga, Eri Sato, Shingo Nakajima, Yoshiro Kitahara, Yuzuru Eto, Hiroshi Hara

  FASEB JOURNAL 27 0892-6638 2013/04
• Glycochenodeoxycholic acid promotes proliferation of intestinal epithelia via reduction of cyclic AMP and increase in H2AX phosphorylation after exposure to gamma-rays

  Satoshi Ishizuka, Maiko Shiwaku, Masahito Hagio, Takuya Suzuki, Tohru Hira, Hiroshi Hara

  BIOMEDICAL RESEARCH-TOKYO 3 33 (3) 159 - 165 0388-6107 2012/06 [Refereed][Not invited]
   

  Bile acids (BAs) are considered to be promotive factors in colorectal carcinogenesis. We investigated whether BAs in the cellular environment influence proliferation of intestinal epithelial cell lines. Some BAs induced proliferation in several epithelial cell lines. In the proliferation assay, significant increases in IEC-6 cell proliferation were observed in response to glycodeoxycholic acid or glycochenodeoxycholic acid (GCDCA). Among the glycine-conjugated derivatives of BAs, especially GCDCA reduced cAMP production in IEC-6 cells. Pertussis toxin completely inhibited the GCDCA-induced increase in IEC-6 proliferation, suggesting GCDCA-induced proliferation required G alpha i activation and cAMP reduction. Treatment with 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, also suppressed GCDCA-induced IEC-6 proliferation. We confirmed an increase in MEK1/2 phosphorylation in GCDCA-treated IEC-6 cells, and inhibition of MEK1/2 by U0126 clearly suppressed GCDCA-induced IEC-6 cell proliferation. A significant increase was observed in the phosphorylation of histone H2AX in GCDCA-treated IEC-6 cells after exposure to gamma-rays. Cell cycle analysis revealed that GCDCA increased the proportion of cells in S phase only after gamma-ray exposure. These results indicate that glycine-conjugated BAs in the cellular environment are potent inducers of cell proliferation accompanied by genomic instability in intestinal epithelia.
• Suppressive Effect on Food Intake of a Potato Extract (Potein (R)) Involving Cholecystokinin Release in Rats

  Wenya Chen, Tohru Hira, Shingo Nakajima, Hiroshi Tomozawa, Masahito Tsubata, Kazuya Yamaguchi, Hiroshi Hara

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 6 76 (6) 1104 - 1109 0916-8451 2012/06 [Refereed][Not invited]
   

  We have recently reported that oral gavage of a potato extract (Potein (R)) suppressed the food intake in rats. The satiating effect of the potato extract was compared in the present study to other protein sources, and the involvement of endogenous cholecystokinin (CCK) secretion was examined. Food consumption was measured in 18-h fasted rats after oral gavage of the potato extract or other protein sources. The CCK-releasing activity of the potato extract was then examined in anesthetized rats with a portal cannula. Oral gavage of the potato extract reduced the food intake in the rats, the effect being greater than with casein and a soybean beta-conglycinin hydrolysate. The suppressive effect on appetite of the potato extract was attenuated by treating with a CCK-receptor antagonist (devazepide). The portal CCK concentration was increased after a duodenal administration of the potato extract to anesthetized rats. These results indicate that the potato extract suppressed the food intake in rats through CCK secretion.
• Calcium-sensing receptor mediates dietary peptide-induced CCK secretion in enteroendocrine STC-1 cells

  Shingo Nakajima, Tohru Hira, Hiroshi Hara

  MOLECULAR NUTRITION & FOOD RESEARCH 56 (5) 753 - 760 1613-4125 2012/05 [Refereed][Not invited]
   

  Scope Dietary peptides are potent stimulators of cholecystokinin (CCK) secretion, but the sensing mechanism in CCK-producing cells is poorly understood. Recently, it has been demonstrated that the calcium-sensing receptor (CaSR) mediates CCK secretion induced by amino acids. We investigated the role of CaSR in CCK secretions induced by various protein hydrolysates (egg albumin, meat, casein, azuki bean, soybean beta-conglycinin, and potato) in the enteroendocrine cell line STC-1. Methods and results CCK secretions in response to these hydrolysates were measured in the STC-1 cells with or without CaSR antagonist (NPS 2143) treatment. Changes in intracellular calcium concentration ([Ca2+]i) in response to protein hydrolysates were measured in Human embryonic kidney (HEK) 293 cells transfected with CaSR-expression vector. Protein hydrolysates-induced CCK secretions were decreased by CaSR antagonist treatment, except meat hydrolysate-induced secretion. Protein hydrolysates increased [Ca2+]i in CaSR-transfected HEK 293 cells. CaSR antagonist treatment suppressed low molecular weight fractions of azuki hydrolysate-induced CCK secretion, but the secretion induced by both low and high molecular weight fractions of beta-conglycinin hydrolysate. Further, CCK secretion induced by peptide fractions (>500 Da) derived from various protein hydrolysates were also reduced by CaSR antagonist. Conclusion These results demonstrate that CaSR plays a significant role in sensing various dietary peptides in triggering CCK secretion in enteroendocrine cells.
• Acute effect of soybean beta-conglycinin hydrolysate ingestion on appetite sensations in healthy humans

  Tohru Hira, Naomi Mori, Toshihiro Nakamori, Hitoshi Furuta, Kozo Asano, Hitoshi Chiba, Hiroshi Hara

  APPETITE 57 (3) 765 - 768 0195-6663 2011/12 [Refereed][Not invited]
   

  A hydrolysate prepared from soybean beta-conglycinin reduced food intake through cholecystokinin release in rats; however, effects of the hydrolysate on human appetites are unknown. In this study, healthy volunteers ingested 3 g of the beta-conglycinin hydrolysate (BconB) and/or a soy protein hydrolysate (HN) contained in a beverage or in a jelly. Appetite profiles (hunger, fullness and prospective consumption) after the ingestion and palatability of test jellies were recorded. Fullness was rated higher, and hunger was rated lower after BconB ingestion as compared to HN ingestion. These results demonstrate that 3 g of BconB is effective to enhance fullness and reduce hunger sensations in healthy humans. (C) 2011 Elsevier Ltd. All rights reserved.
• The G-protein on cholesterol-rich membrane microdomains mediates mucosal sensing of short-chain fatty acid and secretory response in rat colon

  T. Yajima, R. Inoue, M. Yajima, T. Tsuruta, S. Karaki, T. Hira, A. Kuwahara

  ACTA PHYSIOLOGICA 203 (3) 381 - 389 1748-1708 2011/11 [Refereed][Not invited]
   

  Aim: Short-chain fatty acids (SCFA) stimulate colonic contraction and secretion, which are mediated by an enteric reflex via a mucosal sensing and cholinergic mechanisms. The involvement of G-protein signal transduction was examined in the secretory response to luminal propionate sensing in rat distal colon. Methods: Mucosa-submucosa and mucosa preparations were used to measure short-circuit current (I-sc) and acetylcholine (ACh) release respectively. Cholesterol-rich membrane microdomains, lipid rafts/caveolae, were fractionated using a sucrose gradient ultra-centrifugation after detergent-free extraction of the isolated colonic crypt. Results: Luminal addition of methyl-beta-cyclodextrin (10 mm) and mastoparan (30 mu m), lipid rafts/caveolae disruptors, significantly inhibited luminal propionate-induced (0.5 mm) increases in I-sc, but did not affect increases in I-sc induced by serosal ACh (0.05 mm) or electrical field stimulation (EFS). Luminal addition of YM-254890 (10 mu m), a G alpha(q/11)-selective inhibitor, markedly inhibited propionate-induced increase in I-sc, but did not affect I-sc responses to ACh and EFS. Both methyl-beta-cyclodextrin and YM-254890 significantly inhibited luminal propionate-induced non-neuronal release of ACh from colonocytes. Real-time PCR demonstrated that in mRNA expression of SCFA receptors, GPR 43 was far higher than that of GPR41 in the colon. Western blotting analysis revealed that the cholesterol-rich membrane microdomains that fractionated from colonic crypt cells were associated with caveolin-1, flotillin-1 and G alpha(q/11), but not GPR43. Uncoupling of G alpha(q/11) from flotillin-1 in lipid rafts occurred under desensitization of the I-sc response to propionate. Conclusions: These data demonstrate that the secretory response to luminal propionate in rat colon is mediated by G-protein on cholesterol-rich membrane microdomains, provably via G alpha(q/11).
• Potato Extract (Potein) Suppresses Food Intake in Rats through Inhibition of Luminal Trypsin Activity and Direct Stimulation of Cholecystokinin Secretion from Enteroendocrine Cells

  Shingo Nakajima, Tohru Hira, Masahito Tsubata, Kinya Takagaki, Hiroshi Hara

  JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 59 (17) 9491 - 9496 0021-8561 2011/09 [Refereed][Not invited]
   

  Dietary proteins and trypsin inhibitors are known to stimulate the secretion of the satiety hormone cholecystokinin (CCK). A potato extract (Potein) contains 60% carbohydrate and 20% protein including trypsin inhibitory proteins. In this study, we examined whether Potein suppresses food intake in rats and whether it directly stimulates CCK secretion in enteroendocrine cells. In fasted rats, food consumption was measured up to 6 h after the oral administration of Potein or soybean trypsin inhibitor (SBTI). CCK-releasing activities of Potein and SBTI were examined in the murine CCK-producing cell line STC-1. Potein inhibited the trypsin activity in vitro with a potency 20-fold lower than that of SBTI. Oral administration of Potein dose-dependently suppressed food intake for 1-6 h. Potein, but not the SBTI, dose-dependently induced CCK secretion in STC-1 cells. These results suggest that Potein suppresses food intake through the CCK secretion induced by direct stimulation on enteroendocrine cells and through inhibition of luminal trypsin.
• Soybean beta-Conglycinin Bromelain Hydrolysate Stimulates Cholecystokinin Secretion by Enteroendocrine STC-1 Cells to Suppress the Appetite of Rats under Meal-Feeding Conditions

  Md. Kaosar Niaz Bin Sufian, Tohru Hira, Toshihiro Nakamori, Hitoshi Furuta, Kozo Asano, Hiroshi Hara

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 5 75 (5) 848 - 853 0916-8451 2011/05 [Refereed][Not invited]
   

  A peptic digest of soybean beta-conglycinin (BconP) suppresses the appetite in rats through cholecystokinin (CCK) secretion by enteroendocrine cells. We investigate in this study more appetite-suppressing hydrolysates. beta-Conglycinin hydrolyzed with food-processing proteases thermolysin (BconT), bromelain (BconB), chymotrypsin, protease S, and protease M was examined for CCK-secreting activity in a CCK-producing cell line for comparison with BconP. The potent CCK-releasing hydrolysates were then tested for their suppression of the food intake by rats. BconB, BconT, and BconP stimulated high CCK secretion, with the highest by BconB. Orogastric preloading by BconB, but not by BconT, suppressed the 60-min food intake. A meal-feeding trial twice a day in the morning (a.m.) and evening (p.m.) for 10 d showed that BconB preloading before every meal attenuated the p.m. meal size, but not that a.m., resulting in an overall reduction of the daily meal size. These results demonstrate that the bromelain hydrolysate of beta-conglycinin having potent CCK-releasing activity suppressed the appetite of rats under meal-feeding conditions.
• GLP-1 Secretion in Response to Oral and Luminal Palatinose (Isomaltulose) in Rats

  Tohru Hira, Maya Muramatsu, Masahiro Okuno, Hiroshi Hara

  JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY 57 (1) 30 - 35 0301-4800 2011/02 [Refereed][Not invited]
   

  Palatinose (isomaltulose). a slowly digested disaccharide, is used as a noncariogenic sugar and as a sucrose substitute in several foods. Because of its ability to lower postprandial glycemia, palatinose may be beneficial as a treatment for impaired glucose metabolism. Glucagon-like peptide-1 (GLP-1) improves glycemia via enhancing pancreatic beta-cell functions. The secretion of GLP-1 is stimulated by sugars, including glucose and artificial sweeteners. In this study, we examined whether palatinose induced GLP-1 secretion in vivo and in vitro. Firstly, portal GLP-1 and glucose were measured after oral administration of palatinose or sucrose in conscious rats. Secondly, portal GLP-1 and glucose were measured after jejunal or ileal administration of each sugar in anesthetized rats. Finally, GLUTag, a murine GLP-1-producing cell line, was exposed to several sugars, including palatinose and sucrose, to observe the direct effect of these sugars on GLP-1 secretion. Compared with sucrose, palatinose enhanced portal GLP-1 level when administered orally in conscious rats. Both palatinose and sucrose induced a significant increase in portal GLP-1 after jejunal or ileal administration of each sugar in anesthetized rats. Ileal administration triggered a greater response than did jejunal administration. Glycemic responses were higher in sucrose-treated rats than in palatinose-treated rats in every experiment. In GLUTag cells, glucose induced a significant increase in GLP-1 secretion, but neither sucrose nor palatinose had an effect. These data demonstrate that luminal palatinose induces GLP-1 secretion in rats. However, it is likely that GLP-1 secretion is triggered mainly by glucose released in the lumen rather than by palatinose itself.
• The Corn Protein, Zein Hydrolysate, Administered into the Ileum Attenuates Hyperglycemia via Its Dual Action on Glucagon-Like Peptide-1 Secretion and Dipeptidyl Peptidase-IV Activity in Rats

  Taisuke Mochida, Tohru Hira, Hiroshi Hara

  ENDOCRINOLOGY 151 (7) 3095 - 3104 0013-7227 2010/07 [Refereed][Not invited]
   

  We previously showed that a hydrolysate prepared from corn zein [zein hydrolysate (ZeinH)] strongly stimulates glucagons-like peptide-1 (GLP-1) secretion from the murine GLP-1-producing enteroendocrine cell line and in the rat small intestine, especially in the ileum. Here, we investigated whether ZeinH administered into the ileum affects glucose tolerance via stimulating GLP-1 secretion. To observe the effect of luminal ZeinH itself on GLP-1 secretion and glycemia, ip glucose tolerance tests were performed in conscious rats with ileal and jugular catheters, and plasma glucose, insulin, and GLP-1 (total and active) were measured. In addition, plasma dipeptidyl peptidase-IV activities in the ileal vein were measured after the administration of ZeinH into the ileal-ligated loop in anesthetized rats. The ileal administration of ZeinH attenuated the glucose-induced hyperglycemia accompanied by the enhancement of insulin secretion, whereas meat hydrolysate (MHY) neither induced insulin secretion nor attenuated hyperglycemia. The antihyperglycemic effect was also demonstrated by the oral administration of ZeinH. From these results, it was predicted that the GLP-1-releasing potency of ZeinH was higher than that of MHY. However, both peptides induced a similar increase in total GLP-1 concentration after the ileal administration. In contrast, active GLP-1 concentration was increased only in ZeinH-treated rats. In anesthetized rats, ileal administration of ZeinH, but not MHY, decreased plasma dipeptidyl peptidase-IV activity in the ileal vein. These results indicate that the ileal administration of a dietary peptide, ZeinH, has the dual functions of inducing GLP-1 secretion and inhibiting GLP-1 degradation, resulting in the enhancement of insulin secretion and the prevention of hyperglycemia in rats. (Endocrinology 151: 3095-3104, 2010)
• Soybean beta 51-63 peptide stimulates cholecystokinin secretion via a calcium-sensing receptor in enteroendocrine STC-1 cells

  Shingo Nakajima, Tohru Hira, Yuzuru Eto, Kozo Asano, Hiroshi Hara

  REGULATORY PEPTIDES 159 (1-3) 148 - 155 0167-0115 2010/01 [Refereed][Not invited]
   

  We previously demonstrated that intraduodenal administration of an arginine-rich beta 51-63 peptide in soybean beta-conglycinin suppresses food intake via cholecystokinin (CCK) secretion in rats. However, the cellular mechanisms by which the beta 51-63 peptide induces CCK secretion remain to be clarified. In the present study, we examined whether the extracellular calcium-sensing receptor (CaR) mediates beta 51-63-induced CCK secretion in murine CCK-producing enteroendocrine cell line STC-1. CCK secretion and changes in intracellular Ca2+ concentration in response to beta 51-63 peptide were measured in STC-1 cells under various extracellular Ca2+ concentrations and after treatment with a CaR antagonist. Intracellular Ca2+ concentrations in response to beta 51-63 peptide and extracellular Ca2+ were also measured in CaR-expressing human embryonic kidney (HEK-293) cells. The beta 51-63 peptide induced CCK secretion and intracellular Ca2+ mobilization in STC-1 cells under normal (1.2 mM) extracellular Ca2+ conditions in a dose-dependent manner. These responses to beta 51-63 peptide were reduced by the removal of intra- or extracellular Ca2+ but enhanced by increasing extracellular Ca2+ concentrations. Intracellular Ca2+ mobilization induced by extracellular Ca2+ was also increased by the pretreatment with beta 51-63 peptide. Treatment with a specific CaR antagonist (NPS2143) inhibited beta 51-63-induced CCK secretion and intracellular Ca2+ mobilization. In addition, HEK-293 cells transfected with CaR acquired sensitivity to the beta 51-63 peptide. From these results, we conclude that CaR is the beta 51-63 peptide sensor responsible for the stimulation of CCK secretion in enteroendocrine STC-1 cells. (C) 2009 Elsevier B.V. All rights reserved.
• GLP-1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats

  Tohru Hira, Taisuke Mochida, Kyoko Miyashita, Hiroshi Hara

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 297 (4) G663 - G671 0193-1857 2009/10 [Refereed][Not invited]
   

