研究者情報

マスター

アカウント（マスター）

• 氏名

  比良　徹(ヒラ　トオル), ヒラ　トオル

所属（マスター）

• 農学研究院　基盤研究部門　生物機能化学分野

所属（マスター）

• 農学研究院　基盤研究部門　生物機能化学分野

独自項目

syllabus

• 2021, 大学院共通授業科目（一般科目）：自然科学・応用科学, Inter-Graduate School Classes(General Subject):Natural and Applied Sciences, 修士課程, 大学院共通科目, 食品、消化管、食品機能、腸内細菌叢、生理活性
• 2021, 食品科学特論, Advanced Review of Food Science, 修士課程, 農学院, 食品、消化管、食品機能、腸内細菌叢、生理活性
• 2021, 食品科学特論演習, Advanced Seminar on Food Science, 修士課程, 農学院, 食品、消化管、食品機能、腸内細菌叢、生理活性
• 2021, 一般教育演習(ﾌﾚｯｼｭﾏﾝｾﾐﾅｰ), Freshman Seminar, 学士課程, 全学教育, 食料、安全、作物生産、放射能汚染、食品微生物、酵素利用技術、毒物、ガン、アレルギー、メタボリックシンドローム、腸内細菌叢、保健機能食品
• 2021, 栄養化学Ⅱ, Nutritional Biochemistry II, 学士課程, 農学部
• 2021, 生物機能化学実験Ⅳ, Laboratry Work on Bioscience and Chemistry IV, 学士課程, 農学部, 実験動物、食品、消化、吸収、生理作用

researchmap

プロフィール情報

学位

• 博士（農学）（北海道大学）

プロフィール情報

• 姓

  比良, ヒラ

• 名

  徹, トオル

• ID各種

  200901025842820520

業績リスト

研究キーワード

• 消化管内分泌細胞   消化管ホルモン   栄養生理学   消化管生理学   Nutritional physiology   

研究分野

• ライフサイエンス / 食品科学 / 栄養生理学
• ライフサイエンス / 生理学

経歴

• 2020年04月 - 現在 北海道大学大学院農学研究院 准教授
• 2013年04月 - 2020年03月 北海道大学大学院農学研究院 講師
• 2007年04月 - 2013年03月 北海道大学大学院農学研究院 助教
• 2005年01月 - 2007年03月 北海道大学大学院農学研究科（院） 助手
• 2003年 - 2004年 北海道大学大学院農学研究科 研究員
• 2001年11月 - 2003年03月 マンチェスター大学（英国） Visiting Research Fellow
• 2000年 - 2003年 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年 - 2000年 北海道科学・技術振興財団 研究員

学歴

•         - 1999年09月   北海道大学   大学院農学研究科   農芸化学専攻 博士後期課程修了
•         - 1997年03月   北海道大学   大学院農学研究科   農芸化学専攻 修士課程修了
•         - 1995年03月   北海道大学   農学部   農芸化学科 卒業
•         -   鹿児島県立志布志高等学校 卒業

委員歴

• 2024年02月 - 現在   Endocrinology   Editorial board
• 2023年11月 - 現在   日本食物繊維学会   理事
• 2019年11月 - 現在   日本栄養・食糧学会   代議員
• 2015年04月 - 現在   日本アミノ酸学会   評議員
• 2011年09月 - 現在   日本栄養・食糧学会 北海道支部   参与
• 2024年05月 - 2025年03月   日本農芸化学会2025年度大会, 実行委員（プログラム）
• 2024年 - 2025年   日本農芸化学会2025年度大会, 実行委員
• 2022年06月 - 2024年05月   日本栄養・食糧学会北海道支部   庶務幹事
• 2022年 - 2024年   日本栄養・食糧学会   広報委員
• 2022年 - 2024年   日本栄養・食糧学   用語委員会
• 2022年 - 2024年   日本栄養・食糧学会   学会誌編集委員
• 2021年09月 - 2023年10月   日本食物繊維学会   評議員
• 2022年 - 2023年   第77回日本栄養・食糧学会大会   実行委員（総務・会計責任者）
• 2019年06月 - 2021年05月   日本農芸化学会北海道支部   庶務幹事
• 2015年 - 2016年   日本農芸化学会2016年度大会   実行委員（総務）
• 2013年 - 2014年   第68回日本栄養・食糧学会大会   実行委員（会計責任者）
• 2006年 - 2014年   日本栄養・食糧学会 北海道支部   会計幹事
• 2005年   日本農芸化学会2005年度大会   実行員（会場）

受賞

• 2024年05月 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年05月 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年12月 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年11月 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年11月 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年07月 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年05月 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年12月 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年03月 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年11月 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年11月 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年09月 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年07月 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年05月 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年11月 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年07月 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年05月 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年11月 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年05月 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年09月 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年11月 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年11月 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年09月 The 25th Anniversary of the Discovery of GLP-1 symposium Young Investigator Abstract Competition Honorable Mention
   

  受賞者: 比良 徹
• 2012年05月 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年11月 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年11月 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年09月 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年09月 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年11月 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

