2021年03月, 日本生理学会, 入澤彩記念女性生理学者奨励賞　　　　　　　　　　　　　　　

2020年09月, 日本獣医学会, 日本獣医学会賞　　　　　　　　　　　　　　　

2019年11月, 日本肥満学会, 学術奨励賞　　　　　　　　　　　　　　　

2008年03月, 北海道大学 大塚賞　　　　　　　　　　　　　　　

2005年10月, 日本肥満学会 若手研究奨励賞　　　　　　　　　　　　　　　

2004年08月, アディポサイエンス研究会シンポジウム 若手優秀ポスター賞　　　　　　　　　　　　　　　

Regulation of mitochondrial metabolism by hibernating bear serum: Insights into seasonal metabolic adaptations
Mohamed Elfeky, Ayumi Tsubota, Michito Shimozuru, Toshio Tsubota, Kazuhiro Kimura, Yuko Okamatsu-Ogura
Biochemical and Biophysical Research Communications, 736, 150510, 150510, Elsevier BV, 2024年12月
研究論文（学術雑誌）

Time-dependent changes in retinoids content in liver and adipose tissue after feeding of a vitamin A-deficient diet to mice.
Mira Kato-Suzuki, Yuko Okamatsu-Ogura, Osamu Inanami, Kazuhiro Kimura
Experimental animals, 2024年02月21日, ［国内誌］
英語, 研究論文（学術雑誌）, Vitamin A is an important nutrient for multiple physiological functions. To elucidate the role of vitamin A in vivo, vitamin A-deficient diets have been often used in mice to establish a vitamin A-deficiency model. However, the information on the appropriate feeding periods and time course of changes in vitamin A content in organs after the start of vitamin A-deficient diet feeding is lacking. This study aimed to assess the retinoids levels in liver and white adipose tissue in mice fed a vitamin A-deficient diet for £8 weeks. High-performance liquid chromatography was used to measure the retinoids levels in liver and white adipose tissue every 2 weeks for £8 weeks. Vitamin A-deficient diet feeding significantly decreased retinol in the liver over 6 weeks, but retinyl palmitate, a main storage form of vitamin A, was not changed over 8 weeks. The plasma retinol level remained constant throughout the experiment. In white adipose tissue, retinyl palmitate gradually decreased over 8 weeks. These results indicate that vitamin A-deficient diet feeding longer than 6 weeks reduced retinol in liver and retinyl palmitate in white adipose tissue over 8 weeks, although it is not enough for the induction of a whole-body vitamin A deficiency.

White adipose tissue undergoes browning during preweaning period in association with microbiota formation in mice.
Anju Tsukada, Yuko Okamatsu-Ogura, Emi Futagawa, Yuki Habu, Natsumi Takahashi, Mira Kato-Suzuki, Yuko Kato, Satoshi Ishizuka, Kei Sonoyama, Kazuhiro Kimura
iScience, 26, 7, 107239, 107239, 2023年07月21日, ［国際誌］
英語, 研究論文（学術雑誌）, Beige adipocytes are transiently induced during early postnatal period in mice. Previous studies have suggested that, unlike in adults, the induction is independent of the sympathetic nerve activity; however, the mechanism is yet unknown. Here, we showed that beige adipocytes are induced during the preweaning period in association with the formation of microbiota in mice. Alteration of gut microbiota composition in preweaning mice by maternal treatment with antibiotics or high-fat diet feeding substantially suppressed WAT browning. The suppression was also found in pups transplanted cecal microbiota from pups of high-fat diet-fed dams. These treatments reduced the hepatic expression of genes involved in bile acid synthesis and the serum bile acids level. The abundance of Porphyromonadaceae and Ruminococcaceae in microbiota showed a positive and negative correlation with the induction of beige adipocytes, respectively. This finding may provide comprehensive understanding of the association between gut microbiota and adipose tissue development in the neonatal period.

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, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Mevalonate biosynthesis pathway regulates the development and survival of brown adipocytes.
Jungin Kwon, Yu-Sheng Yeh, Satoko Kawarasaki, Hiroto Minamino, Yoshihito Fujita, Yuko Okamatsu-Ogura, Haruya Takahashi, Wataru Nomura, Shigenobu Matsumura, Rina Yu, Kazuhiro Kimura, Masayuki Saito, Nobuya Inagaki, Kazuo Inoue, Teruo Kawada, Tsuyoshi Goto
iScience, 26, 3, 106161, 106161, 2023年03月17日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The high thermogenic activity of brown adipose tissue (BAT) has received considerable attention. Here, we demonstrated the role of the mevalonate (MVA) biosynthesis pathway in the regulation of brown adipocyte development and survival. The inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in the MVA pathway and the molecular target of statins, suppressed brown adipocyte differentiation by suppressing protein geranylgeranylation-mediated mitotic clonal expansion. The development of BAT in neonatal mice exposed to statins during the fetal period was severely impaired. Moreover, statin-induced geranylgeranyl pyrophosphate (GGPP) deficiency led to the apoptosis of mature brown adipocytes. Brown adipocyte-specific Hmgcr knockout induced BAT atrophy and disrupted thermogenesis. Importantly, both genetic and pharmacological inhibition of HMGCR in adult mice induced morphological changes in BAT accompanied by an increase in apoptosis, and statin-treated diabetic mice showed worsened hyperglycemia. These findings revealed that MVA pathway-generated GGPP is indispensable for BAT development and survival.