  Hira T, Mochida T, Miyashita K, Hara H. GLP-1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats. Am J Physiol Gastrointest Liver Physiol 297: G663-G671, 2009. First published August 6, 2009; doi: 10.1152/ajpgi.90635.2008.-Glucagon-like peptide-1 (GLP-1) is released from enteroendocrine cells ( L cells) in response to food ingestion. The mechanism by which dietary peptides stimulate GLP-1 secretion in the gut is unknown. In the present study, we found that a hydrolysate prepared from zein, a major corn protein [zein hydrolysate (ZeinH)], strongly stimulates GLP-1 secretion in enteroendocrine GLUTag cells. Stimulatory mechanisms of GLP-1 secretion induced by ZeinH were investigated in the rat small intestine under anesthesia. Blood was collected through a portal catheter before and after ZeinH administration into different sites of the small intestine. The duodenal, jejunal, and ileal administration of ZeinH induced dose-dependent increases in portal GLP-1 concentration. GLP-1 secretion in response to the ileal administration of ZeinH was higher than that in the duodenal or jejunal administration. Capsaicin treatment on esophageal vagal trunks abolished the GLP-1 secretion induced by duodenal ZeinH but did not affect the secretion induced by jejunal or ileal ZeinH. These results suggest that ZeinH in the jejunum or ileum directly stimulates GLP-1 secretion but duodenal ZeinH indirectly stimulates GLP-1 secretion via the vagal afferent nerve. A direct blood sampling method from the duodenal vein and ileal mesenteric vein revealed that ZeinH administered into the ligated duodenal loop enhanced GLP-1 concentration in the ileal mesenteric vein but not in the duodenal vein. This confirmed that ZeinH in the duodenum induces GLP-1 secretion from L cells located in the ileum by an indirect mechanism. These results indicate that a potent GLP-1-releasing peptide, ZeinH, induces GLP-1 secretion by direct and indirect mechanisms in the rat intestine.
• Administration of anti-glucagon-like peptide-2 serum suppresses epithelial cell proliferation of the distal small intestine in weanling rats

  Satoshi Ishizuka, Ayako Inafune, Tohru Hira, Hirohisa Izumi, Kazuhiro Ozawa, Mitsunori Takase, Hiroshi Hara

  BIOMEDICAL RESEARCH-TOKYO 30 (4) 259 - 261 0388-6107 2009/08 [Refereed][Not invited]
   

  We investigated the effects of endogenous glucagon-like peptide-2 (GLP-2) on the development of intestinal mucosa in weanling rats. Three-week-old male weanling Sprague-Dawley rats were administered either anti-GLP-2 or normal rabbit serum every other day for 2 weeks. We then measured length, weight, and bromodeoxyuridine incorporation in the intestine on day 13 following the first injection. Administration of anti-GLP-2 serum significantly inhibited both epithelial proliferation in the distal ileum and elongation of the small intestine. These results Suggest that intrinsic GLP-2 contributes to the growth of the small intestine during the weanling period.
• alpha-Lactalbumin Hydrolysate Stimulates Glucagon-Like Peptide-2 Secretion and Small Intestinal Growth in Suckling Rats

  Hirohisa Izumi, Satoshi Ishizuka, Ayako Inafune, Tohru Hira, Kazuhiro Ozawa, Takashi Shimizu, Mitsunori Takase, Hiroshi Hara

  JOURNAL OF NUTRITION 139 (7) 1322 - 1327 0022-3166 2009/07 [Refereed][Not invited]
   

  We investigated whether bovine milk constituents influenced glucagon-like peptide (GLP)-2 secretion and intestinal growth in suckling rats. Male Sprague-Dawley rats (14 d old) received i.g. infusions of a milk protein fraction, a lactose solution, or the cream fraction of milk. The serum concentration of GLP-2, but not GLP-1, markedly increased in rats administered milk protein compared with those given the lactose solution or the cream fraction from 60 to 120 min after administration. In another experiment, both casein (CN) and whey protein isolate stimulated GLP-2 secretion at 120 min after administration, but soy protein and ovalbumin did not. Stimulation of GLP-2 secretion by several milk proteins was similar, including alpha-CN, alpha-lactalbumin (alpha-La), and beta-lactoglobulin, in a separate experiment. A hydrolysate of alpha-La obtained by incubation with protease A extracted from Aspergillus oryzae (LaHPA) caused almost twice the GLP-2 release due to intact alpha-La and other alpha-La hydrolysates. Free aminoacid concentrations and molecular size distributions did not differ among alpha-La hydrolysates, including LaHPA. In rat pups reared with milk formulae containing alpha-La or LaHPA, LaHPA significantly promoted small intestinal elongation and increased the number of crypt epithelial cells compared with a formula containing intact alpha-La. LaHPA administration also increased the maltase:lactase activity ratio, a marker of maturation of the intestinal mucosa. In conclusion, milk proteins stimulate GLP-2 secretion and contribute to growth and maturation of the small intestine in suckling rats. J. Nutr. 139: 1322-1327, 2009.
• Cholecystokinin secretion induced by beta-conglycinin peptone depends on G alpha q-mediated pathways in enteroendocrine cells

  Tohru Hira, Toshihiro Maekawa, Kozo Asano, Hiroshi Hara

  EUROPEAN JOURNAL OF NUTRITION 48 (2) 124 - 127 1436-6207 2009/03 [Refereed][Not invited]
   

  Intraduodenal administration of peptone prepared from soybean beta-conglycinin (BconP) stimulates cholecystokinin (CCK) secretion from enteroendocrine cells, and suppresses food intake in rats. However, the sensing mechanism of BconP by CCK-producing cells is unknown.We investigated signal transduction pathways mediating CCK secretion in response to BconP in the murine CCK-producing cell line, STC-1.STC-1 cells were seeded in 48-well culture plates until sub-confluent and CCK secretion was examined under various conditions. CCK concentration was determined by the enzyme immunoassay.BconP dose-dependently induced CCK secretion in STC-1 cells. Treatment with BAPTA-AM, an intracellular Ca(2+) chelator, reduced BconP-induced CCK secretion, however, removal of extracellular Ca(2+) did not affect the secretory response. Treatment with 2-amino borate (2-APB) reduced CCK releasing responses, suggesting the involvement of IP(3). In addition, BconP failed to induce CCK secretion after treatment with the G alpha q protein inhibitor (YM-254890).These results indicate that G alpha q pathway is responsible for BconP-induced CCK secretion in STC-1 cells, and suggest the involvement of a G alpha q-coupled GPCR(s) in dietary peptide sensing in enteroendocrine cells.
• Calcium-sensing receptor mediates phenylalanine-induced cholecystokinin secretion in enteroendocrine STC-1 cells

  Tohru Hira, Shingo Nakajima, Yuzuru Eto, Hiroshi Hara

  FEBS JOURNAL 275 (18) 4620 - 4626 1742-464X 2008/09 [Refereed][Not invited]
   

  Intraluminal L-phenylalanine (Phe) stimulates cholecystokinin (CCK) secretion in vivo and in vitro. However, the cellular mechanism by which CCK-producing enteroendocrine cells sense Phe is unknown. The calcium-sensing receptor (CaR) can sense amino acids, and is expressed in the gastrointestinal tract. In the present study, we examined whether CaR functions as a receptor for Phe in CCK-producing enteroendocrine cells. CCK secretion and intracellular Ca2+ concentration in response to Phe were measured in the murine CCK-producing enteroendocrine cell line STC-1 at various extracellular Ca2+ concentrations or after treatment with a CaR antagonist. At more than 20 mM, Phe induced dose-dependent CCK secretion and intracellular Ca2+ mobilization in STC-1 cells. In the presence of 3.0 mM extracellular Ca2+, 10 and 20 mM Phe induced significantly higher CCK secretion than under normal conditions (1.2 mM extracellular Ca2+). Intracellular Ca2+ mobilization, induced by 10 or 20 mM Phe, was also enhanced by increasing extracellular Ca2+ concentrations. In addition, intracellular Ca2+ mobilization induced by addition of extracellular Ca2+ was augmented by the presence of Phe. These results closely match the known CaR properties. Treatment with a specific CaR antagonist (NPS2143) completely inhibited Phe-induced CCK secretion and the latter phase of intracellular Ca2+ mobilization. CaR mRNA expression was demonstrated by RT-PCR in STC-1 cells, as well as in other mouse tissues including the kidney, thyroid, stomach and intestine. In conclusion, CaR functions as a receptor for Phe, stimulating CCK secretion in enteroendocrine STC-1 cells.
• Peptides derived from dolicholin, a phaseolin-like protein in country beans (Dolichos lablab), potently stimulate cholecystokinin secretion from Enteroendocrine STC-1 cells

  Md. Kaosar Nlaz Bin Suman, Tohru Hira, Kozo Asano, Hiroshi Hara

  JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 55 (22) 8980 - 8986 0021-8561 2007/10 [Refereed][Not invited]
   

  Peptides derived from soybean P-conglycinin and pork protein stimulate cholecystokinin (CCK) secretion from the enteroendocrine cells (EECs) and suppress food intake. Here we examined CCK-releasing activities from the enteroendocrine cell line STC-1, in peptides derived from underutilized legumes, and found much higher activity in the peptic hydrolysate of Country beans (CBP) compared to that from other legume-derived peptides including P-conglycinin peptone. Active components in CBP were separated into acetonitrile-soluble fractions, but the activities were abolished after pronase treatment. To identify the Country bean protein containing the active peptides, Country bean protein extracts in an alkaline solution (CBE) were fractionated based on isoelectric point or molecular weight. Peptones prepared from CBE fractions containing a 51 kDa major protein stimulated CCK release, but other fractions did not. N-Terminal sequence analysis indicated that the 51 kDa protein is a phaseolin-like globular protein, and we designated this protein dolicholin. These results indicate that Country bean-derived peptides are very potent legume peptides in stimulating CCK secretion from EECs and that the stimulant peptides originate from dolicholin, a newly identified phaseolin-like globular protein in Country beans.
• Sucrose fatty acid esters suppress pancreatic secretion accompanied by peptide YY release in pancreatico-biliary diverted rats

  Tohru Hira, Katsuhiko Takahashi, Hiroshi Hara

  EXPERIMENTAL PHYSIOLOGY 92 (4) 687 - 694 0958-0670 2007/07 [Refereed][Not invited]
   

  Our previous study demonstrated that intestinal administration of triglycerides suppressed protein-induced increases in pancreatic exocrine secretion in pancreatico-biliary diverted (PBD) rats, though the mechanism has not been clarified. The present study was conducted to determine whether esterified fatty acids or free fatty acids are responsible for this suppression, and whether an esterified fatty acid stimulates secretion of a pancreatic inhibitory hormone, peptide YY (PYY). We examined the effects of cocoa butter or non-digestible sucrose fatty acid esters on protein-induced pancreatic secretion in conscious PBD rats whose bile-pancreatic juice was diverted from the proximal small intestine through a catheter. Intraduodenal administration of the protein guanidinated casein hydrolysate (HGC, 150 mg in 1 ml water) enhanced pancreatic protein and trypsin secretion. However, administration of HGC with cocoa butter (100 mg ml(-1)) partly suppressed the increase in pancreatic secretion, and HGC with a highly esterified sucrose fatty acid ester, F-10 (100 mg ml(-1)), completely suppressed it. The low-esterified, water-soluble sucrose fatty acid ester F-160 also completely inhibited protein-induced pancreatic secretion in the presence or absence of the lipase inhibitor orlistat.In anaesthetized PBD rats, intraduodenal administration of HGC with sucrose ester F-160 suppressed HGC-induced pancreatic secretion, and induced PYY secretion more strongly than HGC with sucrose. These results suggest that the esterified fatty acid itself stimulates PYY release in the distal intestine, thereby inhibiting protein-induced pancreatic secretion.
• Pork peptone stimulates cholecystokinin secretion from enteroendocrine cells and suppresses appetite in rats

  M. K. N. B. Sufian, Tohru Hira, Kyoko Miyashita, Takashi Nishi, Kozo Asano, Hiroshi Hara

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 70 (8) 1869 - 1874 0916-8451 2006/08 [Refereed][Not invited]
   

  We found that soybean beta-conglycinin peptone (BconP) suppresses food intake through cholecystokinin (CCK) release from enteroendocrine cells in association with binding of the peptone to rat small intestinal brush border membrane (BBM). The aim of the present study was to find new appetite suppressing peptides. Peptones from chicken, pork, beef, beef liver, and egg white were examined for activities to bind with rat BBM, CCK-release from enteroendocrine cell line STC-1, and induce satiety in rats. Chicken and pork peptone (ChicklP and PorklP) bound to BBM with highest ability as evaluated with a surface plasmon biosensor. PorkP and ChickP released CCK in higher amounts than BconP from STC-1 cells dose-dependently, with highest stimulation by PorkP. An orogastric preload of PorkP but not ChickP, suppressed food intake similarly to BconP, dose-dependently. These results suggest that PorkP interacts directly with the small intestinal CCK cells to release CCK, and that it suppresses appetite in rats.
• Mouse GPR40 heterologously expressed in Xenopus oocytes is activated by short-, medium-, and long-chain fatty acids

  G Stewart, T Hira, A Higgins, CP Smith, JT McLaughlin

  AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 290 (3) C785 - C792 0363-6143 2006/03 [Refereed][Not invited]
   

  Several orphan G protein-coupled receptors, including GPR40, have recently been shown to be responsive to fatty acids. Although previous reports have suggested GPR40 detects medium-and long-chain fatty acids, it has been reported to be unresponsive to short chain fatty acids. In this study, we have heterologously expressed mouse GPR40 in Xenopus laevis oocytes and measured fatty acid-induced increases in intracellular Ca2+, via two electrode voltage clamp recordings of the endogenous Ca2+-activated chloride conductance. Exposure to 500 mu M linoleic acid (C18:2), a long-chain fatty acid, stimulated significant currents in mGPR40-injected oocytes (P < 0.01, ANOVA), but not in water-injected control oocytes (not significant, ANOVA). These currents were confirmed as Ca2+-activated chloride conductances because they were biphasic, sensitive to changes in external pH, and inhibited by DIDS. Similar currents were observed with medium-chain fatty acids, such as lauric acid (C12:0) (P < 0.01, ANOVA), and more importantly, with short-chain fatty acids, such as butyric acid (C4:0) (P < 0.01, ANOVA). In contrast, no responses were observed in mGPR40-injected oocytes exposed to either acetic acid (C2:0) or propionic acid (C3:0). Therefore, GPR40 has the capacity to respond to fatty acids with chain lengths of four or greater. This finding has important implications for understanding the structure: function relationship of fatty acid sensors, and potentially for short-chain fatty acid sensing in the gastrointestinal tract.
• Multiple fatty acid sensing mechanisms operate in enteroendocrine cells - Novel evidence for direct mobilization of stored calcium by cytosolic fatty acid

  T Hira, AC Elliott, DG Thompson, RM Case, JT McLaughlin

  JOURNAL OF BIOLOGICAL CHEMISTRY 279 (25) 26082 - 26089 0021-9258 2004/06 [Refereed][Not invited]
   

  Fatty acids ( FA) with at least 12 carbon atoms increase intracellular Ca2+ ([Ca2+](i)) to stimulate cholecystokinin release from enteroendocrine cells. Using the murine enteroendocrine cell line STC-1, we investigated whether candidate intracellular pathways transduce the FA signal, or whether FA themselves act within the cell to release Ca2+ directly from the intracellular store. STC-1 cells loaded with fura-2 were briefly ( 3 min) exposed to saturated FA above and below the threshold length (C-8, C-10, and C-12). C-12, but not C-8 or C-10, induced a dose-dependent increase in [Ca2+](i), in the presence or absence of extracellular Ca2+. Various signaling inhibitors, including D-myo-inositol 1,4,5-triphosphate receptor antagonists, all failed to block FA-induced Ca2+ responses. To identify direct effects of cytosolic FA on the intracellular Ca2+ store, [Ca2+](i) was measured in STC-1 cells loaded with the lower affinity Ca2+ dye magfura-2, permeabilized by streptolysin O. In permeabilized cells, again C-12 but not C-8 or C-10, induced release of stored Ca2+. Although C-12 released Ca2+ in other permeabilized cell lines, only intact STC-1 cells responded to C-12 in the presence of extracellular Ca2+. In addition, 30 min exposure to C-12 induced a sustained elevation of [Ca2+](i) in the presence of extracellular Ca2+, but only a transient response in the absence of extracellular Ca2+. These results suggest that at least two FA sensing mechanisms operate in enteroendocrine cells: intracellularly, FA (greater than or equal to C-12) transiently induce Ca2+ release from intracellular Ca2+ stores. However, they also induce sustained Ca2+ entry from the extracellular medium to maintain an elevated [Ca2+](i).
• Casein binds to the cell membrane and induces intracellular calcium signals in the enteroendocrine cell: A brief communication

  T Hira, H Hara, F Tomita, Y Aoyama

  EXPERIMENTAL BIOLOGY AND MEDICINE 228 (7) 850 - 854 1535-3702 2003/07 [Refereed][Not invited]
   

  Dietary protein but not amino acids stimulates cholecystokinin (CCK) secretion in rat mucosal cells. However, the dietary protein sensory mechanisms and the intracellular signal pathway in the enteroendocrine cells have not yet been clarified. The relationship between dietary protein binding to cell membrane and intracellular calcium responses were examined in the CCK-producing enteroendocrine cell line STC-1. The binding of solubilized STC-1 cell membrane to proteins was analyzed using a surface plasmon resonance sensor. Intracellular calcium concentrations of STC-1 cell suspensions loaded with Fura-2 AM were measured using a spectrafluorophotometer system with continuous stirring. Intracellular calcium concentrations in STC-1 cells were increased by exposure to alpha-casein or casein sodium, but not to bovine serum albumin. Solubilized STC-1 membranes bound to alpha-casein and casein sodium but did not bind to bovine serum albumin. alpha-Casein demonstrated higher membrane binding and intracellular calcium stimulating activities than casein sodium. Thus, protein binding to the STC-1 cell membrane and intracellular calcium responses were correlated. Intracellular calcium responses to alpha-casein were suppressed by an L-type calcium channel blocker. These results suggest that casein, a dietary protein, binds to a putative receptor on the CCK-producing enteroendocrine cell membrane and elicits the subsequent intracellular calcium response via an L-type calcium channel.
• L-homoarginine suppresses exocrine pancreas in rats