論文

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

  Shiori Mizuma, Tohru Hira

  Endocrinology 2024年09月27日 [査読有り][招待有り]
  
• 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年04月 [査読有り][通常論文]
   

  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年02月 [査読有り][招待有り]
  
• 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 2023年11月 [査読有り][通常論文]
  
• 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年09月04日 [査読有り]
   

  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年06月18日 [査読有り]
   

  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年05月04日 [査読有り]
   

  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 2023年04月 [査読有り]
   

  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.
• ルミナコイドによる消化管ホルモン分泌促進作用に関する研究

  比良徹

  ルミナコイド研究 27 1 1 - 7 2023年 [査読有り][招待有り]
  
• 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年04月04日 [査読有り]
   

  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年03月10日 [査読有り]
   

  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年01月14日 [査読有り]
   

  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 2022年 [査読無し][招待有り]
   

  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.
• 難消化性デキストリン,フルクトオリゴ糖長期摂取ラットにおける,食品ペプチド誘導性GLP-1分泌応答

  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 2022年 [査読有り]
  
• 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 2021年09月17日 [査読有り]
  
• 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年08月28日 [査読有り]
   

  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年06月21日 [査読有り][招待有り]
   

  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年06月02日 [査読有り]
   

  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年05月11日 [査読有り]
   

  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年02月28日 [査読有り]
   

  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年 [査読有り]
   

  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 2020年10月 [査読有り]
   

  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.
• 難消化性糖質・希少糖の消化管内分泌系への作用

  比良 徹, 原 博

  ルミナコイド研究 : 日本食物繊維学会会誌 24 1 11 - 18 日本食物繊維学会 2020年06月 [査読有り][招待有り]
  
• 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 2020年06月 [査読有り][通常論文]
   

  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 2020年02月 [査読有り][通常論文]
   

  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年01月15日 [査読有り][通常論文]
   

  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 2020年
• 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 2019年09月 [査読有り][通常論文]
  
• 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 2019年08月28日 [査読有り][通常論文]
   

  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 2019年06月 [査読有り][通常論文]
   

  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 2019年03月30日 [査読有り][通常論文]
   

  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 2018年11月 [査読有り][通常論文]
   

  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  2018年10月 [査読有り][通常論文]
   

  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 2018年04月 [査読有り][通常論文]
   

  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 2018年02月02日 [査読有り][通常論文]
   

  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 2018年01月09日 [査読有り][通常論文]
   

  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 3 2 140 - 146 (有)科学評論社 2018年 [査読無し][招待有り]
  
• 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 2017年11月 [査読有り][通常論文]
   

  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 2017年10月14日 [査読有り][通常論文]
   

  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 2016年07月 [査読有り][通常論文]
   

  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 2016年 [査読無し][招待有り]
   

  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 2015年09月 [査読有り][通常論文]
   

  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 2015年07月 [査読有り][通常論文]
   

  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 2015年05月 [査読有り][通常論文]
   

  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 2015年 [査読有り][通常論文]
   

  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 2014年09月 [査読有り][通常論文]
   

  '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, α-glucosyl-isoquercitrin, on glucagon-like peptide 1 (GLP-1) secretion in rat intestine and enteroendocrine cells.

  Phuwamongkolwiwat P, Hira T, Hara H

  Molecular nutrition & food research 58 7 1581 - 1584 2014年07月 [査読有り][通常論文]
   

  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 2014年06月 [査読有り][通常論文]
   

  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 2014年05月 [査読有り][通常論文]
   

  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-β-glucoside on insulin sensitivity and plasma total cholesterol with promotion of flavonoid absorption in sucrose-fed rats.

  Phuwamongkolwiwat P, Suzuki T, Hira T, Hara H

  European journal of nutrition 53 2 457 - 468 2 2014年03月 [査読有り][通常論文]
   

  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.
• ジャガイモエキスの食事量抑制作用および満腹感亢進作用

  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

  薬理と治療 42 3 211 - 216 2014年03月 [査読有り]
  
• 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 2013年09月 [査読有り][通常論文]
   

  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 2013年04月
• Glycochenodeoxycholic acid promotes proliferation of intestinal epithelia via reduction of cyclic AMP and increase in H2AX phosphorylation after exposure to γ-rays.

  Ishizuka S, Shiwaku M, Hagio M, Suzuki T, Hira T, Hara H

  Biomedical research (Tokyo, Japan) 33 3 159 - 165 3 2012年06月 [査読有り][通常論文]
   

  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®) involving cholecystokinin release in rats.

  Chen W, Hira T, Nakajima S, Tomozawa H, Tsubata M, Yamaguchi K, Hara H

  Bioscience, biotechnology, and biochemistry 76 6 1104 - 1109 6 2012年06月 [査読有り][通常論文]
   

  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 2012年05月 [査読有り][通常論文]
   

  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 2011年12月 [査読有り][通常論文]
   

  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 2011年11月 [査読有り][通常論文]
   

  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 a direct stimulation of cholecystokinin secretion from enteroendocrine cells.