UCP1レポーター脂肪細胞株を用いたβ-アドレナリンシグナル調節遺伝子の探索　　　　　　　　　　　　　　　
川原崎 聡子, 瀬尾 茂人, 岡松 優子, 高橋 春弥, 野村 亘, 神戸 大朋, 木村 和弘, 斉藤 昌之, 松田 秀雄, 井上 和生, 後藤 剛
日本栄養・食糧学会大会講演要旨集, 77回, 267, 267, (公社)日本栄養・食糧学会, 2023年03月
日本語

体温維持における骨格筋の役割と臓器間代謝ネットワークの解明　　　　　　　　　　　　　　　
三島 優奈, 堤 理恵, 藤本 紗織, 谷口 萌々花, 志内 哲也, 岡松 優子, 米代 武司, 黒田 雅士, 阪上 浩
肥満研究, 28, Suppl., 277, 277, (一社)日本肥満学会, 2022年11月
日本語

廃用性筋萎縮モデルにおける多臓器代謝動態の連関の意義　　　　　　　　　　　　　　　
藤本 紗織, 堤 理恵, 三島 優奈, 志内 哲也, 岡松 優子, 黒田 雅士, 阪上 浩
糖尿病, 65, Suppl.1, S, 218, (一社)日本糖尿病学会, 2022年04月
日本語

骨格筋不動化モデルにおける体温維持機構の解明　　　　　　　　　　　　　　　
三島 優奈, 堤 理恵, 藤本 紗織, 志内 哲也, 岡松 優子, 黒田 雅士, 阪上 浩
糖尿病, 65, Suppl.1, S, 218, (一社)日本糖尿病学会, 2022年04月
日本語

Bacteroides spp. promotes branched-chain amino acid catabolism in brown fat and inhibits obesity
Naofumi Yoshida, Tomoya Yamashita, Tatsunori Osone, Tetsuya Hosooka, Masakazu Shinohara, Seiichi Kitahama, Kengo Sasaki, Daisuke Sasaki, Takeshi Yoneshiro, Tomohiro Suzuki, Takuo Emoto, Yoshihiro Saito, Genki Ozawa, Yushi Hirota, Yasuyuki Kitaura, Yoshiharu Shimomura, Yuko Okamatsu-Ogura, Masayuki Saito, Akihiko Kondo, Shingo Kajimura, Takeshi Inagaki, Wataru Ogawa, Takuji Yamada, Ken-ichi Hirata
iScience, 24, 11, 103342, 103342, Elsevier BV, 2021年11月, ［国際誌］
英語, 研究論文（学術雑誌）, The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be elucidated. We found that the levels of circulating branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) were significantly correlated with the body weight in humans and mice and that BCAA catabolic defects in BAT were associated with obesity in diet-induced obesity (DIO) mice. Pharmacological systemic enhancement of BCAA catabolic activity reduced plasma BCAA and BCKA levels and protected against obesity; these effects were reduced in BATectomized mice. DIO mice gavaged with Bacteroides dorei and Bacteroides vulgatus exhibited improved BAT BCAA catabolism and attenuated body weight gain, which were not observed in BATectomized DIO mice. Our data have highlighted a possible link between the gut microbiota and BAT BCAA catabolism and suggest that Bacteroides probiotics could be used for treating obesity.

Adipocytes and Stromal Cells Regulate Brown Adipogenesis Through Secretory Factors During the Postnatal White-to-Brown Conversion of Adipose Tissue in Syrian Hamsters
Junnosuke Mae, Kazuki Nagaya, Yuko Okamatsu-Ogura, Ayumi Tsubota, Shinya Matsuoka, Junko Nio-Kobayashi, Kazuhiro Kimura
Frontiers in Cell and Developmental Biology, 9, Frontiers Media SA, 2021年07月05日, ［査読有り］, ［責任著者］
研究論文（学術雑誌）, Brown adipose tissue (BAT) is a specialized tissue that regulates non-shivering thermogenesis. In Syrian hamsters, interscapular adipose tissue is composed primarily of white adipocytes at birth, which is converted to BAT through the proliferation and differentiation of brown adipocyte progenitors and the simultaneous disappearance of white adipocytes. In this study, we investigated the regulatory mechanism of brown adipogenesis during postnatal BAT formation in hamsters. Interscapular adipose tissue of a 10-day-old hamster, which primarily consists of brown adipocyte progenitors and white adipocytes, was digested with collagenase and fractioned into stromal–vascular (SV) cells and white adipocytes. SV cells spontaneously differentiated into brown adipocytes that contained multilocular lipid droplets and expressed uncoupling protein 1 (Ucp1), a marker of brown adipocytes, without treatment of adipogenic cocktail such as dexamethasone and insulin. The spontaneous differentiation of SV cells was suppressed by co-culture with adipocytes or by the addition of white adipocyte-conditioned medium. Conversely, the addition of SV cell-conditioned medium increased the expression of Ucp1. These results indicate that adipocytes secrete factors that suppress brown adipogenesis, whereas SV cells secrete factors that promote brown adipogenesis. Transcriptome analysis was conducted; however, no candidate suppressing factors secreted from adipocytes were identified. In contrast, 19 genes that encode secretory factors, including bone morphogenetic protein (BMP) family members, BMP3B, BMP5, and BMP7, were highly expressed in SV cells compared with adipocytes. Furthermore, the SMAD and MAPK signaling pathways, which represent the major BMP signaling pathways, were activated in SV cells, suggesting that BMPs secreted from SV cells induce brown adipogenesis in an autocrine manner through the SMAD/MAPK signaling pathways. Treatment of 5-day-old hamsters with type I BMP receptor inhibitor, LDN-193189, for 5 days reduced p38 MAPK phosphorylation and drastically suppressed BAT formation of interscapular adipose tissue. In conclusion, adipocytes and stromal cells regulate brown adipogenesis through secretory factors during the postnatal white-to-brown conversion of adipose tissue in Syrian hamsters.

イソプレノイド合成経路による褐色脂肪細胞分化調節機構の検討　　　　　　　　　　　　　　　
Kwon Jungin, Yeh Yu-Sheng, 川原崎 聡子, 南野 寛人, 藤田 義人, 岡松 優子, 野村 亘, 高橋 春弥, 木村 和弘, 斉藤 昌之, 稲垣 暢也, 井上 和生, 河田 照雄, 後藤 剛, 京大・生理化学研究ユニット
日本栄養・食糧学会大会講演要旨集, 75回, 71, 71, (公社)日本栄養・食糧学会, 2021年07月
日本語

Brown Fat as a Regulator of Systemic Metabolism beyond Thermogenesis
Okamatsu-Ogura Yuko, Masayuki Saito
Diabetes & Metabolism Journal, Korean Diabetes Association, 2021年06月25日, ［査読有り］, ［筆頭著者］
研究論文（学術雑誌）