  T Hira, S Ohyama, H Hara

  AMINO ACIDS 24 (4) 389 - 396 0939-4451 2003 [Refereed][Not invited]
   

  Previously, we found that guanidinated casein, a L-homoarginine-containing protein, was a more potent stimulator of pancreatic enzyme secretion than intact casein in rats. In this study, we examined secretory response and adaptation of the exocrine pancreas to the administration of free L-homoarginine in normal and bile-pancreatic juice (BPJ)-diverted rats. An intraperitoneal injection Of L-homoarginine (10 mg/rats) produced immediate and transient reduction in pancreatic secretion in BPJ-diverted rats, but not in normal rats. The BPJ-diverted rats were fed with either a 25% casein. 45% casein, or 45% casein diet supplemented with L-homoarginine (19 g/kg diet) for 4 days. Feeding of a diet containing L-homoarginine inhibited the pancreatic adaptation induced by the high-protein diet. These results indicate that L-homoarginine has an inhibitory effect on the secretion and production of exocrine pancreatic enzyme in BPJ-diverted rats, and L-homoarginine may have an antagonistic effect on CCK receptors.
• Dietary protein peptic hydrolysates stimulate cholecystokinin release via direct sensing by rat intestinal mucosal cells

  T Nishi, H Hara, T Hira, F Tomita

  EXPERIMENTAL BIOLOGY AND MEDICINE 226 (11) 1031 - 1036 1535-3702 2001/12 [Refereed][Not invited]
   

  We previously demonstrated that a peptic hydrolysate of guanidinated casein strongly stimulates exocrine pancreatic secretion in chronic bile-pancreatic juice-diverted rats and cholecystokinin (CCK) release from dispersed rat intestinal mucosal cells. These results reveal that the chemically modified protein hydrolysate stimulates CCK secretion and Increases pancreatic secretion by a luminal trypsin-independent direct action on the small intestine. In the present study, we examined the direct effect of peptic hydrolysates of naturally occurring dietary proteins, casein, soybean protein isolate (SPI), egg white, and wheat gluten on CCK release under in vitro trypsin-independent conditions. All protein hydrolysates significantly stimulated CCK release from dispersed rat intestinal mucosal cells. Among the hydrolysates treated, SPI hydrolysate was the most effective In stimulating CCK release. The potential of SPI hydrolysate to stimulate CCK release was increased by long-term peptic digestion. However, an SPI-like amino acid mixture did not effect CCK release. In conclusion, peptic hydrolysates of commonly ingested dietary proteins stimulate CCK release via trypsin-independent direct sensing by Intestinal mucosal cells.
• Dietary protein peptic hydrolysates stimulate cholecystokinin release via direct sensing by rat intestinal mucosal cells

  Takashi Nishi, Hirosh Hara, Tohru Hira, Fusao Tomita

  Experimental Biology and Medicine 226 (11) 1031 - 1036 0037-9727 2001/12 [Refereed][Not invited]
   

  We previously demonstrated that a peptic hydrolysate of guanidinated casein strongly stimulates exocrine pancreatic secretion in chronic bile-pancreatic juice-diverted rats and cholecystokinin (CCK) release from dispersed rat intestinal mucosal cells. These results reveal that the chemically modified protein hydrolysate stimulates CCK secretion and increases pancreatic secretion by a luminal trypsin-independent direct action on the small intestine. In the present study, we examined the direct effect of peptic hydrolysates of naturally occurring dietary proteins, casein, soybean protein isolate (SPI), egg white, and wheat gluten on CCK release under in vitro trypsin-independent conditions. All protein hydrolysates significantly stimulated CCK release from dispersed rat intestinal mucosal cells. Among the hydrolysates treated, SPI hydrolysate was the most effective in stimulating CCK release. The potential of SPI hydrolysate to stimulate CCK release was increased by long-term peptic digestion. However, an SPI-like amino acid mixture did not effect CCK release. In conclusion, peptic hydrolysates of commonly ingested dietary proteins stimulate CCK release via trypsin-independent direct sensing by intestinal mucosal cells.
• Endogenous cholecystokinin plays a role in down-regulation of pancreatic amylase independent of dietary carbohydrate in rats

  H Hara, S Ohyama, T Hira

  REGULATORY PEPTIDES 99 (2-3) 103 - 110 0167-0115 2001/06 [Refereed][Not invited]
   

  The role of cholecystokinin (CCK) in the regulation of pancreatic amylase has not been fully clarified. We examined the effects of hyperCCKemia with chronic pancreatico-biliary diversion (PBD) and blockade of CCKA-receptor on rat pancreatic amylase activity and mRNA abundance. Also, we examined the relationship between diet and CCK in terms of regulation of pancreatic amylase. PBD was produced by transposition of the duodenal segment containing the ampulla of Vater to the upper ileum. A potent CCKA-receptor antagonist, devazepide, was injected (6 mg/kg body weight per day for 5 days) in the PBD rats fed with diets containing normal or low level of carbohydrate (695 or 345 g sucrose/kg diet). The specific activity and mRNA abundance of the pancreatic amylase were constantly lower 4, 10 and 28 days after PBD than those after the sham operation. Devazepide treatment completely restored the amylase activity lowered by PBD without any increases in amylase mRNA. Feeding a high-protein low-carbohydrate diet suppressed the pancreatic amylase activity and mRNA abundance in PBD rats to a similar degree in those treated, and those untreated, with devazepide. We conclude that endogenous CCK suppresses pancreatic amylase production, and we speculate that CCK reduced translational efficiency of amylase mRNA. The effect of CCK on amylase production is independent of regulation by dietary carbohydrate. (C) 2001 Elsevier Science B.V. All rights reserved.
• Characterization of binding between the rat small intestinal brush-border membrane and dietary proteins in the sensory mechanism of luminal dietary proteins

  T Hira, H Hara, F Tomita

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 65 (5) 1007 - 1015 0916-8451 2001/05 [Refereed][Not invited]
   

  Dietary proteins are recognized by the gastrointestinal tract to display physiological functions, however, the sensory mechanism of the intestinal mucosa is not known. We examined binding properties between the rat small intestinal brush-border membrane (BBM) and proteins by using a surface plasmon resonance biosensor. BBM and solubilized BBM prepared from the rat jejunum bound to casein immobilized on the sensor surface, but not to bovine serum albumin. The ileal BBM showed less binding to casein than the jejunal BBM. Solubilized BBM binding to immobilized ol-casein was slightly inhibited by aminopeptidase inhibitors, but still more inhibited by addition of casein with the inhibitors. Guanidinated casein inhibited the solubilized BBM binding to ol-casein more strongly than casein (casein sodium and ol-casein) inhibited. Trypsinization of solubilized BBM abolished its binding activity to or-casein. These results indicate that some membrane protein, but not aminopeptidases, contained in BBM interacts with dietary proteins, and that guanidinated casein has a higher affinity for BBM than intact casein. These binding intensities for proteins were closely correlated to physiological responsiveness, and are possibly involved in a sensory system for dietary protein in the intestine.
• Luminal dietary protein, not amino acids, induces pancreatic protease via CCK in pancreaticobiliary-diverted rats

  H Hara, S Ohyama, T Hira

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 278 (6) G937 - G945 0193-1857 2000/06 [Refereed][Not invited]
   

  We determined whether pancreatic adaptation to a high-protein diet depends on ingested protein in the intestinal lumen and whether such adaptation depends on a CCK or capsaicin-sensitive vagal afferent pathway in pancreaticobiliary-diverted (PBD) rats. Feeding a high-casein (60%) diet but not a high-amino acid diet to PBD rats increased pancreatic trypsin and chymotrypsin activities compared with those after feeding a 25% casein diet. In contrast, feeding both the high-nitrogen diets induced pancreatic hypertrophy in PBD rats. These pancreatic changes by the diets were abolished by treatment with devazepide, a CCK-A receptor antagonist. Protease zymogen mRNA abundance in the PBD rat was not increased by feeding the high-casein diet and was decreased by devazepide. Perivagal capsaicin treatment did not influence the values of any pancreatic variables in PBD rats fed the normal or high-casein diet. We concluded that luminal protein or peptides were responsible for the bile pancreatic juice-independent induction of pancreatic proteases on feeding a high-protein diet. The induction was found to be dependent on the direct action of CCK on the pancreas. Pancreatic growth induced by high-protein feeding in PBD rats may depend at least partly on absorbed amino acids.
• Stimulative effect of a casein hydrolysate on exocrine pancreatic secretion that is independent of luminal trypsin inhibitory activity in rats

  T Hira, H Hara, Y Aoyama

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 63 (7) 1192 - 1196 0916-8451 1999/07 [Refereed][Not invited]
   

  We have previously demonstrated that proteins could stimulate pancreatic secretion independently of luminal bile-pancreatic juice (BPJ) in a BPJ-diverted rat. To determine whether luminal protease-independent pancreatic secretion occurs in normal rats with BPJ returned to the upper small intestine, we investigated the pancreatic secretory response to intraduodenal instillation of a casein hydrolysate or the synthetic trypsin inhibitor, FOY 305, at concentrations which could almost equally inhibit hydrolysis of the synthetic substrate for trypsin with the luminal content. FOY 305 at 10 mu g/ml and casein hydrolysate solutions at both 100 and 200 mg/ml similarly inhibited approx. 80% of the tryptic activity in the luminal contents of the proximal small intestine. Intraduodenal administration of casein hydrolysate solutions (100 and 200 mg/ml) significantly increased pancreatic secretion in a dose-dependent manner. However, intraduodenal administration of FOY 305 (10 mu g/ml) was ineffective for stimulating pancreatic secretion. These results demonstrate that dietary protein enhances pancreatic secretion independently of the masking of luminal trypsin activity in rats.
• Effects of DFA IV in rats: Calcium absorption and metabolism of DFA IV by intestinal microorganisms

  K Saito, T Hira, T Suzuki, H Hara, A Yokota, F Tomita

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 63 (4) 655 - 661 0916-8451 1999/04 [Refereed][Not invited]
   

  Di-n-fructose-2,6':6,2'-dianhydride (DFA IV) is a disaccharide consisting of two fructose residues that can be prepared from levan by levan fructotransferase from Arthrobacter nicotinovorans GS-9, and it can be expected to have novel physiological functions from its unique structure. In this study, the effects of DFA IV on calcium absorption and the metabolism of DFA IV by intestinal microorganisms were studied in rats to examine the physiological functions of DFA IV. The apparent calcium absorption in rats fed with DFA IV was significantly higher than that in the control rats, and it seems that calcium absorption had almost been completed at the end of the small intestine. DFA IV also increased the calcium absorption in in vitro experiments, using everted jejunal and ileal sacs, and this result supports the finding obtained in the in vivo experiments. These results indicate that DFA IV may have a function for increasing the calcium absorption in the small intestine of rats. However, the effect in the large intestine could not be clearly observed because of the lack of calcium that reached there. The results of analyses of organic acids in the cecal and colonic contents and of DFA IV in the fecal, cecal, and colonic contents showed that the metabolism of DFA IV by microorganisms in the large intestine progressed gradually, and that DFA IV was converted mainly to acetate, butyrate, and lactate.
• Guanidino group is involved in the stimulation of exocrine pancreatic secretion by protamine in normal and chronic bile pancreatic juice-diverted rats

  T Hira, H Hara, T Kasai

  PANCREAS 18 (2) 165 - 171 0885-3177 1999/03 [Refereed][Not invited]
   

  We previously demonstrated that the feeding of guanidinated casein, whose lysine residues are converted to homoarginine, stimulates pancreatic secretion much higher than that of intact casein in chronic bile-pancreatic juice (BPJ)-diverted rats, which suggests that the guanidino group is involved in BPJ-independent enhancement of pancreatic secretion. However, the role of the guanidino group in the protein for the enhancement of pancreatic secretion has not been clarified. In this study, we examined the stimulation of pancreatic secretion by a arginine rich dietary protein, protamine (25, 50 mg/ml), and then determined whether the guanidino group in protamine was responsible for the secretory responses in normal and BPJ-diverted rat by comparison with pancreatic secretion between intact and deguanidinated protamine. The deguanidinated protamine was prepared by converting arginine residues of salmon protamine to ornithine using heated hydrazine (conversion rate of arginine residue was 87%). In normal rats, pancreatic protein and chymotrypsin secretion were stimulated in dose-response fashion after a duodenal instillation of native protamine solution (25, 50 mg in 1 ml). In chronic BPJ-diverted rats, native protamine (25 mg) maximally stimulated pancreatic protein and protease secretion. In contrast, deguanidinated protamine (50 mg in 1 ml) did not stimulate pancreatic secretion in both normal and BPJ-diverted rats. In addition, the duodenal administration of arginine, which is equal to the amount contained in 50 mg of native protamine, had no effect on pancreatic secretion in both rats. These results suggest that a naturally occurring protein, protamine, stimulates pancreatic secretion by a luminal BPJ-independent mechanism and that the guanidino group in this protein is responsible for stimulating pancreatic secretion in BPJ-diverted rats.
• Stimulation of exocrine pancreatic secretion by soybean trypsin inhibitor does not depend on the masking of luminal trypsin activity in rats that have bile-pancreatic juice diverted into the ileum

  T Hira, H Hara, T Kasai

  PANCREAS 15 (3) 285 - 290 0885-3177 1997/10 [Refereed][Not invited]
   

  We reported previously that dietary proteins stimulate pancreatic secretion by a mechanism not involved in masking trypsin activity in rats that have bile-pancreatic juice (BPJ) diverted from the proximal small intestine for 7 days. However, BPJ in the distal small intestine is possibly responsible for the stimulation of pancreatic secretion in chronic BPJ-diverted rats, To examine whether the BPJ-dependent mechanism operates in the distal small intestine of chronic BPJ-diverted rats, we investigated pancreatic responses after inhibition or removal of pancreatic trypsin activity in the distal small intestine of conscious rats. Duodenal instillation of soy bean trypsin inhibitor (SBTI), which is a proteinaceous trypsin inhibitor, stimulated pancreatic secretion in the chronic BPJ-diverted rats, whereas a nonpeptidic trypsin inhibitor, FOY 305, did not. Ileal administration of both trypsin inhibitors did not enhance pancreatic secretion in the diverted rats. Exclusion of luminal BPJ from the distal small intestine was also ineffective in causing pancreatic exocrine secretion in the chronic BPJ-diverted rats. These observations reveal that ileal BPJ does not contribute to the stimulation of pancreatic secretion in rats that have BPJ chronically diverted into the ileum, as in intact rats, and that a duodenal instillation of SBTI stimulates pancreatic secretion as a protein, and not as a trypsin inhibitor.

MISC

• 動物実験の新しい展開 食事誘導性肥満モデル、血管カニュレーションモデルを用いた、消化管ホルモンGLP-1の分泌調節に関する研究

  比良 徹  日本栄養・食糧学会大会講演要旨集  78回-  .153  -.153  2024/04
• 「食品タンパク質由来の健康機能性ペプチド研究の最先端」 食品タンパク質・ペプチドによるGLP-1分泌促進とそれによる血糖上昇抑制、体温上昇作用

  比良 徹  日本栄養・食糧学会大会講演要旨集  77回-  152  -152  2023/03
• ラットの胃排出速度への各種香辛料の影響

  土居 悠太, 比良 徹  日本栄養・食糧学会大会講演要旨集  77回-  215  -215  2023/03
• Dietary peptides stimulate GLP-1 secretion and reduce its degradation

  比良徹  アミノ酸研究  16-  (1)  2023
• 大豆タンパク質摂取によるGLP-1シグナルを介した直腸温度上昇作用

  落合 啓太, 岩崎 有作, 比良 徹  肥満研究  28-  (Suppl.)  296  -296  2022/11
• ラットにおけるえごま油長期摂食による食事刺激に対するGLP-1分泌への影響

  木村 梨乃, 佐野 杏莉, 比良 徹  日本栄養・食糧学会大会講演要旨集  76回-  283  -283  2022/05
• 腸内分泌細胞におけるGABAとL-Phenylalanineの相乗的なGLP-1分泌促進作用-トウモロコシタンパク質調製物の有効成分の探索

  野口洋樹, 野口洋樹, 甲田哲之, 原博, 比良徹  日本農芸化学会東北支部大会プログラム・講演要旨集  2022-  2022
• ラット門脈,腸間膜静脈における食後の血中アミノ酸濃度変動

  桂康次朗, 比良徹  アミノ酸研究  15-  (2)  2022
• GLP-1分泌を促進するジペプチド配列の探索

  田口颯, 村井佳奈, 比良徹  日本栄養・食糧学会北海道支部大会講演要旨集  52nd-  2022
• 2-モノアシルグリセロールのCCK分泌活性評価およびその作用機構の解明

  落合 啓太, 廣岡 里菜, 境野 眞善, 竹内 茂雄, 比良 徹  日本栄養・食糧学会大会講演要旨集  75回-  57  -57  2021/07
• ラットにおけるえごま油長期摂取は,食事刺激に対するGLP-1分泌応答および持続性を高める

  木村梨乃, 佐野杏莉, 比良徹, 比良徹  日本栄養・食糧学会東北支部大会およびシンポジウム講演要旨集  55th-  2021
• ラットにおけるカルシウムによる食欲抑制に対する食事組成の影響

  原田和馬, 比良徹  日本農芸化学会北海道支部学術講演会講演要旨集(Web)  2021-  2021
• GLP-1 responses and intestinal tissue analysis in diet-induced obese rats