  NAKAJIMA Shingo, HIRA Tohru, TSUBATA Masahito, TAKAGAKI Kinya, HARA Hiroshi

  Journal of Agricultural and Food Chemistry 59 17 9491 - 9496 2011年09月 [査読有り][通常論文]
   

  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 β-conglycinin bromelain hydrolysate stimulates cholecystokinin secretion by enteroendocrine STC-1 cells to suppress the appetite of rats under meal-feeding conditions.

  Sufian KN, Hira T, Nakamori T, Furuta H, Asano K, Hara H

  Bioscience, biotechnology, and biochemistry 75 5 848 - 853 5 2011年05月 [査読有り][通常論文]
   

  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 2011年02月 [査読有り][通常論文]
   

  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 2010年07月 [査読有り][通常論文]
   

  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 2010年01月 [査読有り][通常論文]
   

  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 2009年10月 [査読有り][通常論文]
   

  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 2009年08月 [査読有り][通常論文]
   

  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 2009年07月 [査読有り][通常論文]
   

  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 2009年03月 [査読有り][通常論文]
   

  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 2008年09月 [査読有り][通常論文]
   

  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 2007年10月 [査読有り][通常論文]
   

  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 2007年07月 [査読有り][通常論文]
   

  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 2006年08月 [査読有り][通常論文]
   

  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 2006年03月 [査読有り][通常論文]
   

  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 2004年06月 [査読有り][通常論文]
   

  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 2003年07月 [査読有り][通常論文]
   

  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 2003年 [査読有り][通常論文]
   

  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 2001年12月 [査読有り][通常論文]
   

  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 2001年12月 [査読有り][通常論文]
   

  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 2001年06月 [査読有り][通常論文]
   

  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 2001年05月 [査読有り][通常論文]
   

  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 2000年06月 [査読有り][通常論文]
   

  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 1999年07月 [査読有り][通常論文]
   

  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 1999年04月 [査読有り][通常論文]
   

  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 1999年03月 [査読有り][通常論文]
   

  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 1997年10月 [査読有り][通常論文]
   

  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

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• 食事誘導性肥満ラットにおける消化管部位別のGLP-1分泌応答と組織解析

  佐野杏莉, 比良徹 日本農芸化学会大会講演要旨集(Web) 2021 2021年
• 消化管内分泌系への作用を介する糖代謝改善ペプチド

  比良徹 日本農芸化学会大会講演要旨集(Web) 2021 2021年
• 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年
• 食後の消化管ホルモン分泌応答における食品たんぱく質の役割

  比良徹 飯島藤十郎記念食品科学振興財団年報 35 149 -153 2020年
• 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年
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月
• 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年
• 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年 [査読無し][通常論文]
  
• 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年09月22日 [査読無し][通常論文]
  
• 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年08月22日 [査読無し][通常論文]
  
• 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年08月20日 [査読無し][通常論文]
  
• 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年04月
• 腸内細菌の代謝産物を介した宿主とのインタラクション 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年04月 [査読無し][通常論文]
  
• 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年04月 [査読無し][通常論文]
  
• 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年04月 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月
• 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年
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年10月 [査読無し][通常論文]
  
• 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年09月 [査読無し][通常論文]
  
• 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年04月28日 [査読無し][通常論文]
  
• 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年04月28日 [査読無し][通常論文]
  
• 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年04月
• 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年04月 [査読無し][通常論文]
  
• 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年
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年09月20日 [査読無し][通常論文]
  
• 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年09月20日 [査読無し][通常論文]
  
• 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年09月11日 [査読無し][通常論文]
  
• 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年04月25日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年09月08日 [査読無し][通常論文]
  
• 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年09月 [査読無し][通常論文]
  
• 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年09月 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年02月27日 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年11月08日 [査読無し][通常論文]
  
• 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年10月10日 [査読無し][通常論文]
  
• 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年10月10日 [査読無し][通常論文]
  
• 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年08月 [査読無し][通常論文]
  
• 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年04月30日 [査読無し][通常論文]
  
• 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年04月30日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年02月 [査読無し][通常論文]
  
• 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年11月02日 [査読無し][通常論文]
  
• 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年11月02日 [査読無し][通常論文]
  
• 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年09月25日 [査読無し][通常論文]
  
• 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年04月30日 [査読無し][通常論文]
  
• 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年04月30日 [査読無し][通常論文]
  
• 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年04月30日 [査読無し][通常論文]
  
• 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年04月25日 [査読無し][通常論文]
  
• 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年04月 [査読無し][通常論文]
  
• 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年04月01日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 小豆子葉部のα-グルコシダーゼ活性およびGLP-1分泌に与える影響

  濱岡 直裕, 中川 良二, 比良 徹, 八巻 幸二 日本食品科学工学会誌 : Nippon shokuhin kagaku kogaku kaishi = Journal of the Japanese Society for Food Science and Technology 60 (1) 43 -47 2013年01月15日 [査読無し][通常論文]
   