Expression of Grainyhead-like 2 in the Process of Ductal Development of Mouse Mammary Gland
Shinya Matsuoka, Hiroyoshi Suzuki, Chieko Kato, Mai Kamikawa-Tokai, Akihiro Kamikawa, Yuko Okamatsu-Ogura, Kazuhiro Kimura
Journal of Histochemistry & Cytochemistry, 69, 6, 373, 388, SAGE Publications, 2021年06月
研究論文（学術雑誌）, Grainyhead-like 2 (Grhl2) is a transcription factor regulating cell adhesion genes. Grhl2 acts as an epithelial–mesenchymal transition suppressor, and it is a proto-oncogene involved in estrogen-stimulated breast cancer proliferation. However, its expression during ovarian hormone–dependent mammary ductal development remains obscure. We here examined Grhl2 expression in the mammary gland of normal and steroid-replaced ovariectomized mice. Grhl2 protein signals were detected in both the mammary luminal epithelial and myoepithelial nuclei. The ratio and density of Grhl2-positive nuclei increased after the onset of puberty and progressed with age, whereas Grhl2-negative epithelial cells were detected in mature ducts. Claudin 3, claudin 4, claudin 7, and E-cadherin gene expression in the mammary gland was upregulated, and their expression was highly correlated with Grhl2 gene expression. Furthermore, Grhl2 mRNA expression and ductal lumen width were significantly increased by the combined treatment of estrogen and progesterone compared with estrogen alone. These results suggest that Grhl2 expressed in the luminal epithelial and myoepithelial cells from the early phase of ductal development, controlling the expression of cell adhesion molecules to establish functional ducts:

Melanin-concentrating hormone-producing neurons in the hypothalamus regulate brown adipose tissue and thus contribute to energy expenditure.
Shuntaro Izawa, Takeshi Yoneshiro, Kunio Kondoh, Shohei Nakagiri, Yuko Okamatsu-Ogura, Akira Terao, Yasuhiko Minokoshi, Akihiro Yamanaka, Kazuhiro Kimura
The Journal of physiology, 600, 4, 815, 827, 2021年04月26日, ［国際誌］
英語, 研究論文（学術雑誌）, KEY POINTS: Melanin-concentrating hormone (MCH) neuron-ablated mice exhibit increased energy expenditure and reduced fat weight. Increased brown adipose tissue (BAT) activity and locomotor activity-independent energy expenditure contributed to body weight reduction in MCH neuron-ablated mice. MCH neurons send inhibitory input to the medullary raphe nucleus to modulate BAT activity. ABSTRACT: Hypothalamic melanin-concentrating hormone (MCH) peptide robustly affects energy homeostasis. However, it is unclear whether and how MCH-producing neurons, which contain and release a variety of neuropeptides/transmitters, regulate energy expenditure in the central nervous system and peripheral tissues. We thus examined the regulation of energy expenditure by MCH neurons, focusing on interscapular brown adipose tissue (BAT) activity. MCH neuron-ablated mice exhibited reduced body weight, increased oxygen consumption, and increased BAT activity, which improved locomotor activity-independent energy expenditure. Trans-neuronal retrograde tracing with the recombinant pseudorabies virus revealed that MCH neurons innervate BAT via the sympathetic premotor region in the medullary raphe nucleus (MRN). MRN neurons were activated by MCH neuron ablation. Therefore, endogenous MCH neuron activity negatively modulates energy expenditure via BAT inhibition. MRN neurons might receive inhibitory input from MCH neurons to suppress BAT activity.

The response of adipose tissues to Mycoplasma pulmonis and Sendai virus infection in C57BL/6 and DBA/2 mice.
Tussapon Boonyarattanasoonthorn, Keisuke Sato, Yuko Okamatsu-Ogura, Masami Morimatsu, Takashi Agui
The Journal of veterinary medical science, 83, 3, 403, 411, 2021年03月11日, ［国内誌］
英語, 研究論文（学術雑誌）, Adipose tissues in mammals are categorized into white and brown adipose tissues in which cellular morphology, cell functions, and tissue distribution are different. White adipose tissue (WAT) plays a major role in energy reservation, while brown adipose tissue (BAT) mainly relates to the thermoregulation of the body. One interesting function of adipose tissue is the response to the infection, especially the pathogens that cause pneumonia. We have previously reported that DBA/2 (D2) mice are susceptible to pathogens causing pneumonia, Mycoplasma (M.) pulmonis and Sendai virus (SeV), whereas C57BL/6 (B6) mice are resistant to them. Furthermore, morphological alteration of mediastinal fat tissue (MFT) was seen after infection of M. pulmonis in D2 mice but not in B6 mice. In this study, we aimed to exhibit the difference in adipose tissue response in other areas, including interscapular brown adipose tissue (iBAT), inguinal white adipose tissue (ingWAT), and perigonadal WAT (perigoWAT) between resistant strain, B6 and susceptible strain, D2 after challenging them with M. pulmonis and SeV. Compared with B6 mice, D2 mice showed an increase in fat-associated lymphoid cluster in MFT, an increase in BAT in both iBAT and ingWAT after M. pulmonis and SeV infection. The results of this study indicate that pneumonia caused by M. pulmonis and SeV infection induces browning of adipocyte, suggesting that BAT plays a role in pathogen infection and inflammation.

Changes in liver microRNA expression and their possible regulatory role in energy metabolism-related genes in hibernating black bears.
Kazuhei Nishida, Michito Shimozuru, Yuko Okamatsu-Ogura, Mitsunori Miyazaki, Tsukasa Soma, Mariko Sashika, Toshio Tsubota
Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology, 191, 2, 397, 409, 2021年03月, ［国際誌］
英語, 研究論文（学術雑誌）, Hibernating bears survive up to 6 months without feeding while yet maintaining metabolic homeostasis. We previously reported expression changes in energy metabolism-related genes in the liver of hibernating Japanese black bears. The present study examined the role of microRNAs in the regulation of hepatic gene expression during hibernation. The quantitative analyses revealed significant increases in the expression of 4 microRNAs (miR-221-3p, miR-222-3p, miR-455-3p, and miR-195a-5p) and decreases of 2 microRNAs (miR-122-5p and miR-7a-1-5p) during hibernation. RNA sequencing and in silico target prediction regarding 3 upregulated microRNAs (miR-221-3p, miR-222-3p and miR-455-3p) found 13 target mRNAs with significantly decreased expression during hibernation. The transfection of microRNA mimics into cells showed that miR-222 and miR-455 reduced solute carrier family 16 member 4 (SLC16A4) and fatty acid synthase (FASN) mRNA expression, respectively. Our results suggest that the increased levels of hepatic miRNA during hibernation (miR-222-3p and miR-455-3p) negatively regulate the expression of targeted genes predicted to be involved in the transport of energy source and de novo fatty acid synthesis, is consistent with a regulatory role of these miRNAs in energy metabolism in hibernating black bears.