  佐野杏莉, 比良徹  日本農芸化学会大会講演要旨集(Web)  2021-  2021
• Dietary peptides module GLP-1 and glucose metabolism

  比良徹  日本農芸化学会大会講演要旨集(Web)  2021-  2021
• ラットへ大豆タンパク質を経口投与すると血中GLP-1濃度が高められ,血中DPP-4活性が低下する

  村井佳奈, 比良徹  アミノ酸研究  14-  (1)  63  -64  2021
• Role of dietary proteins in postprandial gut hormone secretion

  比良徹  飯島藤十郎記念食品科学振興財団年報  35-  149  -153  2020
• ラットにおける大豆タンパク質経口投与時のGLP-1分泌応答と血中DPP-4活性の低下

  村井佳奈, 比良徹  日本栄養・食糧学会大会講演要旨集  74th-  193  -193  2020
• 希少糖D‐AlluloseのGLP‐1分泌促進作用と求心性迷走神経を介した摂食・糖代謝調節作用

  岩崎有作, 岩崎有作, 仙度光麻, 出崎克也, 比良徹, 中田正範, 中田正範, 原博, DRUCKER Daniel J, 山田祐一郎, 徳田雅明, 矢田俊彦, 矢田俊彦  日本農芸化学会大会講演要旨集(Web)  2019-  ROMBUNNO.3B4p09 (WEB ONLY)  2019/03/05  [Not refereed][Not invited]
  
• カルシウム単回経口投与による消化管ホルモン分泌を介した食欲抑制作用機構の検討

  小笠原奨之, 比良徹, 原博  日本農芸化学会大会講演要旨集(Web)  2019-  ROMBUNNO.1B4p12 (WEB ONLY)  2019/03/05  [Not refereed][Not invited]
  
• ラットにおいて経口投与したタンパク質は糖質よりも血中GLP-1濃度を高める

  清水 祐希, 比良 徹, 原 博  アミノ酸研究  12-  (2)  122  -122  2019/03
• 肥満誘導食摂取ラットにおけるたんぱく質投与に対するインクレチン分泌の変化

  田中里実, 原博, 比良徹  日本アミノ酸学会学術大会講演要旨集  13th-  (2)  104  -104  2019
• ラットにおけるD‐アルロースによるGLP‐1分泌促進作用へのセロトニンの関与

  木村夏織, 早川真輝, 比良徹, 飯田哲郎, 岸本由香, 原博  日本栄養・食糧学会大会講演要旨集  73rd-  267  -267  2019  [Not refereed][Not invited]
  
• 消化管内分泌細胞における伸展刺激負荷によるGLP‐1分泌応答

  木村夏織, 比良徹, 原博  日本農芸化学会東北支部大会プログラム・講演要旨集  153rd-  59  2018/09/22  [Not refereed][Not invited]
  
• 各種ケルセチン配糖体摂取による消化管ホルモンGLP‐1分泌能の適応的増強現象

  長瀬僚介, 比良徹, 原博  日本食品科学工学会大会講演集  65th-  79  2018/08/22  [Not refereed][Not invited]
  
• 希少糖アルロースの〈GLP‐1内分泌→求心性迷走神経→脳〉軸を介した過食・肥満・糖尿病改善作用

  岩崎有作, 岩崎有作, 仙度光麻, 出崎克也, 比良徹, 佐藤雄大, 中田正範, 中田正範, GOSWAMI Chayon, GOSWAMI Chayon, KUMARI Parmila, 増田千明, 岡田尚巳, 原博, DRUCKER Daniel J, 山田祐一郎, 徳田雅明, 矢田俊彦, 矢田俊彦  日本糖質学会年会要旨集  37th-  110  2018/08/20  [Not refereed][Not invited]
  
• 希少糖アルロースによるGLP-1放出を介した耐糖能向上 インスリン感受性と初期分泌の亢進

  岩崎 有作, 仙度 光麻, 出崎 克也, 比良 徹, 佐藤 雄大, 原 博, 山田 祐一郎, 徳田 雅明, 矢部 大介, 矢田 俊彦  糖尿病  61-  (Suppl.1)  S  -322  2018/04
• 難消化性糖質の消化管内分泌系への作用

  比良徹, 原博  日本栄養・食糧学会大会講演要旨集  72回-  154  -154  2018/04  [Not refereed][Not invited]
  
• ケルセチン配糖体の長期摂取によるGLP‐1分泌能亢進の解析

  長瀬僚介, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  72回-  210  -210  2018/04  [Not refereed][Not invited]
  
• 小腸腔内のセロトニンはL細胞においてセロトニン受容体HTR4を介してGLP‐1分泌を抑制する

  奥村元, 比良徹, 園山慶  日本栄養・食糧学会大会講演要旨集  72回-  187  -187  2018/04  [Not refereed][Not invited]
  
• 腸内細菌脂質代謝物(修飾脂肪酸)を用いて見出された,CCK分泌を強く促進する脂肪酸の特異的構造

  小笠原奨之, 矢萩明日香, 比良徹, 西村紗希, 山下貴稔, 原博  日本農芸化学会大会講演要旨集(Web)  2018-  ROMBUNNO.2B07p02 (WEB ONLY)  2018/03/05  [Not refereed][Not invited]
  
• 食事中のタンパク質が下部消化管からのGLP-1分泌を誘導する

  関下 まどか, 比良 徹, 原 博  アミノ酸研究  11-  (2)  118  -119  2018/03
• 希少糖アルロースによるGLP-1放出を介した耐糖能向上:インスリン感受性と初期分泌の亢進

  岩崎有作, 仙度光麻, 出崎克也, 比良徹, 佐藤雄大, 原博, 山田祐一郎, 徳田雅明, 矢部大介, 矢田俊彦, 矢田俊彦  糖尿病(Web)  61-  (Suppl)  2018
• Zein加水分解物による小腸部位別でのGLP‐1分泌応答

  清水祐希, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  72nd-  194  -194  2018  [Not refereed][Not invited]
  
• 肥満誘導食摂取ラットにおけるたんぱく質投与に対するGLP‐1分泌応答の変化

  田中里実, 比良徹, 原博  日本栄養・食糧学会東北支部大会およびシンポジウム講演要旨集  52nd-  27  2018  [Not refereed][Not invited]
  
• ラットにおいて経口投与したタンパク質は糖質よりも血中GLP‐1濃度を高める

  清水祐希, 比良徹, 原博  日本アミノ酸学会学術大会講演要旨集  12th-  (2)  35  -122  2018  [Not refereed][Not invited]
  
• ケルセチン配糖体の反復投与は糖負荷後のラットGLP‐1分泌能を増強する

  長瀬僚介, 比良徹, 原博  日本未病システム学会学術総会抄録集  24回-  85  -85  2017/10  [Not refereed][Not invited]
  
• 希少糖AlluloseのGLP‐1放出と求心性迷走神経を介した過食・肥満・糖尿病改善

  矢田俊彦, 岩崎有作, 仙度光麻, 比良徹, 佐藤雄大, GOSWAMI Chayon, 原博, 山田祐一郎, 徳田雅明, 出崎克也  肥満研究  23-  (Suppl.)  187  -187  2017/09  [Not refereed][Not invited]
  
• ラットへのカルシウム単回経口投与は食欲を抑制する

  小笠原奨之, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  71st-  332  2017/04/28  [Not refereed][Not invited]
  
• 肥満誘導食摂取ラットにおける食事刺激に対するGLP‐1分泌応答の解析

  柳原くるみ, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  71st-  276  2017/04/28  [Not refereed][Not invited]
  
• 希少糖D-Alluloseによる糖代謝・摂食調節におけるGLP-1と求心性迷走神経肝臓枝の役割

  矢田 俊彦, 岩崎 有作, 仙度 光麻, Goswami Ghayon, 比良 徹, 原 博, 徳田 雅明, 出崎 克也  糖尿病  60-  (Suppl.1)  S  -274  2017/04
• 希少糖D‐Allulose摂取によるGLP‐1分泌と求心性迷走神経を介した摂食,糖代謝調節

  岩崎有作, GOSWAMI Chayon, 仙度光麻, 出崎克也, 比良徹, 原博, 徳田雅明, 矢田俊彦  日本内分泌学会雑誌  93-  (1)  331  -331  2017/04  [Not refereed][Not invited]
  
• 希少糖D-Alluloseによる糖代謝・摂食調節におけるGLP-1と求心性迷走神経肝臓枝の役割

  矢田俊彦, 岩崎有作, 仙度光麻, GHAYON Goswami, 比良徹, 原博, 徳田雅明, 出崎克也  糖尿病(Web)  60-  (Suppl)  2017
• 希少糖アルロースによるGLP‐1放出,求心性迷走神経を介した摂食・糖代謝制御と肥満症改善

  矢田俊彦, 岩崎有作, 比良徹, 原博, GOSWAMI Chayon, 仙度光麻, 徳田雅明, 出崎克也  日本解剖学会総会・全国学術集会講演プログラム・抄録集  122nd-  108  2017  [Not refereed][Not invited]
  
• 乳たんぱく質素材の消化性とGLP‐1分泌刺激活性に関する検討

  小松陽介, 小松陽介, 和田泰明, 和田泰明, 井上大輔, 和泉裕久, 清水隆司, 武田安弘, 比良徹, 原博  日本農芸化学会大会講演要旨集(Web)  2017-  ROMBUNNO.2A04a08 (WEB ONLY)  2017  [Not refereed][Not invited]
  
• 食品ペプチドで血糖を制御する 消化管内分泌系による栄養素認識を利用する

  比良徹  化学と生物  55-  (5)  296  -298  2017  [Not refereed][Not invited]
  
• 腸管部位別の食後消化管ホルモン分泌変動解析

  関下まどか, 原博, 比良徹  肥満研究  23-  (Supplement)  200  -200  2017  [Not refereed][Not invited]
  
• 食事中のタンパク質が下部消化管からのGLP‐1分泌を誘導する

  関下まどか, 比良徹, 原博  日本アミノ酸学会学術大会講演要旨集  11th-  (2)  78  -119  2017  [Not refereed][Not invited]
  
• 肥満誘導食摂取ラットにおけるカナグリフロジン経口投与に対するGLP‐1分泌応答

  比良徹, 古賀俊希, 原博, 石井伸一, 佐々木一代  肥満研究  22-  (Supplement)  215  2016/09/20  [Not refereed][Not invited]
  
• 希少糖Allulose摂取によるGLP‐1分泌は過食,摂食リズム障害,肥満を改善する

  岩崎有作, KUMARI Parmila, 比良徹, 荒井健, 出崎克也, 原博, 徳田雅明, 矢田俊彦  肥満研究  22-  (Supplement)  182  2016/09/20  [Not refereed][Not invited]
  
• トウモロコシたんぱく質Zainを含む食事が与える消化管ホルモン分泌応答への影響

  関下まどか, 比良徹, 原博  日本アミノ酸学会学術大会講演要旨集  10th-  73  2016/09/11  [Not refereed][Not invited]
  
• D‐プシコースの経口投与はラットにおいてGLP‐1分泌を促進する

  早川真輝, 比良徹, 飯田哲郎, 岸本由香, 原博  日本栄養・食糧学会大会講演要旨集  70th-  267  2016/04/25  [Not refereed][Not invited]
  
• 糖代謝改善ペプチド

  比良徹, 原博  日本農芸化学会大会講演要旨集(Web)  2016-  2SY03‐2 (WEB ONLY)  2016/03/05  [Not refereed][Not invited]
  
• ラットにおける肥満誘導食へのDFA III,ラフィノース添加の影響

  古賀俊希, 比良徹, 高橋敬典, 名倉泰三, 内野浩克, 原博  日本農芸化学会大会講演要旨集(Web)  2016-  4E066 (WEB ONLY)  2016/03/05  [Not refereed][Not invited]
  
• 希少糖によるGLP-1放出,求心性迷走神経を介した摂食抑制と耐糖能向上

  岩崎有作, 比良徹, 出崎克也, 原博, 徳田雅明, 矢田俊彦  日本病態栄養学会誌(Web)  20-  (Supplement)  2016
• ゼロカロリー甘味料である希少糖D‐AlluloseはGLP‐1分泌と迷走神経活性化を介して糖尿病・過食・肥満を改善する

  岩崎有作, 荒井健, KUMARI Parmila, 出崎克也, 比良徹, 原博, 徳田雅明, 矢田俊彦  糖尿病(Web)  59-  (Suppl)  S.450(J‐STAGE)  2016  [Not refereed][Not invited]
  
• 米ペプチドによる消化管ホルモン分泌を介した血糖上昇抑制作用

  比良徹, 原博  日本栄養・食糧学会大会講演要旨集  70th-  149  2016  [Not refereed][Not invited]
  
• 亜鉛は消化管内分泌細胞からのCCK分泌を誘導する

  中島進吾, 比良徹, 岩谷一史, 原博  日本農芸化学会大会講演要旨集(Web)  2016-  4E103 (WEB ONLY)  2016  [Not refereed][Not invited]
  
• たんぱく源の異なる食事による食後ホルモン分泌への影響

  関下まどか, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  70th-  185  2016  [Not refereed][Not invited]
  
• ラット腸管へのtrans,trans‐2,4‐デカジエナール投与は5‐HT3受容体を介して胃排出を抑制する

  矢萩明日香, 比良徹, 西村紗希, 境野眞善, 山下貴稔, 原博  肥満研究  21-  (Supplement)  210  2015/09/08  [Not refereed][Not invited]
  
• Luminal trans, trans-2,4-decadienal reduces gastric emptying in rats

  A. Yahagi, T. Hira, S. Nishimura, M. Sakaino, T. Yamashita, H. Hara  DIABETOLOGIA  58-  S305  -S305  2015/09  [Not refereed][Not invited]
  
• Changes in postprandial glucagon-like peptide-1 secretion during the development of diet-induced obesity in rats

  T. Hira, A. Kanehira, H. Hara  DIABETOLOGIA  58-  S271  -S271  2015/09  [Not refereed][Not invited]
  
• trans,trans‐2,4‐デカジエナールは,ラットにおいて腸管への作用を介して胃排出を抑制する

  矢萩明日香, 比良徹, 西村紗希, 境野眞善, 山下貴稔, 原博  日本農芸化学会大会講演要旨集(Web)  2015-  2F11P18 (WEB ONLY)  2015/03/05  [Not refereed][Not invited]
  
• 米タンパク質の新規生体調節機能性の先導的開発と機構解析 第2章 機能性成分の生体調整機能の研究開発 6 消化管ホルモンGLP‐1分泌促進/分解抑制作用の解明

  原博, 比良徹  農林水産省農林水産技術会議事務局研究成果  (529)  419  -425  2015/02/27  [Not refereed][Not invited]
  
• トウモロコシ由来ペプチドにおけるGLP‐1分泌促進機構の解析

  井上大輔, 比良徹, 原博  日本農芸化学会北海道支部講演会講演要旨  2015-  19  2015  [Not refereed][Not invited]
  
• トウモロコシZein由来のGLP‐1分泌促進ペプチドの探索

  山田菜央, 比良徹, 谷口正之, 原博  日本アミノ酸学会学術大会講演要旨集  8th-  53  2014/11/08  [Not refereed][Not invited]
  
• 水溶性難消化性糖質の肥満誘導食への添加はラットのGLP‐1産生を高め,過食,脂肪蓄積を軽減する

  須藤僚也, 比良徹, 岸本由香, 原博  肥満研究  20-  (Supplement)  213  2014/10/10  [Not refereed][Not invited]
  
• 高脂肪・高ショ糖食摂取ラットにおける食後GLP‐1分泌の解析

  金平葵, 比良徹, 原博  肥満研究  20-  (Supplement)  208  2014/10/10  [Not refereed][Not invited]
  
• ORAL ADMINISTRATION OF TRANS, TRANS-2,4-DECADIENAL REDUCES GASTRIC EMPTYING IN RATS

  Asuka Yahagi, Tohru Hira, Chigusa Nishiyama, Takatoshi Yamashita, Jun Imagi, Hiroshi Hara  JOURNAL OF MOLECULAR NEUROSCIENCE  53-  S170  -S171  2014/08  [Not refereed][Not invited]
  
• 長期高脂肪・高ショ糖食摂取による絶食時および食後GLP‐1分泌への影響

  金平葵, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  68th-  283  2014/04/30  [Not refereed][Not invited]
  
• ラットにおいて高脂肪高ショ糖食への難消化性糖質添加は,血中GLP‐1レベルを上昇させ,脂肪蓄積を軽減する

  須藤僚也, 比良徹, 岸本由香, 原博  日本栄養・食糧学会大会講演要旨集  68th-  257  2014/04/30  [Not refereed][Not invited]
  
• 米糠・胚乳ペプチドはラットにおいてGLP‐1分泌を促進し,血中GLP‐1のActive/Total比を高める

  石川結貴, 比良徹, 原田幸和, 橋本博之, 藤井幹夫, 門脇基二, 原博  日本農芸化学会大会講演要旨集(Web)  2014-  4B05A17 (WEB ONLY)  2014/03/05  [Not refereed][Not invited]
  
• trans,trans‐2,4‐デカジエナールの経口投与によるラット胃排出遅延作用

  矢萩明日香, 比良徹, 西山千草, 山下貴稔, 今義潤, 原博  日本農芸化学会大会講演要旨集(Web)  2014-  4B05A16 (WEB ONLY)  2014/03/05  [Not refereed][Not invited]
  
• 食品ペプチドの消化管での作用を介した血糖制御に関する研究

  比良徹  アミノ酸研究  7-  (2)  79  -84  2014/02  [Not refereed][Not invited]
  
• 食品ペプチドの消化管での作用を介した血糖制御に関する研究

  比良徹  日本アミノ酸学会学術大会講演要旨集  7th-  29  2013/11/02  [Not refereed][Not invited]
  