  小豆について，特に種皮以外の部分が有する血糖上昇を抑制する機能性を評価した．その結果，種皮付きおよび種皮を除去した小豆ペプシン分解物にαグルコシダーゼ阻害およびグルカゴン様ペプチド-1 (GLP-1）分泌の活性が確認された．αグルコシダーゼ阻害活性については種皮を除去しても安定であり，かつトリプシン消化に対する耐性も有することが明らかになった．これらの結果より，小豆の子葉部は食後高血糖を抑制しうる生理活性を有することが明らかになり，糖尿病や肥満症の予防などに有効な機能性食品素材として活用できる可能性が示唆された．
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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 (第7回学術大会(JSAAS2013)) -- (日本アミノ酸学会 科学・技術賞の受賞講演)

  比良 徹 アミノ酸研究 7 (2) 79 -84 2013年 [査読無し][通常論文]
  
• 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年11月01日 [査読無し][通常論文]
  
• 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年11月01日 [査読無し][通常論文]
  
• 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年06月21日 [査読無し][通常論文]
  
• 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年04月27日 [査読無し][通常論文]
  
• 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年04月27日 [査読無し][通常論文]
  
• 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年04月27日 [査読無し][通常論文]
  
• 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年04月27日 [査読無し][通常論文]
  
• 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年04月 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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:（平成24年度日本栄養・食糧学会奨励賞受賞）

  比良 徹 日本栄養・食糧学会誌 65 (5) 215 -220 2012年 [査読無し][通常論文]
   

  本研究では，腸上皮に散在する消化管内分泌細胞が，管腔内の栄養素を認識して消化管ホルモンを分泌する機構の解明と，食品ペプチドによる消化管ホルモン分泌を介した食欲抑制，血糖上昇抑制の確立を目的とした。膵酵素分泌，満腹感誘導等の作用を持つコレシストキニン（CCK）の分泌機構に関して，カルシウム感知受容体が，フェニルアラニンや各種食品ペプチドの受容体としてCCK分泌に関与することを見いだした。トウモロコシ由来のペプチドが，グルカゴン様ペプチド-1（GLP-1）の分泌を促進し，さらに血中ジペプチヂルペプチダーゼ-IV活性を低下させることで，GLP-1の作用を高めて，血糖上昇が抑制されることをラットにおいて示した。これらの研究成果は，消化管での栄養素認識機構の一部を明らかにし，食品成分による消化管ホルモン分泌コントロールを介した，メタボリック症候群の予防，病態改善へ応用しうるものと考えられる。
• 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年12月31日 [査読無し][通常論文]
  
• 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年12月31日 [査読無し][通常論文]
  
• 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年11月04日 [査読無し][通常論文]
  
• 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年09月01日 [査読無し][通常論文]
  
• 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年05月 [査読無し][通常論文]
   

  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年04月28日 [査読無し][通常論文]
  
• 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年04月25日 [査読無し][通常論文]
  
• 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年04月25日 [査読無し][通常論文]
  
• 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年04月25日 [査読無し][通常論文]
  
• 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年04月25日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年02月 [査読無し][通常論文]
  
• 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年02月 [査読無し][通常論文]
  
• 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年01月01日 [査読無し][通常論文]
  
• 大豆HMF由来ペプチドの消化管ホルモンGLP-1分泌を介した血糖上昇抑制作用に関する研究

  比良 徹, 村松 茉耶, 原 博 大豆たん白質研究 13 (31) 70 -74 2010年12月 [査読無し][通常論文]
  
• 大豆HMF由来ペプチドの消化管ホルモンGLP‐1分泌を介した血糖上昇抑制作用に関する研究

  比良徹, 村松茉耶, 原博 大豆たん白質研究 13 70-74 -74 2010年12月 [査読無し][通常論文]
  
• 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年09月 [査読無し][通常論文]
  
• 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年09月 [査読無し][通常論文]
  
• 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年09月01日 [査読無し][通常論文]
  
• 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年09月01日 [査読無し][通常論文]
  
• 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年09月01日 [査読無し][通常論文]
  
• 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年05月01日 [査読無し][通常論文]
  
• 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年05月01日 [査読無し][通常論文]
  
• 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年05月01日 [査読無し][通常論文]
  
• 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年05月01日 [査読無し][通常論文]
  
• 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年04月 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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 ([日本アミノ酸学会]第4回学術大会(JSAAS2010))

  比良 徹, 持田 泰佑, 原 博 アミノ酸研究 4 (2) 163 -166 2010年 [査読無し][通常論文]
  
• 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年09月17日 [査読無し][通常論文]
  
• 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年09月17日 [査読無し][通常論文]
  
• 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年08月 [査読無し][通常論文]
  
• 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年05月01日 [査読無し][通常論文]
  
• 「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年05月01日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• SHORT CHAIN FATTY ACIDS INDUCE GLP-1 SECRETION IN ENTEROENDOCRINE GLUTAG CELLS