Opposing functions of α- and β-adrenoceptors in the formation of processes by cultured astrocytes.
Taisuke Kitano, Ryota Eguchi, Yuko Okamatsu-Ogura, Soichiro Yamaguchi, Ken-Ichi Otsuguro
Journal of pharmacological sciences, 145, 3, 228, 240, 2021年03月, ［国内誌］
英語, 研究論文（学術雑誌）, Astrocytes are glial cells with numerous fine processes which are important for the functions of the central nervous system. The activation of β-adrenoceptors induces process formation of astrocytes via cyclic AMP (cAMP) signaling. However, the role of α-adrenoceptors in the astrocyte morphology has not been elucidated. Here, we examined it by using cultured astrocytes from neonatal rat spinal cords and cortices. Exposure of these cells to noradrenaline and the β-adrenoceptor agonist isoproterenol increased intracellular cAMP levels and induced the formation of processes. Noradrenaline-induced process formation was enhanced with the α1-adrenoceptor antagonist prazosin and α2-adrenoceptor antagonist atipamezole. Atipamezole also enhanced noradrenaline-induced cAMP elevation. Isoproterenol-induced process formation was not inhibited by the α1-adrenoceptor agonist phenylephrine but was inhibited by the α2-adrenoceptor agonist dexmedetomidine. Dexmedetomidine also inhibited process formation induced by the adenylate cyclase activator forskolin and the membrane-permeable cAMP analog dibutyryl-cAMP. Moreover, dexmedetomidine inhibited cAMP-independent process formation induced by adenosine or the Rho-associated kinase inhibitor Y27632. In the presence of propranolol, noradrenaline inhibited Y27632-induced process formation, which was abolished by prazosin or atipamezole. These results demonstrate that α-adrenoceptors inhibit both cAMP-dependent and -independent astrocytic process formation.

Chronic low-dose exposure to imidacloprid potentiates high fat diet-mediated liver steatosis in c57bl/6j male mice.
Collins Nimako, Yoshinori Ikenaka, Yuko Okamatsu-Ogura, Jussiaea V Bariuan, Atsushi Kobayashi, Ryo Yamazaki, Kumiko Taira, Nobuhiko Hoshi, Tetsushi Hirano, Shouta M M Nakayama, Mayumi Ishizuka
The Journal of veterinary medical science, 83, 3, 487, 500, 2021年01月25日, ［国内誌］
英語, 研究論文（学術雑誌）, Hepatic steatosis is known to precede a continuum of events that lead to hepatic metabolic dysfunction, inflammation and carcinogenesis. Recently, studies have linked xenobiotic exposures to hepatic steatogenesis and its associated metabolic disorders; however, the underlying mechanisms remain elusive. This study aimed to elucidate the mechanistic role of imidacloprid in the prevalence of high fat diet (HFD)-induced liver steatosis, using a C57BL/6J mice model. Mice (3 weeks old) were fed with HFD and treated with 0.6 mg/kg bw/day (one-tenth of the NOAEL) of imidacloprid through water or diet, for 24 weeks. In a controlled group, mice were fed with only HFD. At the end of the study, imidacloprid treatment significantly potentiated HFD-induced body weight gain in mice. Also, imidacloprid increased the liver weights of mice, with complimentary reductions in mesenteric and gonadal white adipose tissue weights. Histopathological analysis of liver revealed a drastic steatosis in imidacloprid treated mice. Following a real-time qPCR analysis, imidacloprid upregulated transcriptions of hepatic fatty acid biosynthesis-related transcription factors and genes. Imidacloprid also induced hepatic expression of the gene encoding pregnane X receptor; but had no significant effect on hepatic expressions of liver X receptor and aryl hydrocarbon receptor. The imidacloprid treatment further enhanced serum alanine aminotransferase levels but downregulated hepatic antioxidant mRNA expressions. Ultimately, this study suggested an imidacloprid-potentiation effects on prevalence of HFD-induced liver steatosis via transcriptional modulations of the hepatic FA biosynthesis pathway.

Kruppel-like factor 15 regulates fuel switching between glucose and fatty acids in brown adipocytes.
Yuko Nabatame, Tetsuya Hosooka, Chikako Aoki, Yusei Hosokawa, Makoto Imamori, Yoshikazu Tamori, Yuko Okamatsu-Ogura, Takeshi Yoneshiro, Shingo Kajimura, Masayuki Saito, Wataru Ogawa
Journal of diabetes investigation, 2021年01月21日, ［国内誌］
英語, 研究論文（学術雑誌）, AIMS/INTRODUCTION: Brown adipose tissue (BAT) utilizes large amounts of fuel for thermogenesis, but the mechanism by which fuel substrates are switched in response to changes in energy status is poorly understood. We have now investigated the role of Kruppel-like factor 15 (KLF15), a transcription factor expressed at a high level in adipose tissue, in the regulation of fuel utilization in BAT. MATERIALS AND METHODS: Depletion or overexpression of KLF15 in HB2 differentiated brown adipocytes was achieved by adenoviral infection. Glucose and fatty acid oxidation were measured with radioactive substrates, pyruvate dehydrogenase complex activity was determined with a colorimetric assay, and gene expression was examined by reverse transcription and real-time polymerase chain reaction analysis. RESULTS: Knockdown of KLF15 in HB2 cells attenuated fatty acid oxidation in association with downregulation of the expression of genes related to this process including Acox1 and Fatp1, whereas it increased glucose oxidation. Expression of the gene for pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of pyruvate dehydrogenase complex, was increased or decreased by KLF15 overexpression or knockdown, respectively, in HB2 cells, with these changes being accompanied by a respective decrease or increase in pyruvate dehydrogenase complex activity. Chromatin immunoprecipitation showed that Pdk4 is a direct target of KLF15 in HB2 cells. Finally, fasting increased expression of KLf15, Pdk4 and genes involved in fatty acid utilization in BAT of mice, whereas refeeding suppressed Klf15 and Pdk4 expression. CONCLUSIONS: Our results implicate KLF15 in the regulation of fuel switching between glucose and fatty acids in response to changes in energy status in BAT.