• トウモロコシペプチドによるin vivo,in vitroでのGLP‐1分泌作用

  山田菜央, 比良徹, 原博  日本アミノ酸学会学術大会講演要旨集  7th-  70  2013/11/02  [Not refereed][Not invited]
  
• 難消化性デキストリン摂取は,ラット血中GLP‐1濃度を高め,耐糖能を改善する

  池江明日香, 比良徹, 岸本由香, 原博  肥満研究  19-  (Supplement)  189  2013/09/25  [Not refereed][Not invited]
  
• 消化管内分泌系調節ペプチド

  原博, 比良徹  日本栄養・食糧学会大会講演要旨集  67th-  75  2013/04/30  [Not refereed][Not invited]
  
• ラットにおいて難消化性デキストリンの長期摂取は血中GLP‐1濃度を高める

  池江明日香, 比良徹, 岸本由香, 原博  日本栄養・食糧学会大会講演要旨集  67th-  89  2013/04/30  [Not refereed][Not invited]
  
• ポリリジンはラット腸管において胃排出を遅延し,血糖値上昇を抑制する

  佐藤恵理, 比良徹, 満永有美, 中島進吾, 江藤譲, 原博  日本栄養・食糧学会大会講演要旨集  67th-  91  2013/04/30  [Not refereed][Not invited]
  
• ラットにおいてトウモロコシペプチドの経口投与が,インクレチン分泌促進を介して血糖上昇を抑制する

  比良徹, 樋口謹行, 原博  糖尿病  56-  (Supplement 1)  S.197  2013/04/25  [Not refereed][Not invited]
  
• Fructooligosaccharides augments the effect of a flavonoid, alpha- glucosyl-isoquercitrin, on glucagon-like peptide 1 (GLP-1) secretion

  Panchita Phuwamongkolwiwat, Tohru Hira, Hiroshi Hara  FASEB JOURNAL  27-  2013/04  [Not refereed][Not invited]
  
• 食欲促進ホルモン・グレリンとその活性化酵素GOATの遺伝子発現にはSiT1/FoxO1/Foxo3aが関与する

  岩崎泰正, 西山充, 田口崇文, 次田誠, 岡崎瑞穂, 中山修一, 江間宏樹, 寺田典生, 藤本新平, 置村康彦, 比良徹, 神林真知子, 川村和夫  日本内分泌学会雑誌  89-  (1)  274  2013/04/01  [Not refereed][Not invited]
  
• 消化管内分泌細胞株において不飽和アルデヒドはTRPA1を介してCCK分泌を誘導する

  中島進吾, 比良徹, 西山千草, 山下貴俊, 今義潤, 原博  日本農芸化学会大会講演要旨集(Web)  2013-  WEB ONLY 4A15A02  2013/03/05  [Not refereed][Not invited]
  
• 米胚乳ペプチドはラットにおいてGLP‐1分泌を促進して血糖上昇を抑制する

  石川結貴, 比良徹, 藤井幹夫, 門脇基二, 原博  日本農芸化学会大会講演要旨集(Web)  2013-  WEB ONLY 4A15A04  2013/03/05  [Not refereed][Not invited]
  
• Effect of Adzuki Bean Vigna Angularis Cotyledon on Intestinal Alpha-glucosidase Activity and Glucagon-like Peptide-1 Secretion in vitro

  HAMAOKA Naohiro, NAKAGAWA Ryoji, HIRA Tohru, YAMAKI Kohji  Nippon Shokuhin Kagaku Kogaku Kaishi  60-  (1)  43  -47  2013/01/15  [Not refereed][Not invited]
   

  The anti-hyperglycemic functions of Adzuki beans Vigna angularis cotyledon were examined in vitro. Various Adzuki beans with or without seed coats were boiled and crushed, then hydrolyzed with pepsin at 37°C for 30min. The Adzuki bean hydrolysates (4.2mg/ml) inhibited the activity of alpha-glucosidase prepared from rat intestinal powder by 18.9% to 29.0% as compared with the control. This inhibitory effect was not diminished by trypsin treatment. In addition, the hydrolysates (10mg/ml) induced glucagon-like peptide-1 (GLP-1) secretion in a murine enteroendocrine cell model. These activities were found in the hydrolysates prepared from the beans without seed coats as well as those with seed coats. These two effects of Adzuki bean cotyledon hydrolysates, namely, inhibition of alpha-glucosidase activity and induction of GLP-1 secretion, suggest the potential application of Adzuki beans hydrolysates to a functional food material for preventing hyperglycemia.
• FRUCTOOLIGOSACCHARIDES ENHANCES THE EFFECT OF A FLAVONOID, alpha-GLUCOSYL-ISOQUERCITRIN, ON GLUCAGON-LIKE PEPTIDE-1 (GLP-1) SECRETION IN RAT INTESTINE AND ENTEROENDOCRINE CELLS

  P. Phuwamongkolwiwat, T. Hira, H. Hara  ANNALS OF NUTRITION AND METABOLISM  63-  1576  -1576  2013  [Not refereed][Not invited]
  
• Diversity of physiological functions of amino acids and peptides PHYSIOLOGICAL FUNCTION OF SOYBEAN PEPTIDES

  H. Hara, S. Nakajima, T. Hira  ANNALS OF NUTRITION AND METABOLISM  63-  98  -98  2013  [Not refereed][Not invited]
  
• Study on glycemic control by luminal dietary peptides

  比良 徹  アミノ酸研究  7-  (2)  79  -84  2013  [Not refereed][Not invited]
  
• 食品ペプチドによるGLP‐1分泌/分解制御機構の解明

  比良徹  三島海雲記念財団研究報告書  (49)  58  -61  2012/11/01  [Not refereed][Not invited]
  
• 腸管での食品ペプチド認識と消化管ホルモン分泌に関する研究

  比良徹  日本農芸化学会北海道支部講演会講演要旨  2012-  9  2012/11/01  [Not refereed][Not invited]
  
• 小豆子葉部の高血糖改善機能の評価

  濱岡直裕, 比良徹, 八巻幸二, 中川良二, 太田智樹, 長島浩二  日本食品化学学会総会・学術大会講演要旨集  18th-  108  2012/06/21  [Not refereed][Not invited]
  
• 難消化性デキストリンのラット腸管におけるGLP‐1分泌作用の検討

  池江明日香, 比良徹, 岸本由香, 原博  日本栄養・食糧学会大会講演要旨集  66th-  100  2012/04/27  [Not refereed][Not invited]
  
• トウモロコシZein加水分解物の経口投与はインクレチン分泌を介して血糖上昇を抑制する

  樋口謹行, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  66th-  100  2012/04/27  [Not refereed][Not invited]
  
• 腸管での栄養素認識と消化管ホルモン分泌に関する研究

  比良徹  日本栄養・食糧学会大会講演要旨集  66th-  9  2012/04/27  [Not refereed][Not invited]
  
• 甘藷若葉「すいおう」のGLP‐1分泌促進作用と血糖値上昇抑制作用

  永峰里花, 上野栞, 田頭英樹, 友澤寛, 鍔田仁人, 比良徹, 原博, 津田孝範  日本栄養・食糧学会大会講演要旨集  66th-  219  2012/04/27  [Not refereed][Not invited]
  
• Fructooligosaccharides (FOS) enhance beneficial effects of a flavonoid, quercetin-3-glucoside (Q3G), on insulin sensitivity in rats fed high sucrose diet

  Panchita Phuwamongkolwiwat, Takuya Suzuki, Tohru Hira, Hiroshi Hara  FASEB JOURNAL  26-  2012/04  [Not refereed][Not invited]
  
• 甘藷若葉「すいおう」の血糖値上昇抑制作用とGLP‐1分泌への影響

  永峰里花, 上野栞, 友澤寛, 鍔田仁人, 比良徹, 原博, 津田孝範  日本農芸化学会大会講演要旨集(Web)  2012-  2J12P10 (WEB ONLY)  2012/03/05  [Not refereed][Not invited]
  
• 消化管内分泌細胞におけるカゼインによるCCK分泌機構の解析

  後藤健仁, 比良徹, 中島進吾, 原博  日本農芸化学会大会講演要旨集(Web)  2012-  WEB ONLY 3C29P05  2012/03/05  [Not refereed][Not invited]
  
• 異なる分子量の食品ペプチドがカルシウム感知受容体を介したCholecystokinin分泌を誘導する

  中島進吾, 比良徹, 原博  日本農芸化学会大会講演要旨集(Web)  2012-  WEB ONLY 3J13A01  2012/03/05  [Not refereed][Not invited]
  
• Study on Nutrient Sensing and Gut Hormone Secretion:(Young Investigator Award of JSFNS (2012))

  Hira Tohru  Nippon Eiyo Shokuryo Gakkaishi  65-  (5)  215  -220  2012  [Not refereed][Not invited]
   

  Enteroendocrine cells sense luminal nutrients, but the molecular mechanisms by which dietary peptides induce gut hormone secretions are still unclear. Using a cholecystokinin (CCK)-producing enteroendocrine cell line, it was revealed that the calcium-sensing receptor functions as the receptor for phenylalanine and also for various dietary peptides. Oral administration of a dietary peptide that stimulates CCK secretion reduced both food intake in rats and appetite sensation in humans. Stimulation of glucagon-like peptide-1 (GLP-1) secretion is a promising way to attenuate postprandial hyperglycemia. We found that a dietary peptide prepared from corn zein strongly stimulated GLP-1 secretion in vitro and in vivo. The zein peptide administered into the ileum of rats effectively attenuated the elevation of glycemia through enhancement of GLP-1 secretion and subsequent insulin secretion. The peptide also reduced plasma dipeptidyl peptidase-IV (DPP-IV) activity after intraluminal administration. These findings are important for understanding nutrient-sensing mechanisms in the gut, and also suggest that enhancement of gut hormone secretion by luminal food factors such as dietary peptides could be a novel strategy for control of appetite and glucose metabolism.
• 難消化性デキストリンは消化管内分泌細胞に直接作用してGLP‐1分泌を促進する

  池江明日香, 比良徹, 岸本由香, 原博  ルミナコイド研究  15-  (2)  103-104  -104  2011/12/31  [Not refereed][Not invited]
  
• トウモロコシたんぱく質Zeinの加水分解物による血糖上昇抑制へのGLP‐1の関与

  樋口謹行, 比良徹, 原博  ルミナコイド研究  15-  (2)  105  2011/12/31  [Not refereed][Not invited]
  
• ビール酵母抽出物中のCCK分泌促進ペプチドの探索

  須田和希, 比良徹, 原博  日本アミノ酸学会学術大会講演要旨集  5th-  71  2011/11/04  [Not refereed][Not invited]
  
• Calcium‐sensing receptorアゴニストによる血糖上昇抑制とその作用機構の解明

  比良徹, 村松茉耶, 江藤譲, 原博  肥満研究  17-  (Supplement)  190  2011/09/01  [Not refereed][Not invited]
  
• Soybean beta-Conglycinin Bromelain Hydrolysate Stimulates Cholecystokinin Secretion by Enteroendocrine STC-1 Cells to Suppress the Appetite of Rats under Meal-Feeding Conditions

  Md. Kaosar Niaz Bin Sufian, Tohru Hira, Toshihiro Nakamori, Hitoshi Furuta, Kozo Asano, Hiroshi Hara  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY  75-  (5)  848  -853  2011/05  [Not refereed][Not invited]
   

  A peptic digest of soybean beta-conglycinin (BconP) suppresses the appetite in rats through cholecystokinin (CCK) secretion by enteroendocrine cells. We investigate in this study more appetite-suppressing hydrolysates. beta-Conglycinin hydrolyzed with food-processing proteases thermolysin (BconT), bromelain (BconB), chymotrypsin, protease S, and protease M was examined for CCK-secreting activity in a CCK-producing cell line for comparison with BconP. The potent CCK-releasing hydrolysates were then tested for their suppression of the food intake by rats. BconB, BconT, and BconP stimulated high CCK secretion, with the highest by BconB. Orogastric preloading by BconB, but not by BconT, suppressed the 60-min food intake. A meal-feeding trial twice a day in the morning (a.m.) and evening (p.m.) for 10 d showed that BconB preloading before every meal attenuated the p.m. meal size, but not that a.m., resulting in an overall reduction of the daily meal size. These results demonstrate that the bromelain hydrolysate of beta-conglycinin having potent CCK-releasing activity suppressed the appetite of rats under meal-feeding conditions.
• 生理活性ペプチド・機能性ペプチド—研究の最先端—消化管ホルモンを介して食欲をコントロールする食品由来ペプチド

  原博, 中島進吾, 比良徹  臨床化学  40-  (2)  119-126  -126  2011/04/28  [Not refereed][Not invited]
  
• トウモロコシZein加水分解物はラットへの経口投与によりインクレチン分泌を介して血糖上昇を抑制する

  樋口謹行, 比良徹, 比良徹, 原博, 原博  日本栄養・食糧学会大会講演要旨集  65th-  221  2011/04/25  [Not refereed][Not invited]
  
• 甘藷若葉「すいおう」の糖尿病抑制作用の検討

  史文磊, 待井沙織, 中村早岐, 永峰里花, 鍔田仁人, 高垣欣也, 比良徹, 原博, 津田孝範  日本栄養・食糧学会大会講演要旨集  65th-  195  2011/04/25  [Not refereed][Not invited]
  
• Calcium‐sensing receptorはCCK産生細胞における食品ペプチド受容体として多様なペプチドを認識する

  中島進吾, 比良徹, エムディーカオサルニァビン スフィアン, 江藤譲, 原博  日本栄養・食糧学会大会講演要旨集  65th-  193  2011/04/25  [Not refereed][Not invited]
  
• ビール酵母抽出物中のCCK分泌促進ペプチドの探索とラットでの食欲抑制作用

  須田和希, 比良徹, KAOSAR Sufian, 原博  日本栄養・食糧学会大会講演要旨集  65th-  189  2011/04/25  [Not refereed][Not invited]
  
• 甘藷若葉「すいおう」は耐糖能を改善する

  史文磊, 待井沙織, 中村早岐, 永峰里花, 鍔田仁人, 高垣欣也, 比良徹, 原博, 津田孝範  日本農芸化学会大会講演要旨集  2011-  289  2011/03/05  [Not refereed][Not invited]
  
• ラットにおけるトウモロコシZein加水分解物によるGLP‐1分泌を介した血糖上昇抑制

  比良徹, 持田泰佑, 原博  アミノ酸研究  4-  (2)  163-166  -166  2011/02  [Not refereed][Not invited]
  
• ラットにおけるCalcium‐sensing receptorアゴニストによる血糖上昇抑制作用とその作用機構

  村松茉耶, 比良徹, 江藤譲, 原博  アミノ酸研究  4-  (2)  198-199  -199  2011/02  [Not refereed][Not invited]
  
• インクレチン分泌を刺激する食品ペプチド,アミノ酸 消化管内分泌細胞による栄養素認識,Nutrient‐sensingの解明と応用に期待

  比良徹  化学と生物  49-  (1)  11  -13  2011/01/01  [Not refereed][Not invited]
  
• Effect of a hydrolysate prepared from soy protein high molecular weight fraction on GLP-1 secretion and glycemia in rats

  比良 徹, 村松 茉耶, 原 博  Soy protein research,Japan  13-  (31)  70  -74  2010/12  [Not refereed][Not invited]
  
• Effect of a Hydrolysate Prepared from Soy Protein High Molecular Weight Fraction on GLP-1 Secretion and Glycemia in Rats

  HIRA TOORU, MURAMATSU MAYA, HARA HIROSHI  大豆たん白質研究  13-  70-74  -74  2010/12  [Not refereed][Not invited]
  
• Corn protein hydrolysate stimulates GLP-1 secretion and attenuates hyperglycaemia in rats

  T. Hira, T. Mochida, H. Hara  REGULATORY PEPTIDES  164-  (1)  43  -43  2010/09  [Not refereed][Not invited]
  
• Calcium-sensing receptor is a sensor for dietary peptides to stimulate cholecystokinin secretion in the enteroendocrine cell line STC-1

  S. Nakajima, T. Hira, M. K. N. B. Sufian, Y. Eto, H. Hara  REGULATORY PEPTIDES  164-  (1)  45  -45  2010/09  [Not refereed][Not invited]
  
• 食欲抑制作用を有するジャガイモ抽出物(ポテイン)は消化管ホルモン分泌を強く刺激する

  比良徹, 中島進吾, 鍔田仁人, 高垣欣也, 原博  肥満研究  16-  (Supplement)  170  2010/09/01  [Not refereed][Not invited]
  
• パラチノースによるGLP‐1分泌促進機構の解析

  比良徹, 村松茉耶, 奥野雅浩, 原博  肥満研究  16-  (Supplement)  171  2010/09/01  [Not refereed][Not invited]
  
• ポテト抽出物(ポテイン)の満腹感持続作用—朝食併用時の昼食量へ及ぼす影響—

  神谷智康, 松田朋子, 真島明日香, 草場宣廷, 池口主弥, 高垣欣也, 比良徹, 原博  肥満研究  16-  (Supplement)  170  2010/09/01  [Not refereed][Not invited]
  
• プロタミンはラット腸管においてGLP‐1分泌を刺激し血糖上昇を抑制する

  村松茉耶, 比良徹, 江藤譲, 原博  日本栄養・食糧学会大会講演要旨集  64th-  188  2010/05/01  [Not refereed][Not invited]
  
• ポテインの食欲へ及ぼす効果(1)ヒト長期摂取による抗肥満作用の検証

  真島明日香, 松田朋子, 草場宣廷, 神谷智康, 池口主弥, 高垣欣也, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  64th-  141  2010/05/01  [Not refereed][Not invited]
  