  Tohru Hira, Hiroshi Hara JOURNAL OF PHYSIOLOGICAL SCIENCES 59 389 -389 2009年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年01月 [査読無し][通常論文]
  
• 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年07月11日 [査読無し][通常論文]
  
• 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年04月01日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月 [査読無し][通常論文]
  
• 1Dp18 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(生体情報工学,遺伝子工学,核酸工学,一般講演)

  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 20 (0) 117 -117 2008年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年09月06日 [査読無し][通常論文]
  
• 消化管内分泌細胞における食品ぺ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 0 (178) 20 -27 2007年06月 [査読無し][通常論文]
  
• 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年06月 [査読無し][通常論文]
  
• 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年04月20日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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 年報 2007 (0) 140 -144 2007年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年 [査読無し][通常論文]
  
• 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年08月 [査読無し][通常論文]
  
• 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年08月 [査読無し][通常論文]
  
• Casein sensing mechanisms in the cholecystokinin-producing enteroendocrine cells

  T. Hira, K. Iura, H. Hara REGULATORY PEPTIDES 135 (3) 129 -129 2006年08月 [査読無し][通常論文]
  
• 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年08月 [査読無し][通常論文]
   

  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年04月01日 [査読無し][通常論文]
  
• 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年04月01日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年03月 [査読無し][通常論文]
   

  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年09月20日 [査読無し][通常論文]
  
• 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年04月 [査読無し][通常論文]
  
• 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年04月01日 [査読無し][通常論文]
  
• 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年04月01日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年10月 [査読無し][通常論文]
  
• 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 7 108-113 -113 2004年10月 [査読無し][通常論文]
  
• 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年04月01日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 消化管内分泌細胞における脂肪酸認識機構の解析

  比良 徹, Elliott Austin C., Thompson David G., Case R. Maynard, McLaughlin John T. 日本生理学会大会発表要旨集 2004 (0) S116 -S116 2004年 

  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年04月 [査読無し][通常論文]
  
• 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 辰男, 青山 頼孝 消化と吸収 24 (1) 24 -28 2001年12月30日 [査読無し][通常論文]
  
• 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, 冨田辰男, 青山頼孝 消化と吸収 24 (1) 24-28 -28 2001年12月30日 [査読無し][通常論文]
  
• 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年12月 [査読無し][通常論文]
   

  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年10月17日 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年04月01日 [査読無し][通常論文]
  
• すい外分泌を刺激するタンパク質は腸管内分泌細胞株STC‐1においてCCK放出を刺激する

  比良徹, 原博, 青山頼孝 日本栄養・食糧学会総会講演要旨集 53rd 87 1999年04月20日 [査読無し][通常論文]
  
• 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年04月 [査読無し][通常論文]
   

  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.
• ラットにおいてカゼインによるすい外分泌刺激作用は小腸内トリプシン阻害能に依存しない

  比良徹, 原博, 青山頼孝 日本栄養・食糧学会総会講演要旨集 52nd 57 1998年03月 [査読無し][通常論文]
  
• 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年03月05日 [査読無し][通常論文]
  
• 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年07月05日 [査読無し][通常論文]
  

書籍等出版物

• 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 (範囲: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年07月 (ISBN: 9784781318097) viii, 253p
• 食品免疫学事典

  比良 徹 (担当:分担執筆範囲:９章(9-13) 消化管内分泌系を介した作用)
  朝倉書店 2021年11月
• 食品免疫学事典

  比良 徹, 原 博 (担当:分担執筆範囲:２章(2-14) 消化管ホルモン)
  朝倉書店 2021年11月
• エッセンシャル栄養化学 (KS農学専門書)

  比良 徹 (担当:分担執筆範囲: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年08月 (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 (担当:分担執筆範囲:難消化性糖質の消化管内分泌系への作用)
  建帛社 2019年05月
• 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 (担当:分担執筆範囲: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年10月
• 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. (担当:分担執筆範囲:396-412)
  The Royal Society of Chemistry 2015年10月
• 機能性タンパク質・ペプチドと生体利用

  原 博, 比良 徹 (担当:分担執筆範囲: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年05月
• 腸管細胞機能実験法

  原 博, 西 隆司, 比良 徹 (担当:分担執筆範囲: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年10月 274 88-96

講演・口頭発表等

• 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  [招待講演]

  比良 徹

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

  比良 徹

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

  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年12月 シンポジウム・ワークショップパネル（指名）
• 食品成分による消化管ホルモン分泌の調節  [招待講演]

  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年10月 シンポジウム・ワークショップパネル（指名）
• 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年05月 シンポジウム・ワークショップパネル（指名）
• 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年03月 公開講演，セミナー，チュートリアル，講習，講義等
• 食におけるタンパク質の重要性について  [招待講演]

  比良 徹

  令和４年度地域バイオ育成講座講演会 2023年01月 公開講演，セミナー，チュートリアル，講習，講義等
• Adaptive changes in nutrient-induced GLP-1 secretion in diet-induced obese model rats