Cold-induced Conversion of Connective Tissue Skeleton in Brown Adipose Tissues
Masako Yudasaka, Yuko Okamatsu-Ogura, Takeshi Tanaka, Kumiko Saeki, Hiromichi Kataura
ACTA HISTOCHEMICA ET CYTOCHEMICA, 54, 5, 131, 141, JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY, 2021年
英語, 研究論文（学術雑誌）, Thermogenesis via fatty acid-induced uncoupled mitochondrial respiration is the primary function of brown adipose tissue (BAT). In response to changes in ambient temperatures, the weight and specific gravity of BAT change, depending on the quantity of lipid droplets stored in brown adipocytes (BA). Such conditions should result in the reconstruction of connective tissue skeletons, especially of collagen fiber networks, although the mechanisms have not been clarified. This study showed that, within 4 hr of exposing mice to a cold environment, collagen fibers in the extracellular matrix (ECM) of BAT became discontinuous, twisted, emancipated, and curtailed. Surprisingly, the structure of collagen fibers returned to normal after the mice were kept at room temperature for 19 hr, indicating that the alterations in collagen fiber structures are physiological processes association with adaptation to cold environments. These dynamic changes in connective tissue skeletons were not observed in white adipose tissues, suggesting that they are unique to BAT. Interestingly, the vascular permeability of BAT was also augmented by exposure to cold. Collectively, these findings indicate that dynamic changes in ECM collagen fibers provide high flexibility to BAT, enabling the adjustment of tissue structures and the regulation of vascular permeability, resulting in adaptation to changes in ambient temperatures.

UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice.
Yuko Okamatsu-Ogura, Masashi Kuroda, Rie Tsutsumi, Ayumi Tsubota, Masayuki Saito, Kazuhiro Kimura, Hiroshi Sakaue
Metabolism: clinical and experimental, 113, 154396, 154396, 2020年12月, ［筆頭著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Brown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates UCP1-mediated thermogenesis in BAT and causes drastic changes in glucose, lipid, and amino acid metabolism; however, the relationship between these metabolic changes and UCP1-mediated thermogenesis is not fully understood. METHODS: We conducted metabolomic and GeneChip array analyses of BAT after 4-h exposure to cold temperature (10 °C) in wild-type (WT) and UCP1-KO mice. RESULTS: Cold exposure largely increased metabolites of the glycolysis pathway and lactic acid levels in WT, but not in UCP1-KO, mice, indicating that aerobic glycolysis is enhanced as a consequence of UCP1-mediated thermogenesis. GeneChip array analysis of BAT revealed that there were 2865 genes upregulated by cold exposure in WT mice, and 838 of these were upregulated and 74 were downregulated in UCP1-KO mice. Pathway analysis revealed the enrichment of genes involved in fatty acid (FA) β oxidation and triglyceride (TG) synthesis in both WT and UCP1-KO mice, suggesting that these metabolic pathways were enhanced by cold exposure independently of UCP1-mediated thermogenesis. FA and cholesterol biosynthesis pathways were enhanced only in UCP1-KO mice. Cold exposure also significantly increased the BAT content of proline, tryptophan, and phenylalanine amino acids in both WT and UCP1-KO mice. In WT mice, cold exposure significantly increased glutamine content and enhanced the expression of genes related to glutamine metabolism. Surprisingly, aspartate was almost completely depleted after cold exposure in UCP1-KO mice. Gene expression analysis suggested that aspartate was actively utilized after cold exposure both in WT and UCP1-KO mice, but it was replenished from intracellular N-acetyl-aspartate in WT mice. CONCLUSIONS: These results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.

Characterization of brown adipose tissue thermogenesis in the naked mole-rat (Heterocephalus glaber), a heterothermic mammal.
Yuki Oiwa, Kaori Oka, Hironobu Yasui, Kei Higashikawa, Hidemasa Bono, Yoshimi Kawamura, Shingo Miyawaki, Akiyuki Watarai, Takefumi Kikusui, Atsushi Shimizu, Hideyuki Okano, Yuji Kuge, Kazuhiro Kimura, Yuko Okamatsu-Ogura, Kyoko Miura
Scientific reports, 10, 1, 19488, 19488, 2020年11月10日, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The naked mole-rat (NMR) is a heterothermic mammal that forms eusocial colonies consisting of one reproductive female (queen), several reproductive males, and subordinates. Despite their heterothermy, NMRs possess brown adipose tissue (BAT), which generally induces thermogenesis in cold and some non-cold environments. Previous studies suggest that NMR-BAT induces thermogenesis by cold exposure. However, detailed NMR-BAT characteristics and whether NMR-BAT thermogenesis occurs in non-cold environments are unknown. Here, we show beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential of NMR-BAT, which contributes to thermogenesis in the isolated queen in non-cold environments (30 °C). NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activity in vitro and in vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment (20 °C), it was insufficient to prevent the decrease in the body temperatures. Even at 30 °C, NMRs are known to prevent the decrease of and maintain their body temperature by heat-sharing behaviors within the colony. However, isolated NMRs maintained their body temperature at the same level as when they are in the colony. Interestingly, we found that queens, but not subordinates, induce BAT thermogenesis in this condition. Our research provides novel insights into NMR thermoregulation.