• CCK産生細胞においてCalcium‐sensing receptorはペプトン受容体として機能する

  中島進吾, 比良徹, SUFAN Kaosar, 江藤譲, 原博  日本栄養・食糧学会大会講演要旨集  64th-  210  2010/05/01  [Not refereed][Not invited]
  
• ポテインの食欲へ及ぼす効果(2)健常成人での単回摂取による空腹感緩和作用の検証

  松田朋子, 真島明日香, 草場宣廷, 神谷智康, 池口主弥, 高垣欣也, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  64th-  141  2010/05/01  [Not refereed][Not invited]
  
• Identification of Peptides Derived from Azuki Bean (Vigna angularis) which Stimulate Cholecystokinin Secretion from the Enteroendocrine STC-1 Cells

  Md Kaosar Niaz Bin Sufian, Tohru Hira, Hiroshi Hara  FASEB JOURNAL  24-  2010/04  [Not refereed][Not invited]
  
• ポテインはCCK分泌作用を有し,経口投与によりラットの食欲を抑制する

  中島進吾, 比良徹, 永峰里花, 高垣欣也, 原博  日本農芸化学会大会講演要旨集  2010-  49  2010/03/05  [Not refereed][Not invited]
  
• ポテインの単回および繰り返し摂取による,摂餌量と体重増加抑制作用

  永峰里花, 鮫島まゆ, 池口主弥, 高垣欣也, 比良徹, 原博  日本農芸化学会大会講演要旨集  2010-  49  2010/03/05  [Not refereed][Not invited]
  
• Zein hydrolysate stimulates GLP-1 secretion and attenuates hyperglycemia in rats

  比良 徹, 持田 泰佑, 原 博  Amino acid research  4-  (2)  163  -166  2010  [Not refereed][Not invited]
  
• ポテインの食欲へ及ぼす効果(2)満腹感持続作用

  真島明日香, 草場宣廷, 神谷智康, 池口主弥, 高垣欣也, 比良徹, 原博  肥満研究  15-  (Supplement)  236  2009/09/17  [Not refereed][Not invited]
  
• ポテインの食欲へ及ぼす効果(1)食事量抑制作用

  鍔田仁人, 杉山大二朗, 鮫島まゆ, 永峰里花, 草場宣廷, 真島明日香, 神谷智康, 池口主弥, 高垣欣也, 比良徹, 原博  肥満研究  15-  (Supplement)  237  2009/09/17  [Not refereed][Not invited]
  
• トウモロコシZein加水分解物による消化管ホルモンGlucagon‐like peptide‐1分泌機構の解明

  比良徹  飯島記念食品科学振興財団年報  2007-  140-144  -144  2009/08  [Not refereed][Not invited]
  
• トウモロコシZein加水分解物はラット腸管においてGLP‐1分泌を刺激して血糖上昇を抑制する

  持田泰佑, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  63rd-  135  2009/05/01  [Not refereed][Not invited]
  
• 「機能性食品の研究」(第21回)ペプチド栄養学の新展開

  原博, 比良徹  Monthlyフードリサーチ  (647)  62-66  -66  2009/05/01  [Not refereed][Not invited]
  
• 消化管内分泌細胞株におけるトウモロコシZein加水分解物による消化管ホルモンGlucagon‐like peptide‐1分泌機構

  川村侑輝, 比良徹, 原博  日本農芸化学会大会講演要旨集  2009-  208  2009/03/05  [Not refereed][Not invited]
  
• SHORT CHAIN FATTY ACIDS INDUCE GLP-1 SECRETION IN ENTEROENDOCRINE GLUTAG CELLS

  Tohru Hira, Hiroshi Hara  JOURNAL OF PHYSIOLOGICAL SCIENCES  59-  389  -389  2009  [Not refereed][Not invited]
  
• マウス甘味・うま味受容体T1R3遺伝子の転写調節領域の解析

  豊野孝, 瀬田祐司, 片岡真司, 小田昌史, 比良徹, 豊島邦昭  日本分子生物学会年会講演要旨集  32nd-  (Vol.4)  89  2009  [Not refereed][Not invited]
  
• 膵腺房細胞タンパク質翻訳開始の制御におけるロイシンとコレシストキニンの相互作用

  瀬戸菜実子, 鈴木卓弥, 比良徹, 原博  アミノ酸研究  2-  (2)  166  2009/01  [Not refereed][Not invited]
  
• 組換え大腸菌による大豆由来生理活性ペプチドの大量生産系構築

  加藤里佳, 白鳥優子, 曾根輝雄, 比良徹, 原博, 浅野行蔵  日本生物工学会大会講演要旨集  60th-  117  2008/07/11  [Not refereed][Not invited]
  
• 大豆由来β51‐63ペプチドはCalcium‐sensing receptorを介してSTC‐1細胞のCholecystokinin分泌を刺激する

  中島進吾, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  62nd-  192  2008/04/01  [Not refereed][Not invited]
  
• トウモロコシZein加水分解物は,ラット腸管で内分泌細胞への直接的,間接的作用によりGlucagon‐like peptide‐1分泌を刺激する

  持田泰佑, 比良徹, 原博  日本農芸化学会大会講演要旨集  2008-  288  2008/03/05  [Not refereed][Not invited]
  
• フェニルアラニンは,Calcium‐sensing receptorを介してSTC‐1細胞からのCholecystokinin分泌を刺激する

  比良徹, 原博  アミノ酸研究  1-  (1)  51-52  -52  2008/03  [Not refereed][Not invited]
  
• 1Dp18 Production of soybean bioactive peptides by recombinant E. coli.

  KATO Rika, SHIRATORI Yuko, SONE Teruo, HIRA Tohru, HARA Hiroshi, ASANO Kozo  日本生物工学会大会講演要旨集  20-  (0)  117  -117  2008  [Not refereed][Not invited]
  
• 野生エゾヒグマの腸管における免疫グロブリンA(IgA)産生細胞の組織分布

  園山慶, 武村直紀, 比良徹, 釣賀一二三, 間野勉  日本農芸化学会北海道支部・日本土壌肥料学会北海道支部・日本生物工学会北日本支部・日本応用糖質科学会北海道支部・北海道農芸化学協会合同学術講演会講演要旨  2008-  18  2008  [Not refereed][Not invited]
  
• 消化管内分泌細胞株STC‐1において大豆β51‐63ペプチドはCalcium‐sensing receptorを介してCholecystokinin分泌を刺激する

  中島進吾, 比良徹, 原博  生化学  4P-0352  2008  [Not refereed][Not invited]
  
• インスリン分泌を促進する消化管ホルモンGLP‐1の分泌を刺激する食品ペプチドの探索と,消化管における受容機構の解明

  比良徹  上原記念生命科学財団研究報告集(CD−ROM)  22-  ROMBUNNO.33  2008  [Not refereed][Not invited]
  
• 消化管内分泌細胞株GLUTagにおける,トウモロコシペプチドによる消化管ホルモンGlucagon‐like peptide‐1分泌機構

  川村侑輝, 比良徹, 原博  日本農芸化学会北海道支部・日本土壌肥料学会北海道支部・日本生物工学会北日本支部・日本応用糖質科学会北海道支部・北海道農芸化学協会合同学術講演会講演要旨  2008-  17  2008  [Not refereed][Not invited]
  
• フェニルアラニンによる消化管内分泌細胞でのCholecystokinin分泌誘導におけるCalcium‐sensing receptorの関与

  比良徹, 中島進吾, 原博  生化学  4P-0351  2008  [Not refereed][Not invited]
  
• 新規評価方法を用いたビールの開発

  三浦裕, 真島紘子, 小泉英樹, 志村雅子, 高山知香子, 西澤祐子, 伏木亨, 比良徹, 原博, 太田雄人  日本食品科学工学会大会講演集  54th-  53  2007/09/06  [Not refereed][Not invited]
  
• Cell signaling pathways for activation of enteroendocrine cells by food peptides: CCK producing cell line, STC-1

  比良 徹, 前川 敏宏, 原 博  Reports of the Research Committee of Essential Amino Acids(Japan)  0-  (178)  20  -27  2007/06  [Not refereed][Not invited]
  
• 消化管内分泌細胞における食品ペプチドの認識とその情報伝達

  比良徹, 前川敏宏, 原博  必須アミノ酸研究  (178)  20-27  -27  2007/06  [Not refereed][Not invited]
  
• α‐カゼインによるSTC‐1細胞からのコレシストキニン分泌にはGαsタンパクが関与する

  谷仲真太郎, 井浦和也, 比良徹, 原博  日本栄養・食糧学会大会講演要旨集  61st-  148  2007/04/20  [Not refereed][Not invited]
  
• トウモロコシzein加水分解物は,ラット腸管において消化管ホルモンGlucagon‐like peptide‐1分泌を刺激する

  比良徹, 宮下京子, 原博  日本農芸化学会大会講演要旨集  2007-  237  2007/03/05  [Not refereed][Not invited]
  
• Mechanism of corn zein hydrolysate-stimulated glucagon-like peptide-1 secretion in rat

  比良 徹  Annual report  2007-  (0)  140  -144  2007  [Not refereed][Not invited]
  
• ラット腸管においてトウモロコシZein加水分解物は,内分泌細胞への直接的,間接的作用により消化管ホルモンGlucagon‐like peptide‐1分泌を刺激する

  持田泰佑, 比良徹, 原博  日本農芸化学会北海道支部・日本土壌肥料学会北海道支部・日本生物工学会北日本支部・日本応用糖質科学会北海道支部・北海道農芸化学協会合同学術講演会講演要旨  2007-  24  2007  [Not refereed][Not invited]
  
• 消化管内分泌細胞株STC‐1におけるα_s‐カゼイン応答性コレシストキニン分泌機構の解析

  谷仲真太郎, 井浦和也, 比良徹, 原博  生化学  3P-0267  2007  [Not refereed][Not invited]
  
• Food peptides directly stimulate glucagon-like peptide-1 secretion in enteroendocrine L-cell without intracellular Ca signaling

  K. Miyashita, T. Hira, H. Hara  REGULATORY PEPTIDES  135-  (3)  144  -144  2006/08  [Not refereed][Not invited]
  
• Cholecystokinin-releasing peptide derived from soybean beta-conglycinin suppress appetite in human

  T. Hira, K. Sufian, H. Chiba, K. Asano, H. Hara  REGULATORY PEPTIDES  135-  (3)  129  -129  2006/08  [Not refereed][Not invited]
  
• Casein sensing mechanisms in the cholecystokinin-producing enteroendocrine cells

  T. Hira, K. Iura, H. Hara  REGULATORY PEPTIDES  135-  (3)  129  -129  2006/08  [Not refereed][Not invited]
  
• Pork peptone stimulates cholecystokinin secretion from enteroendocrine cells and suppresses appetite in rats

  M. K. N. B. Sufian, Tohru Hira, Kyoko Miyashita, Takashi Nishi, Kozo Asano, Hiroshi Hara  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY  70-  (8)  1869  -1874  2006/08  [Not refereed][Not invited]
   

  We found that soybean beta-conglycinin peptone (BconP) suppresses food intake through cholecystokinin (CCK) release from enteroendocrine cells in association with binding of the peptone to rat small intestinal brush border membrane (BBM). The aim of the present study was to find new appetite suppressing peptides. Peptones from chicken, pork, beef, beef liver, and egg white were examined for activities to bind with rat BBM, CCK-release from enteroendocrine cell line STC-1, and induce satiety in rats. Chicken and pork peptone (ChicklP and PorklP) bound to BBM with highest ability as evaluated with a surface plasmon biosensor. PorkP and ChickP released CCK in higher amounts than BconP from STC-1 cells dose-dependently, with highest stimulation by PorkP. An orogastric preload of PorkP but not ChickP, suppressed food intake similarly to BconP, dose-dependently. These results suggest that PorkP interacts directly with the small intestinal CCK cells to release CCK, and that it suppresses appetite in rats.
• 摂食調節ペプチド

  原博, 比良徹, 西隆司, 前川敏宏  日本栄養・食糧学会総会講演要旨集  60th-  19  2006/04/01  [Not refereed][Not invited]
  
• βコングリシニンペプトンはGαqタンパクを介してSTC‐1細胞からのコレシストキニン分泌を刺激する

  比良徹, 前川敏宏, 原博  日本栄養・食糧学会総会講演要旨集  60th-  299  2006/04/01  [Not refereed][Not invited]
  
• カゼインは,消化管内分泌細胞株STC‐1におけるカゼイン感受性を亢進させる

  比良徹, 原博  日本農芸化学会大会講演要旨集  2006-  278  2006/03/05  [Not refereed][Not invited]
  
• 大豆たん白質由来の摂食抑制ペプチド

  原博, 西隆司, 比良徹, 浅野行蔵, 中森俊宏  日本農芸化学会大会講演要旨集  2006-  SHI144  2006/03/05  [Not refereed][Not invited]
  
• 消化管ホルモンGlucagon‐like peptide‐1(GLP‐1)の分泌を刺激する食品ペプチドの探索および細胞内情報伝達経路の解析

  宮下京子, 比良徹, 原博  日本農芸化学会大会講演要旨集  2006-  275  2006/03/05  [Not refereed][Not invited]
  
• Mouse GPR40 heterologously expressed in Xenopus oocytes is activated by short-, medium-, and long-chain fatty acids

  G Stewart, T Hira, A Higgins, CP Smith, JT McLaughlin  AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY  290-  (3)  C785  -C792  2006/03  [Not refereed][Not invited]
   

  Several orphan G protein-coupled receptors, including GPR40, have recently been shown to be responsive to fatty acids. Although previous reports have suggested GPR40 detects medium-and long-chain fatty acids, it has been reported to be unresponsive to short chain fatty acids. In this study, we have heterologously expressed mouse GPR40 in Xenopus laevis oocytes and measured fatty acid-induced increases in intracellular Ca2+, via two electrode voltage clamp recordings of the endogenous Ca2+-activated chloride conductance. Exposure to 500 mu M linoleic acid (C18:2), a long-chain fatty acid, stimulated significant currents in mGPR40-injected oocytes (P < 0.01, ANOVA), but not in water-injected control oocytes (not significant, ANOVA). These currents were confirmed as Ca2+-activated chloride conductances because they were biphasic, sensitive to changes in external pH, and inhibited by DIDS. Similar currents were observed with medium-chain fatty acids, such as lauric acid (C12:0) (P < 0.01, ANOVA), and more importantly, with short-chain fatty acids, such as butyric acid (C4:0) (P < 0.01, ANOVA). In contrast, no responses were observed in mGPR40-injected oocytes exposed to either acetic acid (C2:0) or propionic acid (C3:0). Therefore, GPR40 has the capacity to respond to fatty acids with chain lengths of four or greater. This finding has important implications for understanding the structure: function relationship of fatty acid sensors, and potentially for short-chain fatty acid sensing in the gastrointestinal tract.
• 大豆βコングリシニンペプチドは,ヒトの食欲を抑制する

  比良徹, SUFIAN Kaosar, 千葉仁志, 浅野行蔵, 原博  肥満研究  11-  (Supplement)  147  2005/09/20  [Not refereed][Not invited]
  
• CCK-secreting enteroendocrine cell lines express the novel fatty acid receptor, Gpr40

  G Stewart, T Hira, A Higgins, C Smith, J McLaughlin  GASTROENTEROLOGY  128-  (4)  A98  -A98  2005/04  [Not refereed][Not invited]
  
• グルタミン,アスパラギンはコレシストキニン産生細胞株STC‐1の細胞内カルシウムシグナルを活性化する

  比良徹, 原博  日本栄養・食糧学会総会講演要旨集  59th-  283  2005/04/01  [Not refereed][Not invited]
  
• 大豆β‐コングリシニンペプチドによる消化管からの飽食ホルモン分泌機構の探索

  前川敏宏, 比良徹, 原博  日本栄養・食糧学会総会講演要旨集  59th-  83  2005/04/01  [Not refereed][Not invited]
  
• カゼインはサブユニットにより異なったシグナル経路で小腸内分泌細胞からのコレシストキニン(CCK)放出を刺激する

  井浦和也, 比良徹, 原博  日本農芸化学会大会講演要旨集  2005-  303  2005/03/05  [Not refereed][Not invited]
  
• 大豆β-コングリシニン内在ペプチドの惹起する飽食促進機構の探索

  原 博, 前川 敏宏, 比良 徹  大豆たん白質研究  7-  (25)  108  -113  2004/10  [Not refereed][Not invited]
  
• Mechanism of Inducing Satiety Effects by Peptides Derived from Soybean .BETA.-Conglycinin

  HARA HIROSHI, MAEKAWA TOSHIHIRO, HIRA TOORU  大豆たん白質研究  7-  108-113  -113  2004/10  [Not refereed][Not invited]
  
• 大豆β‐conglycinin内在ペプチドによるコレシストキニン産生細胞のカルシウムシグナル応答

  前川敏宏, 比良徹, 原博  日本栄養・食糧学会総会講演要旨集  58th-  278  2004/04/01  [Not refereed][Not invited]
  
• 消化管内分泌細胞STC‐1におけるα‐カゼイン認識機構の解析

  比良徹, 原博  日本農芸化学会大会講演要旨集  2004-  191  2004/03/05  [Not refereed][Not invited]
  
• Novel acid fatty acid sensing mechanisms operate in enteroendocrine cells: Calcium release from intracellular stores by cytosolic fatty acid

  Hira Tohru, Elliott Austin C., Thompson David G., Case R. Maynard, McLaughlin John T.  Proceedings of Annual Meeting of the Physiological Society of Japan  2004-  (0)  S116  -S116  2004  

  Fatty acids (FA) with at least 12 carbon atoms increase intracellular Ca²⁺ ([Ca²⁺]_i) to stimulate cholecystokinin (CCK) release from enteroendocrine cells (EEC). Using the murine EEC line STC-1, we investigated whether candidate intracellular pathways transduce the FA signal, or whether FA themselves act within the cell to release Ca²⁺ directly from the intracellular store. In STC-1 cells loaded with fura-2, short (3 minutes) exposure of C12 fatty acid, but not C8 or C10, induced a dose-dependent increase in [Ca²⁺]_i, in the presence or absence of extracellular Ca²⁺. Various signaling inhibitors, including IP₃ receptor antagonists, all failed to block FA-induced Ca²⁺ responses. In permeabilized STC-1 cells loaded with the lower affinity Ca²⁺ dye magfura-2, and permeabilized by Streptolysin O, again C12 but not C8 or C10, induced release of stored Ca²⁺ dose dependently. However, 30 minutes exposure to C12 induced a sustained elevation of [Ca²⁺]_i in the presence of extracellular Ca²⁺, but only a transient response in the absence of extracellular Ca²⁺. These results suggest that at least two FA sensing mechanisms operate in enteroendocrine cells: intracellularly, FA (C12) transiently induces Ca²⁺ release from intracellular Ca²⁺ stores. However, they also induce sustained Ca²⁺ entry from the extracellular medium to maintain an elevated [Ca²⁺]_i. [Jpn J Physiol 54 Suppl:S116 (2004)]
• Fatty acids act directly on intracellular calcium stores to release calcium in the enteroendocrine cell line, STC-1

  T Hira, RM Case, DG Thompson, JT McLaughlin  GUT  52-  A54  -A54  2003/04  [Not refereed][Not invited]
  
• DIETARY PROTEIN INCREASES INTRACELLULAR CALCIUM CONCENTRATION IN CHOLECYSTOKININ PRODUCING ENTEROENDOCRINE CELL LINE STC-1-CORRELATION WITH BINDINGS BETWEEN DIETARY PROTEIN AND STC-1 CELL MEMBRANE

  HIRA Tohru, HARA Hiroshi, TOMITA Fusao, AOYAMA Yoritaka  消化と吸収  24-  (1)  24  -28  2001/12/30  [Not refereed][Not invited]
  
• Dietary protein increases intracellular calcium concentration in cholecystokinin producing enteroendocrine cell line STC-1. Correlation with bindings between dietary protein and STC-1 cell membrane.