  Tohru Hira

  22nd IUNS-ICN International Congress of Nutritio 2022年12月 シンポジウム・ワークショップパネル（指名）
• 食品ペプチドによるGLP-1分泌促進と分解抑制  [招待講演]

  比良 徹

  日本アミノ酸学会第９回夏のシンポジウム 2022年08月 シンポジウム・ワークショップパネル（指名）
• 消化管内分泌系への作用を介する糖代謝改善ペプチド  [招待講演]

  比良 徹

  日本農芸化学会2021年度大会 2021年03月 シンポジウム・ワークショップパネル（指名）
• trans,trans-2,4-Decadienal stimulates cholecystokinin secretion in enteroendocrine cells, and suppresses gastric emptying in rats  [招待講演]

  Tohru Hira

  International symposium on lipids and food ingredients for health promotion 2021年03月 口頭発表（一般）
• 難消化性糖質の消化管内分泌系への作用  [招待講演]

  比良 徹

  日本食物繊維学会第24回学術集会 2019年11月 シンポジウム・ワークショップパネル（指名）
• " 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"  [招待講演]

  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年10月 口頭発表（招待・特別）
• 難消化性糖質の消化管内分泌系への作用  [招待講演]

  比良 徹, 原 博

  第72回日本栄養・食糧学会大会 共催：Hindgut Club Japan 2018年05月 シンポジウム・ワークショップパネル（公募）
• GLP-1を増やす食品成分、食事条件  [通常講演]

  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年12月 シンポジウム・ワークショップパネル（指名）
• 消化管に働きかけて血糖上昇を抑制する食品ペプチド  [招待講演]

  比良 徹

  第３回食科学プラットフォームセミナー 2017年07月 公開講演，セミナー，チュートリアル，講習，講義等
• 食品成分による消化管ホルモン分泌調節  [招待講演]

  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年09月 シンポジウム・ワークショップパネル（指名）
• 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  [招待講演]

  比良徹, 原博

  第７０回日本栄養・食糧学会大会 2016年05月 シンポジウム・ワークショップパネル（指名）
• 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－  [招待講演]

  比良 徹

  第70回日本栄養・食糧学会大会 ランチョンセミナー 2016年05月 公開講演，セミナー，チュートリアル，講習，講義等
• trans,trans-2,4-デカジエナールの胃排出抑制機構  [招待講演]

  比良 徹

  Hindgut Club Japanサテライトシンポジウム 2016年05月 シンポジウム・ワークショップパネル（指名）
• 血糖調節ペプチド  [招待講演]

  比良 徹

  日本農芸化学会2015年度大会 2016年03月 シンポジウム・ワークショップパネル（指名）
• 食品成分による消化管ホルモン分泌の制御と作用機構  [招待講演]

  比良 徹

  第93回日本生理学会大会 2016年03月 シンポジウム・ワークショップパネル（指名）
• 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  [招待講演]

  比良 徹

  第21回Hindgut club Japanシンポジウム 2015年12月 シンポジウム・ワークショップパネル（指名）
• 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  [招待講演]

  比良 徹

  第２７回夏期油脂・コレステロール研究会 2015年07月 シンポジウム・ワークショップパネル（指名）
• 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  [招待講演]

  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年11月 公開講演，セミナー，チュートリアル，講習，講義等
• Effects of resistant maltodextrin and fructooligosaccharides on fasting GLP-1 levels and glucose tolerance in rats  [通常講演]

  比良 徹

  10th Vahouny Dietary Fiber Symposium 2014年03月 シンポジウム・ワークショップパネル（指名）
• 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  [招待講演]

  比良徹

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

  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年08月 シンポジウム・ワークショップパネル（指名）
• 消化管内分泌系調節ペプチド  [通常講演]

  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年05月

担当経験のある科目（授業）

生物学Ⅰ北海道大学
栄養化学Ⅱ北海道大学農学部
食品科学特論演習北海道大学大学院農学院
食品科学特論北海道大学大学院農学院
一般教育演習 食べ物の安全と安心北海道大学
生物機能化学実験Ⅳ北海道大学農学部
化学概論北海道大学
代謝栄養学（旭川医科大学看護学科）
食品栄養学総論・演習北海道大学大学院農学院
食資源科学総論・演習北海道大学大学院農学院

所属学協会

• 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   

共同研究・競争的資金等の研究課題

• 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

  研究期間 : 2024年06月 -2026年03月 

  代表者 : 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)

  研究期間 : 2022年04月 -2025年03月 

  代表者 : 比良 徹
• 食事誘導性肥満におけるGLP-1分泌増大機構の解明

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2019年04月 -2022年03月 

  代表者 : 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。
• 食後の消化管ホルモン分泌応答や栄養吸収の時空間的解析とその栄養学的意義

  日本学術振興会：科学研究費助成事業 挑戦的研究(萌芽)

  研究期間 : 2018年06月 -2020年03月 

  代表者 : 原 博, 比良 徹

   