Fucoxanthin inhibits hepatic oxidative stress, inflammation, and fibrosis in diet-induced nonalcoholic steatohepatitis model mice.
Naoki Takatani, Yuka Kono, Fumiaki Beppu, Yuko Okamatsu-Ogura, Yumiko Yamano, Kazuo Miyashita, Masashi Hosokawa
Biochemical and biophysical research communications, 528, 2, 305, 310, 2020年07月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Nonalcoholic steatohepatitis (NASH) is associated with hepatocyte injury, excessive oxidative stress, and chronic inflammation in fatty liver, and can progress to more severe liver diseases, such as cirrhosis and hepatocellular carcinoma. However, currently there are no effective therapies for NASH. Marine carotenoid, fucoxanthin (Fx), abundant in brown seaweeds, has variable biological properties, such as anti-cancer, anti-inflammatory, anti-oxidative and anti-obesity. However, the effect of Fx on the development of NASH has not been explored. We investigated the protective effects of Fx in diet-induced NASH model mice fed choline-deficient L-amino acid-defined high fat diet (CDAHFD). Fx administration significantly attenuated liver weight gain and hepatic fat accumulation, resulting in the alleviation of hepatic injury. Furthermore, the Fx-fed mice, not only exhibited reduced hepatic lipid oxidation, but also decreased mRNA expression levels of inflammation and infiltration-related genes compared to that of the CDAHFD-fed mice. Moreover, fucoxanthinol and amarouciaxanthin A, two Fx metabolites exerted anti-inflammatory effects in the liver via inhibiting the chemokine production in hepatocytes. In case of fibrosis, one of the features of advanced NASH, the expression of fibrogenic factors including activated-hepatic stellate cell marker was significantly decreased in the liver of Fx-fed mice. Thus, the present study elucidated that dietary Fx not only inhibited hepatic oxidative stress and inflammation but also prevented early phase of fibrosis in the diet-induced NASH model mice.

The effect of temperature acclimation on torpor expression pattern in mice.
Sakamoto KQ, Okamatsu-Ogura Y
JAPANESE JOURNAL OF VETERINARY RESEARCH, 68, 1, 55, 62, HOKKAIDO UNIV, 2020年
英語, 研究論文（学術雑誌）, Torpor is a hibernation like status which drops core body temperature, and continues for several hours. Although torpor is observed among a wide range of mammals, most of the body mass of torpor expressing species is less than 100 g, suggesting the size of the body would be a key factor of torpor expression. In the small animals, continuous heat production is essential to keep body temperature within a certain range. Thus, we hypothesized that torpor expression pattern would be affected by the capacity of heat production. We prepared mice with different capacities of shivering and non-shivering thermogenesis, two major heat producing systems in mice. To modulate the capacity of both thermogenesis, mice were acclimated to cool (18 degrees C) or warm (28 degrees C) ambient temperature. Mice deficient in uncoupling protein 1 (UCP1), a protein that mediates non-shivering thermogenesis, were acclimated to cool ambient temperature to enhance capacity of shivering, but not non-shivering thermogenesis. By food deprivation, all mice in all groups expressed torpor. Although the time for induction and duration of torpor did not show any differences among the groups, the minimum body temperature during torpor in warm-acclimated mice was lower than that in cool-acclimated UCP1-knockout mice. Cool-acclimated UCP1-knockout mice did not show any significant difference in torpor expression pattern compared to cool-acclimated wild-type mice, indicating a minor role of non-shivering thermogenesis in torpor expression in our experiment condition.

Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men.
Masayuki Saito, Mami Matsushita, Takeshi Yoneshiro, Yuko Okamatsu-Ogura
Frontiers in endocrinology, 11, 222, 222, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Since the recent rediscovery of brown adipose tissue (BAT) in adult humans, this thermogenic tissue has been attracting increasing interest. The inverse relationship between BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. Cold exposure activates and recruits BAT, resulting in increased energy expenditure and decreased body fatness. The stimulatory effects of cold exposure are mediated through transient receptor potential (TRP) channels and the sympathetic nervous system (SNS). Most TRP members also function as chemesthetic receptors for various food ingredients, and indeed, agonists of TRP vanilloid 1 such as capsaicin and its analog capsinoids mimic the effects of cold exposure to decrease body fatness through the activation and recruitment of BAT. The antiobesity effect of other food ingredients including tea catechins may be attributable, at least in part, to the activation of the TRP-SNS-BAT axis. BAT is also involved in the facultative thermogenesis induced by meal intake, referred to as diet-induced thermogenesis (DIT), which is a significant component of the total energy expenditure in our daily lives. Emerging evidence suggests a crucial role for the SNS in BAT-associated DIT, particularly during the early phase, but several gut-derived humoral factors may also participate in meal-induced BAT activation. One intriguing factor is bile acids, which activate BAT directly through Takeda G-protein receptor 5 (TGR5) in brown adipocytes. Given the apparent beneficial effects of some TRP agonists and bile acids on whole-body substrate and energy metabolism, the TRP/TGR5-BAT axis represents a promising target for combating obesity and related metabolic disorders in humans.

Hibernating bear serum hinders osteoclastogenesis in-vitro.
Alireza Nasoori, Yuko Okamatsu-Ogura, Michito Shimozuru, Mariko Sashika, Toshio Tsubota
PloS one, 15, 8, e0238132, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Bears do not suffer from osteoporosis during hibernation, which is associated with long-term inactivity, lack of food intake, and cold exposure. However, the mechanisms involved in bone loss prevention have scarcely been elucidated in bears. We investigated the effect of serum from hibernating Japanese black bears (Ursus thibetanus japonicus) on differentiation of peripheral blood mononuclear cells (PBMCs) to osteoclasts (OCs). PBMCs collected from 3 bears were separately cultured with 10% serum of 4 active and 4 hibernating bears (each individual serum type was assessed separately by a bear PBMCs), and differentiation were induced by treatment with macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL). PBMCs that were cultured with the active bear serum containing medium (ABSM) differentiated to multi-nucleated OCs, and were positive for TRAP stain. However, cells supplemented with hibernating bear serum containing medium (HBSM) failed to form OCs, and showed significantly lower TRAP stain (p < 0.001). On the other hand, HBSM induced proliferation of adipose derived mesenchymal stem cells (ADSCs) similarly to ABSM (p > 0.05), indicating no difference on cell growth. It was revealed that osteoclastogenesis of PBMCs is hindered by HBSM, implying an underlying mechanism for the suppressed bone resorption during hibernation in bears. In addition, this study for the first time showed the formation of bears' OCs in-vitro.