  HIRA TOORU, HARA HIROSHI, TOMITA FUSAO, AOYAMA YORITAKA  消化と吸収  24-  (1)  24-28  -28  2001/12/30  [Not refereed][Not invited]
  
• Dietary protein peptic hydrolysates stimulate cholecystokinin release via direct sensing by rat intestinal mucosal cells

  T Nishi, H Hara, T Hira, F Tomita  EXPERIMENTAL BIOLOGY AND MEDICINE  226-  (11)  1031  -1036  2001/12  [Not refereed][Not invited]
   

  We previously demonstrated that a peptic hydrolysate of guanidinated casein strongly stimulates exocrine pancreatic secretion in chronic bile-pancreatic juice-diverted rats and cholecystokinin (CCK) release from dispersed rat intestinal mucosal cells. These results reveal that the chemically modified protein hydrolysate stimulates CCK secretion and Increases pancreatic secretion by a luminal trypsin-independent direct action on the small intestine. In the present study, we examined the direct effect of peptic hydrolysates of naturally occurring dietary proteins, casein, soybean protein isolate (SPI), egg white, and wheat gluten on CCK release under in vitro trypsin-independent conditions. All protein hydrolysates significantly stimulated CCK release from dispersed rat intestinal mucosal cells. Among the hydrolysates treated, SPI hydrolysate was the most effective In stimulating CCK release. The potential of SPI hydrolysate to stimulate CCK release was increased by long-term peptic digestion. However, an SPI-like amino acid mixture did not effect CCK release. In conclusion, peptic hydrolysates of commonly ingested dietary proteins stimulate CCK release via trypsin-independent direct sensing by Intestinal mucosal cells.
• 食品タンパク質は消化管内分泌細胞株STC‐1のカルシウムシグナルを惹起する 細胞膜成分と食品タンパク質結合との相関

  比良徹, 原博, 冨田房男, 青山頼孝  日本消化吸収学会総会プログラム・講演抄録集  32nd-  102  2001/10/17  [Not refereed][Not invited]
  
• ラット小腸刷子縁膜中のカゼイン結合成分の解析 消化管における食品タンパク質受容機構について

  比良徹, 原博, 青山頼孝, 冨田房男  日本農芸化学会誌  75-  78  2001/03/05  [Not refereed][Not invited]
  
• 栄養素に対する消化管ホルモンコレシストキニン産生細胞の適応

  比良徹, 麻田知恵子, 原博, 青山頼孝, 冨田房男  日本栄養・食糧学会総会講演要旨集  54th-  146  2000/04/01  [Not refereed][Not invited]
  
• Protein stimulating excocrine pancreas promotes CCK emission in STC-1, gut endocrine cell stock.

  HIRA TOORU, HARA HIROSHI, AOYAMA YORITAKA  日本栄養・食糧学会総会講演要旨集  53rd-  87  1999/04/20  [Not refereed][Not invited]
  
• Effects of DFA IV in rats: Calcium absorption and metabolism of DFA IV by intestinal microorganisms

  K Saito, T Hira, T Suzuki, H Hara, A Yokota, F Tomita  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY  63-  (4)  655  -661  1999/04  [Not refereed][Not invited]
   

  Di-n-fructose-2,6':6,2'-dianhydride (DFA IV) is a disaccharide consisting of two fructose residues that can be prepared from levan by levan fructotransferase from Arthrobacter nicotinovorans GS-9, and it can be expected to have novel physiological functions from its unique structure. In this study, the effects of DFA IV on calcium absorption and the metabolism of DFA IV by intestinal microorganisms were studied in rats to examine the physiological functions of DFA IV. The apparent calcium absorption in rats fed with DFA IV was significantly higher than that in the control rats, and it seems that calcium absorption had almost been completed at the end of the small intestine. DFA IV also increased the calcium absorption in in vitro experiments, using everted jejunal and ileal sacs, and this result supports the finding obtained in the in vivo experiments. These results indicate that DFA IV may have a function for increasing the calcium absorption in the small intestine of rats. However, the effect in the large intestine could not be clearly observed because of the lack of calcium that reached there. The results of analyses of organic acids in the cecal and colonic contents and of DFA IV in the fecal, cecal, and colonic contents showed that the metabolism of DFA IV by microorganisms in the large intestine progressed gradually, and that DFA IV was converted mainly to acetate, butyrate, and lactate.
• Extramedullary succagogue action by casein does no depend on trypsin inhibitive capacity in intestinum tenue in a rat.

  HIRA TOORU, HARA HIROSHI, AOYAMA YORITAKA  日本栄養・食糧学会総会講演要旨集  52nd-  57  1998/03  [Not refereed][Not invited]
  
• 大豆タンパクトリプシンインヒビターはFOY305より強力な胆膵液非依存性膵外分泌亢進作用を持つ : 動物

  比良 徹, 原 博, 葛西 隆則  日本農藝化學會誌  70-  (0)  30  -30  1996/03/05  [Not refereed][Not invited]
  
• 合成トリプシンインヒビターは長期胆膵液空腸バイパスラットの膵外分泌を亢進するか? : 動物

  比良 徹, 原 博, 葛西 隆則  日本農藝化學會誌  69-  (0)  346  -346  1995/07/05  [Not refereed][Not invited]
  

Books etc

• ペプチドの生体調節機能と応用

  比良 徹, 分担執筆, 松井利郎, 監修 (第14章 消化管ホルモン調節ペプチド)
  シーエムシー出版 2024/07 (ISBN: 9784781318097) viii, 253p
• 食品免疫学事典

  比良 徹 (Contributor９章(9-13) 消化管内分泌系を介した作用)
  朝倉書店 2021/11
• 食品免疫学事典

  比良 徹, 原 博 (Contributor２章(2-14) 消化管ホルモン)
  朝倉書店 2021/11
• エッセンシャル栄養化学 (KS農学専門書)

  比良 徹 (Contributor第３章 体内での栄養素の動態：消化・吸収・分布・代謝・排泄)
  講談社 2021/08 (ISBN: 4065238064) 320
• 腸内細菌-宿主のクロストークとこれを修飾する食事要因

  比良 徹, 原 博 (Contributor難消化性糖質の消化管内分泌系への作用)
  建帛社 2019/05
• 機能性食品開発のための初期評価試験プロトコール集

  比良 徹, 原 博 (Contributorラットを用いた食欲抑制試験、GLUTag 細胞を用いた GLP-1 分泌試験、STC-1 細胞を用いた CCK 分泌試験)
  シーエムシー出版 2017/10
• The Calcium-sensing Receptor in Intestinal Cells / Calcium : Chemistry, Analysis, Function and Effects / Food and Nutritional Components in Focus

  Hira T., Nakajima S., Hara H. (Contributor396-412)
  The Royal Society of Chemistry 2015/10
• 機能性タンパク質・ペプチドと生体利用

  原 博, 比良 徹 (Contributor消化管内分泌系を介して作用する機能性ペプチド)
  建帛社 2010/05
• 腸管細胞機能実験法

  原 博, 西 隆司, 比良 徹 (Contributor上皮細胞機能の実験法 コレシストキンン産生細胞株STC-1における細胞内カルシウム濃度変化の測定)
  学会出版センター 2005/10 274 88-96

Presentations

• 動物実験の新しい展開 食事誘導性肥満モデル、血管カニュレーションモデルを用いた、消化管ホルモンGLP-1の分泌調節に関する研究  [Invited]

  比良 徹

  第78回日本栄養・食糧学会大会  2024/05
• GLP-1産生消化管内分泌細胞が認識するペプチド構造  [Invited]

  比良 徹

  日本農芸化学会2023年度大会  2024/03
• 希少糖D-アルロースによるGLP-1分泌促進機構  [Invited]

  比良 徹

  第14回日本安定同位体・生体ガス医学応用学会大会  2023/12
• 食品成分による消化管ホルモン分泌の調節  [Invited]

  比良 徹

  第111回日本栄養・食糧学会関東支部シンポジウム  2023/10
• 食品タンパク質・ペプチドによる GLP-1 分泌促進とそれによる血糖上昇抑制、 体温上昇作用

  比良 徹

  第77回日本栄養・食糧学会大会  2023/05
• 食品成分による消化管ホルモンの分泌

  比良 徹

  第3回 ファーマラボ EXPO 大阪  2023/03
• 食におけるタンパク質の重要性について  [Invited]

  比良 徹

  令和４年度地域バイオ育成講座講演会  2023/01
• Adaptive changes in nutrient-induced GLP-1 secretion in diet-induced obese model rats

  Tohru Hira

  22nd IUNS-ICN International Congress of Nutritio  2022/12
• 食品ペプチドによるGLP-1分泌促進と分解抑制  [Invited]

  比良 徹

  日本アミノ酸学会第９回夏のシンポジウム  2022/08
• 消化管内分泌系への作用を介する糖代謝改善ペプチド  [Invited]

  比良 徹

  日本農芸化学会2021年度大会  2021/03
• trans,trans-2,4-Decadienal stimulates cholecystokinin secretion in enteroendocrine cells, and suppresses gastric emptying in rats  [Invited]

  Tohru Hira

  International symposium on lipids and food ingredients for health promotion  2021/03
• 難消化性糖質の消化管内分泌系への作用  [Invited]

  比良 徹

  日本食物繊維学会第24回学術集会  2019/11
• " 食品成分による消化管内分泌系のコントロール 主にGLP-1に関して"  [Invited]

  比良 徹

  第98回北海道医学大会生理系分科会・日本生理学会北海道地方会  2018/10
• 難消化性糖質の消化管内分泌系への作用  [Invited]

  比良 徹, 原 博

  第72回日本栄養・食糧学会大会 共催：Hindgut Club Japan  2018/05
• GLP-1を増やす食品成分、食事条件  [Not invited]

  比良 徹

  平成２９年度 公益社団法人日本農芸化学会 北海道支部第２回講演会および公益社団法人日本栄養・食糧学会 第47回北海道支部大会合同大会  2017/12
• 消化管に働きかけて血糖上昇を抑制する食品ペプチド  [Invited]

  比良 徹

  第３回食科学プラットフォームセミナー  2017/07
• 食品成分による消化管ホルモン分泌調節  [Invited]

  比良 徹

  第18回日本神経消化器病学会、第6回IBS研究会、第84回消化器心身医学研究会、第10回機能性ディスペプシア研究会 合同学術集会2016  2016/09
• 米ペプチドによる消化管ホルモン分泌を介した血糖上昇抑制作用  [Invited]

  比良徹, 原博

  第７０回日本栄養・食糧学会大会  2016/05
• 難消化性デキストリンのチカラ－消化管ホルモンを介した新たな機能－  [Invited]

  HIRA Tohru

  第70回日本栄養・食糧学会大会 ランチョンセミナー  2016/05
• trans,trans-2,4-デカジエナールの胃排出抑制機構  [Invited]

  比良 徹

  Hindgut Club Japanサテライトシンポジウム  2016/05
• 血糖調節ペプチド  [Invited]

  比良 徹

  日本農芸化学会2015年度大会  2016/03
• 食品成分による消化管ホルモン分泌の制御と作用機構  [Invited]

  比良 徹

  第93回日本生理学会大会  2016/03
• 食事誘導性肥満の発症過程におけるGLP-1分泌応答〜ラットでの食事負荷試験による解析  [Invited]

  比良 徹

  第21回Hindgut club Japanシンポジウム  2015/12
• 食事誘導性肥満モデルラットにおける食後GLP-1分泌応答  [Invited]

  比良 徹

  第２７回夏期油脂・コレステロール研究会  2015/07
• 食品ペプチドによる消化管内分泌系への作用を介した血糖調節  [Invited]

  比良 徹

  北大リサーチ＆ビジネスパークセミナー おいしくてヘルシーな北海道！ ～新たなフードサイエンスとビジネス環境へ～  2014/11
• Effects of resistant maltodextrin and fructooligosaccharides on fasting GLP-1 levels and glucose tolerance in rats  [Not invited]

  Tohru Hira

  10th Vahouny Dietary Fiber Symposium  2014/03
• 食品ペプチドの消化管での作用を介した血糖制御に関する研究  [Invited]

  比良徹

  2013年度日本アミノ酸学会 科学・技術賞受賞講演  2013/11
• 食品ペプチドによるGLP-1分泌を介した血糖上昇抑制  [Invited]

  比良 徹

  2013年度 生理学研究所研究会 上皮膜輸送の多層的コントロールによる生体の恒常性維持機構  2013/08
• 消化管内分泌系調節ペプチド  [Not invited]

  原博, 比良徹

  第67回日本栄養・食糧学会大会S10-03「ペプチドが拓く健康科学の新しい世界」  2013/05

Teaching Experience

Biology IBiology I Hokkaido University
Nutritional Biochemistry IINutritional Biochemistry II Hokkaido University

Association Memberships

• 日本農芸化学会   日本栄養・食糧学会   日本アミノ酸学会   日本糖尿病学会   日本肥満学会   日本食物繊維学会   

Research Projects

• GLP-1分泌促進と分解抑制の両作用を併せ持つペプチドの創生

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2024/06 -2026/03 

  Author : 比良 徹
• 食事誘導性肥満・耐糖能異常を防ぐ消化管内分泌系の適応機構

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  Date (from‐to) : 2022/04 -2025/03 

  Author : 比良 徹
• Mechanisms underlying enhanced GLP-1 response in diet-induced obesity

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

  Date (from‐to) : 2019/04 -2022/03 

  Author : 比良 徹

   

  消化管ホルモンGLP-1は、食事刺激により消化管内分泌細胞から分泌され、インスリン分泌増強や食欲抑制などをもたらす。これまでに、食事誘導性の肥満や耐糖能異常の発症過程で、食後GLP-1分泌が増大することを見出した。しかし、消化管および消化管内分泌細胞にどのような変化が生じているのかは不明であり、本研究課題は、これを詳細に解析し、その分子メカニズムを明らかにすることを目的とする。 はじめに、遺伝的糖尿病モデルラット（Goto-Kakizakiラット）と正常ラットそれぞれに、普通食または高脂肪高ショ糖食を長期間（６ヶ月）摂取させ、２または４週おきに食事負荷試験を実施した。食事負荷試験の際は、全ての群において経腸栄養剤を一定量経口投与した。糖尿病モデルラットと正常ラットともに、高脂肪高ショ糖食の長期摂取により耐糖能不全が生じたが、その程度は糖尿病モデルラットの方が顕著であった。食後GLP-1分泌は、正常ラットでは高脂肪高ショ糖食の持続摂取により増大し、その増大は実験終了時（６ヶ月後）まで維持された。一方で糖尿病モデルラットではそのような増大は見られなかった。このことから、正常なラットでは長期間の肥満誘導食の持続摂取でも食後GLP-1分泌応答は増大すること、そのような適応は遺伝的糖尿病モデルでは生じないことが明らかとなった。食事誘導性肥満におけるGLP-1分泌の増大は、耐糖能の悪化に対して防御的な適応と考えられ、このような適応機構の欠如が糖尿病へと進展する要因の一つであると考えられた。
• Study on postprandial nutrient and gut hormone responses in different intestinal regions

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

  Date (from‐to) : 2018/06 -2020/03 

  Author : Hara Hiroshi

   

  Changes in plasma nutrient (glucose) levels and gut hormone levels after meal, in different intestinal regions have not been well characterized. We established experimental rat model equipped with a catheter inserted into the ileal mesenteric vein, or the portal vein. After the oral administration of meal having different compositions, plasma glucose levels and gut hormone levels had different responses, dependent on the meal composition, and on the intestinal region of blood sampling. These results demonstrate that the rat model is available for investigating regional nutrient absorption and gut hormone secretion under a physiological condition.
• Study on physiological effects of isomalto-megalo-saccharides

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

  Date (from‐to) : 2017/04 -2020/03 

  Author : Hara Hiroshi

   

  Isomalto-megalo-saccharides are novel saccharides having unique structures. Various health promotive functions are expected due to their specific interactions with food components and with target cells in the gastrointestinal tract. In an intestinal epithelial cell model (Caco2), isomalto-megalo-saccharides prevented impairment of gut barrier function by lipid oxidation products.In animal studies using rats, isomalto-megalo-saccharides enhanced intestinal absorption of quercetin. Furthermore, the combination of isomalto-megalo-saccharides and quercetin potently stimulated secretion of a gastrointestinal hormone, GLP-1. These results demonstrate beneficial effects of isomalto-megalo-saccharides, as a functional food factor.
• Regulation of gut nutrient sensing mechanisms in response to dietary intervention

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

  Date (from‐to) : 2016/04 -2019/03 

  Author : Hira Tohru

   

  We have previously demonstrated that continuous feeding of a high fat and high sucrose diet enhanced nutrient-induced GLP-1 secretion in rats. In this research project, we revealed that the high fat diet, rather than the high sucrose diet, has potent impact on enhancement of nutrient-induced GLP-1 secretion. In addition, the adaptive changes in nutrient-induced GLP-1 secretion was rapidly occurred in young rats than adult rats. Furthermore, by conducting continuous administration of GLP-1 receptor antagonist, we found that the increased GLP-1 response has a role to prevent from glucose intolerance during the development of diet-induced obesity.
• Study on sensing mechanism of low-digestible saccharides in nutrient-sensing enteroendocrine cells

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

  Date (from‐to) : 2016/04 -2018/03 

  Author : Hara Hiroshi

   

  We examined the effects of indigestible saccharides including rare sugar D-allulose on a gut hormone GLP-1 secretion. Single oral administration of resistant maltodextrin (RMD) or D-allulose potently stimulated GLP-1 secretion in rats. D-allulose had larger and continuous stimulatory effect on GLP-1 secretion than RMD. The GLP-1-stimulating effect was observed by oral and luminal but not by intraperitoneal administration of D-allulose, indicating D-allulose exerted the effect in the intestinal lumen. These results demonstrate important role of enteroendocrine cell to sense indigestible saccharides in gut hormone secretions under a physiological condition.
• 食事条件に対する消化管栄養素感受性の適応機構の解明と制御

  文部科学省：基盤研究(C)

  Date (from‐to) : 2016/04 -2018/03 

  Author : 比良 徹
• Study on enteroendocrine, nervous and reproductive systems related to diet for preventing metabolic diseases.