  本申請課題は、食事摂取後の消化管ホルモンの分泌応答や、栄養素あるいは食品成分の吸収が、消化管のどの部位で、どのような経時的変化を示すのかを明らかにすることを目的としている。そのための、下部消化管（回腸部）の腸間膜静脈からの経時的採血を可能とするカニュレーション手技の確立を初期段階の目標とした。 実験動物（ラット）の門脈または回腸部腸間膜静脈にカテーテルを留置して、経時的血液採取を可能とした。糖質含量、タンパク質含量の異なる食事を経口投与すると、採血部位によって血糖値、消化管ホルモン濃度の変動が異なることが観察され、この手法により消化管部位別の変動を解析できることが示された。
• 新規多機能糖質としてデザインされたイソマルトメガロ糖による生理作用とその発現機構

  日本学術振興会：科学研究費助成事業 基盤研究(A)

  研究期間 : 2017年04月 -2020年03月 

  代表者 : 原 博, 比良 徹

   

  イソマルトメガロ糖は、α-1,6結合グルコース主鎖の末端に、「堅い」α-1,4結合のグルコース側鎖を持つ新規糖質である。本研究課題では、消化管上皮のバリア機能に与える効果、ケルセチンの吸収ならびに消化管ホルモンGLP-1の分泌に与える効果を、培養細胞試験ならびに動物試験にて検討した。 細胞試験ではイソマルトメガロ糖は油脂酸化物による上皮バリア障害を抑制することが示唆された。動物試験では、イソマルトメガロ糖とケルセチンを組み合わせることで、ケルセチンの吸収が高まること、消化管ホルモンGLP-1の分泌が増強されることが示された。
• 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

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2016年04月 -2019年03月 

  代表者 : 比良 徹

   

  耐糖能異常、肥満を誘導する高脂肪高ショ糖食をラットに持続的に摂取させると、食事投与に対する消化管ホルモン（GLP-1）分泌応答が、正常ラットに比べて高まることが見出された。これには、高ショ糖食よりも高脂肪食の寄与が大きいことが示唆された。また、GLP-1の作用を抑制する薬剤の処理により、GLP-1の分泌増進は耐糖能異常の発症に対して防御的に働くことが明らかとなった。また、肥満誘導食の持続摂取による食後GLP-1分泌の増加、すなわち消化管の栄養素感受性の亢進は、成熟ラットよりも若齢ラットの方が速やかに観察されることが明らかとなった。
• 栄養センサー細胞(消化管内分泌細胞)が難消化性糖質を感知する仕組みを解き明かす

  日本学術振興会：科学研究費助成事業 挑戦的萌芽研究

  研究期間 : 2016年04月 -2018年03月 

  代表者 : 原 博, 比良 徹

   

  難消化糖質として難消化性デキストリン、ならびに「自然界にその存在量が少ない単糖とその誘導体」と定義される希少糖の一つであるD-アルロースについて、これらを経口投与することでのGLP-1の分泌が促進されることを見出した。 D-アルロースのGLP-1分泌促進作用は、難消化性デキストリンやフルクトースよりも強力で、腸管腔内への直接投与により発現したが腹腔内投与では発現されなかったことから、D-アルロースは腸管腔内で強いGLP-1分泌促進作用を示すことが明らかとなった。このことから難消化性糖質を認識することが消化管ホルモン分泌において重要な生理的意義を有することが示された。
• 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)

  研究期間 : 2016年04月 -2018年03月 

  代表者 : 比良 徹
• 消化管内分泌系と脳神経系および生殖機能系との相互作用による疾病予防・改善食の提案

  日本学術振興会：科学研究費助成事業 基盤研究(A)

  研究期間 : 2014年04月 -2017年03月 

  代表者 : 原 博, 比良 徹

   

  食欲や血糖値など多様な生理現象を調節する消化管ホルモンの分泌は、摂取した食品成分により調節される。本研究課題では、消化管ホルモン分泌を強く促進する食品成分を含む「食事」を摂取した際の、各種消化管ホルモン分泌応答を、門脈カニュレーションラット、マルチプレックスなどの手技を用いて実験動物（ラット）にて検討した。その結果、タンパク質の組成を変えることで消化管ホルモン分泌が大きく異なること、それには共存する炭水化物の種類も影響することが明らかとなった。また、消化管ホルモンGLP-1の分泌を強く促進する難消化性糖質の添加により、肥満誘導食の摂取量を抑制できることが示された。
• 食事誘導性肥満・耐糖能異常の発症過程におけるGLP-1の関与

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2013年04月 -2016年03月 

  代表者 : 比良 徹

   

  肥満や耐糖能異常の発症過程において、消化管ホルモンGLP-1がどのように変動するかを調べるため、ラットに肥満誘導食（高脂肪・高ショ糖食）を５～８週間摂取させた。期間途中の食事負荷試験（普通食を負荷）により、肥満誘導食摂取群は食後GLP-1分泌が高まることが見出された。消化管の各種栄養素受容体の発現を調べたところ、脂肪酸受容体の発現上昇が観察され、このことが食後GLP-1分泌応答の増進に関与することが考えられた。GLP-1受容体アンタゴニストを用いた試験により、この食後GLP-1分泌上昇は、肥満誘導食による耐糖能の悪化に対して防御的な役割を持つことが示された。
• 消化管内分泌系を介する慢性炎症発症回避の機構解明：免疫系細胞と脂肪細胞の連関