Unique Running Pattern and Mucosal Morphology Found in the Colon of Cotton Rats.
Tsolmon Chuluunbaatar, Osamu Ichii, Teppei Nakamura, Takao Irie, Takashi Namba, Md Rashedul Islam, Yuki Otani, Md Abdul Masum, Yuko Okamatsu-Ogura, Yaser Hosny Ali Elewa, Yasuhiro Kon
Frontiers in physiology, 11, 587214, 587214, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Cotton rats are one of the experimental rodents used for testing different infectious and non-infectious diseases, including gastrointestinal tract pathology. However, their intestinal morphological characteristics are still poorly understood. Here, we clarified the anatomical and histological characteristics of the cecum and ascending colon (AC) of young (1-3-month old), adult (4-6-month old), and old (10-12-month old) cotton rats. The large intestine (LI) in cotton rats is composed of the cecum, AC, transverse and descending colons, and rectum, and is similar to that of other mammals. The AC begins with a double or triple spiral loop-like flexure (SLLF) and ends with a coupled horseshoe-like flexure (HSLF). A single longitudinal mucosal fold (SLMF) was found at the beginning of the AC along the mesentery line and developed with age. Furthermore, the SLMF contained several lymphatic nodules (LNs), indicating their role in digestive and immunological functions. Small and large protuberant LNs were found in the cecum and SLLF, respectively, whereas thin and flat LNs were observed in the HSLF and transverse colon, respectively. Regarding sex-related differences, adult females had a significantly longer AC with a higher number of SLLFs compared to males. The SLMF length and LN number were also longer and higher, respectively, in adult females compared to adult males. These are crucial findings, indicating the presence of sex-related differences in the morphology of the LI in cotton rats, and ours is the first study to discover a sex difference in the mammalian LI lining. Our study clarified the unique morphology of the LI in cotton rats, which could serve as the principal model for elucidating species-specific digestive tract functions and gastrointestinal disorders.

Fat-specific protein 27α inhibits autophagy-dependent lipid droplet breakdown in white adipocytes
Nakajima S, Nishimoto Y, Tateya S, Iwahashi Y, Okamatsu-Ogura Y, Saito M, Ogawa W, Tamori Y
J Diabetes Investig, 10, 6, 1419, 1429, 2019年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, AIMS/INTRODUCTION: Fat-specific protein 27 (FSP27) α is the major isoform of FSP27 in white adipose tissue (WAT), and is essential for large unilocular lipid droplet (LD) formation in white adipocytes. In contrast, FSP27β is abundantly expressed in brown adipose tissue (BAT), and plays an important role in small multilocular LD formation. In FSP27 KO mice in which FSP27α and β are both depleted, WAT is characterized by multilocular LD formation, and by increased mitochondrial abundance and energy expenditure, whereas BAT conversely manifests large oligolocular LDs and reduced energy expenditure. MATERIALS AND METHODS: We investigated the effects of autophagy in WAT and BAT of wild type (WT) and FSP27 knockout (KO) mice. In addition, we examined the effects of FSP27α and FSP27β to the induction of autophagy in COS cells. RESULTS: Food deprivation induced autophagy in BAT of WT mice, as well as in WAT of FSP27 KO mice, suggesting that enhanced autophagy is characteristic of adipocytes with small multilocular LDs. Pharmacological inhibition of autophagy attenuated the fasting-induced loss of LD area in adipocytes with small multilocular LDs (BAT of WT mice and WAT of FSP27 KO mice), without affecting that in adipocytes with large unilocular or oligolocular LDs (WAT of WT mice or in BAT of FSP27 KO mice). Overexpression of FSP27α inhibited autophagy induction by serum deprivation in COS cells, whereas that of FSP27β had no such effect. CONCLUSIONS: The present results thus showed that FSP27α inhibits autophagy and might thereby contribute to the energy-storage function of WAT.

Role of brown adipose tissue in body temperature control during the early postnatal period in Syrian hamsters and mice.
Ayumi Tsubota, Yuko Okamatsu-Ogura, Jussiaea Valente Bariuan, Junnosuke Mae, Shinya Matsuoka, Junko Nio-Kobayashi, Kazuhiro Kimura
The Journal of veterinary medical science, 81, 10, 1461, 1467, 2019年10月24日, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Brown adipose tissue (BAT) contributes to non-shivering thermogenesis and plays an important role in body temperature control. The contribution of BAT thermogenesis to body temperature control in a non-cold environment was evaluated using developing hamsters. Immunostaining for uncoupling protein 1 (UCP1), a mitochondrial protein responsible for BAT thermogenesis, indicated that interscapular fat tissue had matured as BAT at day 14. When pups were placed on a thermal plate kept at 23°C, the body surface temperature decreased in day 7- and 10-day-old pups but was maintained at least for 15 min in 14-day-old pups, indicating that hamsters are unable to maintain their body temperature until around day 14 even in a non-cold environment. Body temperature maintenance was also evaluated in UCP1-deficient mice. BAT analysis showed that the UCP1 protein level in Ucp1+/- Hetero mice was 61.3 ± 1.4% of that in wild-type (WT) mice and was undetected in Ucp1-/- knockout (KO) mice. When 12-day-old pups were place on a thermal plate at 23°C, body surface temperature was maintained for at least 15 min in WT and Hetero mice but gradually dropped by 2.4 ± 0.2°C in 15 min in KO mice. It is concluded that BAT thermogenesis is indispensable for body temperature maintenance in pups of hamsters and mice, even in the non-cold circumstances. The early life poikilothermy and the later acquirement of homeothermy in hamsters may be because of the postnatal development of BAT.