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

  Date (from‐to) : 2014/04 -2017/03 

  Author : Hara Hiroshi

   

  In this project, we investigated gut hormone secretory responses to ‘meal’in the conscious animal model equipped with portal cannula. We have found that gut hormone responses (such as GLP-1, GIP,PYY, Ghrelin) are modified by changing the source of dietary proteins. Furthermore, the effect of dietary protein was modified by the source of carbohydrates in the meal. Feeding the diet supplemented with resistant maltodextrin which has GLP-1-releasing activity prevented excess energy intake induced by high fat high sucrose diet. Our results suggest that postprandial gut hormone responses can be desirably manipulated by changing the composition of a meal.
• Role of GLP-1 during the development of diet-induced obesity and glucose impairment

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

  Date (from‐to) : 2013/04 -2016/03 

  Author : HIRA Tohru

   

  It is unclear how postprandial GLP-1 secretory response is affected during the development of diet-induced obesity. Meal tolerance test (MTT) was conducted in rats fed normal or high-fat/high-sucrose (HF/HS) diet, and postprandial GLP-1, insulin and glycemic response were monitored. Postprandial GLP-1 secretion was larger in HF/HS rats than control rats at week 2 and 4, and this was reflected by increased insulin response in HF/HS rats. In the intestinal mucosa, among various nutrient sensing receptors and transporters evaluated, one of fatty acid receptors, FFAR1 had higher mRNA expression in the upper small intestine of HF/HS rats compared to that of control rats. These result demonstrates that postprandial GLP-1 secretion is increased in the early period of developing diet-induced obesity, and that increased postprandial GLP-1 response contributes to normalize postprandial glycemic response by enhancing insulin secretion.
• Elucidation of mechanisms to avoid chronic inflammation via enteroendocrine system: relationships between immune cells and adipocytes

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

  Date (from‐to) : 2012/04 -2015/03 

  Author : ISHIZUKA Satoshi, HIRA Tohru

   

  Diet-induced obesity induces chronic inflammation. At postplandial period, various external antigens other than dietary lipids get into lymph ducts and evoke immune responses. In this study, we evaluated factors in lymph ducts by using lymph-cannulated rats especially at a postplandial period. At several hours after administration of dietary lipids, there was a significant increase of interleukin-6(IL-6) and glucagon-like peptide-1 in the lymph. Gene expression analysis in food-deprived or fed rats indicated that an accumulation of IL-6 producing cells in the intestinal mucosa accompanied by lipid absorption.
• Enhancement of dietary peptide-induced GLP-1 secretion by indigestible saccharides

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

  Date (from‐to) : 2010/04 -2013/03 

  Author : HARA Hiroshi, HIRA Tohru

   

  GLP-1 is one of gastrointestinal hormones, and it has potent anti-obese and anti-diabetic effects. In the present project, we investigated whether indigestible peptides or indigestible saccharides are effective to increase GLP-1 secretion in a cell culture model and animal models. We also examined combined effects of indigestible saccharides and a dietary peptide. We demonstrated that oral administration of a dietary peptide (corn peptide) potently stimulated GLP-1 secretion and it resulted in reduced glycemic response in normal and diabetic rats. Luminal and oral administration of an indigestible saccharide (resistant maltodextrin, RMD) stimulated GLP-1 secretion in rats, and continuous ingestion of RMD also enhanced basal GLP-1 secretion. Furthermore, rats continuously having RMD showed increased GLP-1 secretory response to oral administration the corn peptide. These results revealed potential and combined effects of indigestible saccharides and dietary peptides in vivo.
• Searching for dietary protein/peptide sensing receptors in enteroendocrine cells

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

  Date (from‐to) : 2011 -2012 

  Author : HIRA Tohru

   

  We searched sensor molecules involved in dietary protein/peptide-sensing in enteroendocrine cells. By using enteroendocrine cell models, we found that a TRP channel was highly expressed in CCK-producing cell line. It was demonstrated that the TRP channel is involved in alpha-casein-induced CCK secretion. Furthermore, an aldehyde was found to induce CCK secretion through the TRP channel. Oral administration of the aldehyde reduced gastric emptying rate in rats, suggesting the aldehyde directly acts enteroendocrine cell and reduces gastric emptying in vivo. In separated experiments, we found that calcium-sensing receptor functions as sensor for various protein hydrolysates, rather than for specific peptides.
• Role of CaSR as dietary peptide sensor and search for dietary protein receptor in the gut

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

  Date (from‐to) : 2009 -2010 

  Author : HIRA Tohru

   

  In this research project, we have investigated the function of calcium-sensing receptor (CaSR) as the receptor for luminal dietary peptides in gastrointestinal endocrine cells. Secretions of a gut hormone CCK induced by various dietary peptides were partially inhibited by the presence of CaSR antagonists. CaSR-expressing kidney cells also responded to various dietary peptides. These results suggest that CaSR is one of the receptor for dietary peptides in the gastrointestinal tract.
• Development of anti-obese dietary peptides which functions via gut hormone secretion

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

  Date (from‐to) : 2007 -2009 

  Author : HARA Hiroshi, HIRA Tohru

   

  From various dietary peptides, we found that country bean peptide and beer yeast peptide have potent activity to stimulate a satiating gut hormone CCK in enteroeondcrine cell line. Oral preload of beer yeast peptide reduced following food consumption in rats. We also found that a hydrolysate prepared from corn protein Zein stimulates another gut hormone GLP-1. Ileal administration of Zein hydrolysate strongly induced GLP-1 secretion and subsequent insulin secretion in awake rats, which results in the improvement of glucose tolerance. These findings have revealed that dietary peptides are promising factor for prevention of overeating and hyperglycemia via stimulating gut hormone secretions.
• 食品タンパク質中の満腹感促進ペプチドの探索と消化管内分泌細胞におけるその受容機構

  日本学術振興会：科学研究費助成事業 若手研究(B)

  Date (from‐to) : 2005 -2006 

  Author : 比良 徹

   

  昨年度の研究において、フジ豆(ツル豆)より調製したペプトン(フジ豆ペプトン)に、食欲抑制作用を有する消化管ホルモンコレシストキニン(CCK)の分泌を強く刺激する活性があることを見いだした。このペプトンが由来するタンパクを明らかにするため、フジ豆たんぱくを等電点沈殿により分画し、各フラクションよりペプトンを調製して、CCK放出活性を調べたところ、等電点5にて沈殿する画分由来のペプトンに強い活性が見られた。この画分には分子量50kDa程のフジ豆の主要タンパクが多く含まれており、プロテインシークエンサーを使ったN末端アミノ酸配列の解析により、Phaseolin様のタンパクであった。Phaseolin由来のペプチドに強いCCK放出活性があることが示唆された。 これまでの研究においてCCK産生細胞株STC-1からのCCK放出を刺激することが明らかとなったα-カゼインをリガンドとして、アフィニティー樹脂を用い、CCK産生細胞株STC-1の膜可溶化成分より、種々のα-カゼイン結合タンパクを分離した。プロテインシークエンサーにより解読できた一部のタンパクのアミノ酸配列は、インテグリン、オーファンGPCRと相同性を持っていたことから、これらの分子がα-カゼイン受容体である可能性が考えられた。 また、STC-1細胞における細胞内情報伝達経路の解析により、この細胞のα-カゼイン認識において、Gαsタンパクが関与すること、ナトリウムチャネルを介した脱分極により細胞内カルシウムシグナルが惹起されることが明らかとなった。上記の受容体候補との関係を今後検討する。
• 消化管における未知の食品タンパク質受容体の検索

  日本学術振興会：科学研究費助成事業 特別研究員奨励費

  Date (from‐to) : 2000 -2002 

  Author : 比良 徹

   

  昨年度までにマウス小腸由来の内分泌細胞株STC・1において、カゼインが細胞内カルシウム濃度上昇を引き起こすことを見出した。そのカルシウムの供給源を検討するため、L型カルシウムチャネルブロッカーDiltiazemの影響を調べた。Diltiazemで前処理されたSTC・1細胞において、α・カゼインによる細胞内カルシウム濃度上昇は有意に抑制され、このことから消化管内分泌細胞はα-カゼインを認識して細胞外からカルシウムを導入していることが示唆された。 タンパク質上のグアニジル基が消化管で認識されることを示唆する結果をもとに、グアニジル基を有するアミノ酸であるホモアルギニンの投与に対する膵臓外分泌機能の応答を検討した。高コレシストキニン(CCK))血症のモデルとして使われる胆膵液除去ラットおよび正常ラットを外科手術により作製し、1週間の回復期間後にホモアルギニン溶液(10mg/rat)を投与し、投与前後の胆膵液を採取して膵酵素分泌を観察した。十二指腸へのホモアルギニン投与は両ラットに有意な変化を引き起こさなかったが、腹腔へのホモアルギニン投与により胆膵液除去ラットにおいてのみ、膵外分泌抑制作用が見られた。胆膵液除去ラットでのホモアルギニン長期投与の影響を調べるため、25%カゼイン、45%カゼイン、45%カゼイン+ホモアルギニン(19g/kg diet)を含む飼料を4日間与えたところ、45%カゼイン食により誘導された膵臓重量、膵酵素含量の増加は、ホモアルギニン添加により抑制された。胆膵液除去ラットにおける膵酵素の基礎分泌レベルの上昇および、高タンパク質食摂取による膵外分泌機能更新は血中CCK濃度上昇が関与すると考えられているので、ホモアルギニンは胆膵液除去および高タンパク質食により上昇したCCKの作用を血中で阻害する作用を持つこと、即ちCCKレセプターアンタゴニストとしての作用を持つことが示唆された。
• 消化管における栄養素認識機構
• Nutirent sensing mechanism in the gut

Industrial Property Rights

• 特許第6896247号:GLP-1分泌促進剤  

  矢田 俊彦, 岩崎 有作, 原 博, 比良 徹, 岸本 由香, 南 真知子  学校法人自治医科大学, 国立大学法人北海道大学, 松谷化学工業株式会社  202103004169059868
• WO2018-159546:GLP-1分泌促進剤及び組成物  2018/09/07

  比良 徹, 原 博, 小松 陽介, 和泉 裕久  森永乳業株式会社  202003005757708812
• 特開2018-039776:過剰エネルギー摂取抑制用組成物  2018/03/15

  比良 徹, 原 博, 名倉 泰三, 高橋 敬典, 奥原 康英, 石川 純嗣  国立大学法人北海道大学, 日本甜菜製糖株式会社, 株式会社ファンケル  201803007704700121
• 特許第6977945号:GLP-1分泌促進用組成物、及び該組成物の製造方法  

  比良 徹, 原 博, 藤井 幹夫  亀田製菓株式会社, 国立大学法人北海道大学  201703015130502607
• WO2017-018500:GLP-1分泌促進剤  2017/02/02

  矢田 俊彦, 岩崎 有作, 原 博, 比良 徹, 岸本 由香, 南 真知子  学校法人自治医科大学, 国立大学法人北海道大学, 松谷化学工業株式会社  201803003241411782
• 特許第6077331号:TRPA1活性化組成物  2017/01/20

  比良 徹, 原 博, 西山 千草, 山下 貴稔, 今義 潤  株式会社J-オイルミルズ  201703020704050983
• 特許第5951426号:コレシストキニン分泌促進組成物  2016/06/17

  原 博, 比良 徹, 西山 千草, 土倉 則子, 山下 貴稔, 今義 潤  株式会社J-オイルミルズ  201603003574652790
• 特開2015-231953:TRPA1活性化組成物  2015/12/24

  比良 徹, 原 博, 西山 千草, 山下 貴稔, 今義 潤  株式会社J-オイルミルズ, 国立大学法人北海道大学  201603008520388666
• 特開2015-178459:コレシストキニン分泌促進組成物  2015/10/08

  原 博, 比良 徹, 西山 千草, 土倉 則子, 山下 貴稔, 今義 潤  株式会社J-オイルミルズ, 国立大学法人北海道大学  201503012181907950
• 特許第5794678号:グルカゴン様ペプチド-1分泌促進剤  2015/08/21

  鍔田 仁人, 原 博, 比良 徹  株式会社東洋新薬, 国立大学法人北海道大学  201503019720031422
• 特許第5721232号:グルカゴン様ペプチド-1分泌促進剤  2015/04/03

  鍔田 仁人, 原 博, 比良 徹  株式会社東洋新薬, 国立大学法人北海道大学  201503090086819696
• 特許第5674047号:コレシストキニン分泌促進剤  2015/01/09

  鍔田 仁人, 原 博, 比良 徹  株式会社東洋新薬, 国立大学法人北海道大学  201503084512039326
• WO2014-041885:コレシストキニン分泌促進組成物  2014/03/20

  原 博, 比良 徹, 西山 千草, 土倉 則子, 山下 貴稔, 今義 潤  株式会社J-オイルミルズ  201603018851889814
• 特開2013-082658:経口投与により食欲を抑制する素材  2013/05/09

  原 博, 比良 徹, 池田 潔昭, 市原 敬司, 若村 香菜子  グリコハム株式会社, 国立大学法人北海道大学  201303078826848232
• 特開2012-224547:糖尿病又は肥満病の予防又は治療剤  2012/11/15

  原 博, 比良 徹, 江藤 譲, 安田 礼子  味の素株式会社, 国立大学法人北海道大学  201203001944681210
• 特許第4929455号:摂食抑制作用を有する豚肉由来ペプチドを含有する組成物  2012/02/24

  比良 徹, 原 博, 浅野 行蔵  国立大学法人北海道大学  201303023022744710
• 特開2012-020993:グルカゴン様ペプチド−1分泌促進剤  2012/02/02

  鍔田 仁人, 原 博, 比良 徹  株式会社東洋新薬, 国立大学法人北海道大学  201203018386818743
• 特開2011-182742:血中ジペプチジルペプチダーゼ−IV阻害活性およびグルカゴン様ペプチド−1の分泌促進活性を併せ持つ組成物  2011/09/22

  原 博, 比良 徹, 浅野 行蔵  浅野 行蔵  201103016347682524
• WO2011-068149:コレシストキニン分泌促進剤  2011/06/09

  鍔田 仁人, 原 博, 比良 徹  株式会社東洋新薬, 国立大学法人北海道大学  201303013576442141
• WO2011-068150:グルカゴン様ペプチド−1分泌促進剤  2011/06/09

  鍔田 仁人, 原 博, 比良 徹  株式会社東洋新薬, 国立大学法人北海道大学  201303098218118869
• WO2009-107660:糖尿病又は肥満病の予防又は治療剤  2009/09/03

  原 博, 比良 徹, 江藤 譲  味の素株式会社, 国立大学法人北海道大学  201103074012143866
• 特開2007-230978:摂食抑制作用を有する豚肉由来ペプチドを含有する組成物  2007/09/13

  比良 徹, 原 博, 浅野 行蔵  国立大学法人 北海道大学  200903032408045880
• WO2006-132273:摂食抑制作用を有するペプチドを含有する組成物  2006/12/14

  比良 徹, 廣塚 元彦, 中森 俊宏, 原 博, 浅野 行蔵, 千葉 仁志, 冨田 房男  有限会社A−HITBio, 国立大学法人 北海道大学, 不二製油株式会社  200903047179049769