  日本学術振興会：科学研究費助成事業 挑戦的萌芽研究

  研究期間 : 2012年04月 -2015年03月 

  代表者 : 石塚 敏, 比良 徹

   

  食事誘導性肥満において、脂肪組織やさまざまな臓器で慢性的な炎症が生じる。食事摂取後のリンパ管には脂質以外にも様々な食事由来抗原が流入し、これらの抗原に免疫系が応答すると考えられる。本研究ではリンパ管カニュレーション法を適用して、脂質吸収時にリンパ管に流入する因子を評価した。脂質吸収開始後数時間でinterleukin-6 (IL-6)およびglucagon-like peptide-1濃度が投与前より有意に増加した。絶食時及び脂質食摂取時の消化管粘膜での遺伝子発現解析結果から、脂質の吸収に伴いIL-6産生細胞の粘膜への遊走が生じた可能性が示唆された。
• 食品由来ＧＬＰー１分泌刺激ペプチドの抗メタボ作用を、糖質の消化抵抗性で増強する

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  研究期間 : 2010年04月 -2013年03月 

  代表者 : 原 博, 比良 徹

   

  消化管ホルモンの一つであるGLP-1は、肥満や糖尿病の改善作用を有する。GLP-1の合成と分泌は、腸管腔内の食品成分による調節を受けることから、食品成分を利用して内因性GLP-1の合成・分泌を高めることが肥満や糖尿病の予防、病態改善に有効と考えられた。 培養細胞、実験動物（ラット）を用いた試験により、トウモロコシペプチドの経口投与がGLP-1分泌を促進して血糖上昇を抑制すること、このものは糖尿病モデル動物でも有効であることが明らかとなった。 また消化抵抗性糖質に、GLP-1分泌を直接刺激できる作用、ならびにトウモロコシペプチドに対するGLP-1分泌応答を増強する作用があることが見いだされた。
• 消化管内分泌細胞に発現する新たな食品たんぱく質／ペプチド受容体候補の網羅的探索

  日本学術振興会：科学研究費助成事業 若手研究(B)

  研究期間 : 2011年 -2012年 

  代表者 : 比良 徹

   

  消化管内分泌細胞における食品タンパク質、食品ペプチドの認識機構に関して、網羅的遺伝子発現解析によりTRPチャネルの一つがCCK産生細胞に発現することを見いだした。 牛乳由来の食品タンパク質の認識およびアルデヒドの認識にこの分子が関わることが明らかとなった。さらにラットへのアルデヒドの経口投与により、胃排出の抑制が起きることを明らかにし、これにはTRPA1およびCCKが関与する可能性が考えられた。また、カルシウム感知受容体が種々の食品ペプチドの認識に関与することも明らかとなった。
• 腸管における食品ペプチド受容体CaSRの機能解析と未知の食品たんぱく質受容体探索

  日本学術振興会：科学研究費助成事業 若手研究(B)

  研究期間 : 2009年 -2010年 

  代表者 : 比良 徹

   

  消化管において食品たんぱく質・ペプチドを感知する受容体はこれまでほとんど分かっていなかった。本研究課題において、細胞外カルシウムやアミノ酸の受容体として知られるカルシウム感知受容体(CaSR)が、消化管ホルモンCCKを分泌する細胞において、多くの食品ペプチドの受容に関与し、CaSRの活性化がこのホルモンの分泌を促進することが明らかとなった。これらの結果により、消化管における栄養素認識機構の一つが明らかとなった。
• 消化管ホルモン分泌を介して食欲や血糖をコントロールする抗肥満食品ペプチドの開発

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  研究期間 : 2007年 -2009年 

  代表者 : 原 博, 比良 徹

   

  種々の食品ペプチドの中から、食欲を抑制する消化管ホルモンCCKの分泌を促進するふじ豆ペプチド、ビール酵母ペプチドを見出し、ビール酵母ペプチドをラットに経口投与することでその後の食欲が抑制されることが確認された。また、インスリン分泌を促進する消化管ホルモンGLP-1の分泌を刺激するトウモロコシペプチドを見出した。これをラット回腸に投与することで、GLP-1分泌が促進され、インスリン分泌促進を介して血糖上昇が抑制されることを示し、食品ペプチドによる消化管ホルモン分泌を介した食欲抑制、血糖上昇抑制が実現された。
• 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)

  研究期間 : 2005年 -2006年 

  代表者 : 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

  研究期間 : 2000年 -2002年 

  代表者 : 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

産業財産権

• 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年09月07日

  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年03月15日

  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年02月02日

  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年01月20日

  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年06月17日

  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年12月24日

  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年10月08日

  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年08月21日

  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年04月03日

  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年01月09日

  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年03月20日

  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年05月09日

  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年11月15日

  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年02月24日

  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年02月02日

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