絶食によるマウス褐色脂肪組織における血管外漏出性亢進
湯田坂 雅子, 蓬田 陽平, 張 民芳, 中原 正子, 小林 徳彦, 田中 丈士, 岡松 優子, 佐伯 久美子, 片浦 弘道
肥満研究, 25, Suppl., 284, 284, (一社)日本肥満学会, 2019年10月
日本語

マウス褐色脂肪組織のCNTによるイメージング
湯田坂 雅子, 蓬田 陽平, 張 民芳, 田中 丈士, 中原 正子, 小林 徳彦, 岡松 優子, 町田 拳, 石原 一彦, 佐伯 久美子, 片浦 弘道
肥満研究, 25, Suppl., 302, 302, (一社)日本肥満学会, 2019年10月
日本語

Association of circulating exosomal miR-122 levels with BAT activity in healthy humans.
Yuko Okamatsu-Ogura, Mami Matsushita, Jussiaea Valente Bariuan, Kazuki Nagaya, Ayumi Tsubota, Masayuki Saito
Scientific reports, 9, 1, 13243, 13243, 2019年09月13日, ［査読有り］, ［筆頭著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Brown adipose tissue (BAT) plays an important role in body fat accumulation and the regulation of energy expenditure. Since the role of miRNAs in the pathogenesis of obesity and related metabolic diseases is contentious, we analyzed exosomal miRNAs in serum of healthy subjects with special references to BAT activity and body fat level. Forty male volunteers aged 20-30 years were recruited. Their BAT activity was assessed by fluorodeoxyglucose positron emission tomography and computed tomography after 2 h of cold exposure and expressed as a maximal standardized uptake value (SUVmax). Exosomal miRNA levels was analyzed using microarray and real-time PCR analyses. The miR-122-5p level in the high BAT activity group (SUV ≧ 3) was 53% lower than in the low BAT activity group (SUVmax <3). Pearson's correlation analysis revealed that the serum miR-122-5p level correlated negatively with BAT activity and the serum HDL-cholesterol, and it correlated positively with age, BMI, body fat mass, and total cholesterol and triglyceride serum levels. Multivariate regression analysis revealed that BAT activity was associated with the serum miR-122-5p level independently of the other parameters. These results reveal the serum exosomal miR-122-5p level is negatively associated with BAT activity independently of obesity.

Impaired adrenergic agonist-dependent beige adipocyte induction in obese mice.
Woongchul Shin, Yuko Okamatsu-Ogura, Shinya Matsuoka, Ayumi Tsubota, Kazuhiro Kimura
The Journal of veterinary medical science, 81, 6, 799, 807, 2019年06月06日, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Brown adipocytes, which exist in brown adipose tissue (BAT), are activated by adrenergic stimulation, depending on the activity of uncoupling protein 1 (UCP1). Beige adipocytes emerge from white adipose tissue (WAT) in response to chronic adrenergic stimulation. We investigated obesity-related changes in responses of both types of adipocytes to adrenergic stimulation in mice. Feeding of mice with high-fat diets (HFD: 45%-kcal fat) for 14 weeks resulted in significantly higher body and WAT weight compared to feeding with normal diets (ND: 10%-kcal fat). Injection with β3-adrenergic receptor agonist CL316,243 (CL; 0.1 mg/kg, once a day) for one week elevated the mRNA and protein expression levels of UCP1 in BAT, irrespective of diet. In WAT, CL-induced UCP1 expression in ND mice; however, the responses to CL treatment were attenuated in HFD mice, indicating that CL-induced browning of WAT was impaired in obese mice. Flow cytometric analysis revealed a significant decrease in platelet-derived growth factor receptor (PDGFR) α-expressing beige adipocyte progenitors in WAT of HFD mice compared with those of ND mice. Expression of PDGF-B, a PDGFRα ligand, increased in WAT following CL-injection in ND mice, but not in HFD mice. Treatment of mice with a PDGFR inhibitor significantly decreased CL-dependent UCP1 protein induction in WAT. Our study demonstrates that β3-adrenergic stimulation-dependent beige adipocyte induction in WAT is impaired by obesity in mice, potentially due to obesity-dependent reduction in the number of PDGFRα-expressing progenitors and decreased PDGF-B expression.

Evaluation of Glucose Uptake and Uncoupling Protein 1 Activity in Adipose Tissue of Diabetic Mice upon β-Adrenergic Stimulation.
Narumi Kubo, Mio Kawahara, Yuko Okamatsu-Ogura, Yosuke Miyazaki, Ryuto Otsuka, Kazuki Fukuchi
Molecular imaging and biology, 21, 2, 249, 256, 2019年04月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Regulation of metabolic activity in adipose tissue is of great concern for treating obesity. This study aimed to evaluate the adrenergic regulation of glucose uptake and the thermogenic program in adipose tissues in mouse models of both type 1 and 2 diabetes mellitus (DM). PROCEDURES: Male mice were treated with streptozotocin to induce type 1 (T1) DM, and obese ob/ob mice were used for the type 2 (T2) DM model. After selective β3-adrenoreceptor stimulation by CL 316,243 (CL) treatment, 2-deoxy-D-[14C]glucose ([14C]DG) was administered to DM and corresponding control mice. Radioactivity and uncoupling protein 1 (UCP1) expression were measured and analyzed in adipose tissues. RESULTS: In T1DM, [14C]DG uptake in brown adipose tissue (BAT) decreased both at rest and upon CL stimulation, and UCP1 expression was preserved. However, CL treatment enhanced [14C]DG uptake without impairing UCP1 expression in inguinal white adipose tissue (iWAT). In this model, CL could not alter blood glucose levels. In T2DM mice, the blood glucose level was significantly lowered by CL treatment. There was no decrease in CL-induced [14C]DG uptake in BAT, and UCP1 expression was maintained. However, [14C]DG uptake was not increased in iWAT and no UCP1 expression was observed in iWAT (browning). CONCLUSIONS: The metabolic response against adrenergic stimulation varied depending on the type of adipose tissue and DM. This could be important for the therapeutic activation of adipose tissue metabolism in obese diabetic patients.

Differentiation of bone marrow-derived cells toward thermogenic adipocytes in white adipose tissue induced by the β3 adrenergic stimulation.
Yoneshiro T, Shin W, Machida K, Fukano K, Tsubota A, Chen Y, Yasui H, Inanami O, Okamatsu-Ogura Y, Kimura K
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 4, 5196, 5207, 2019年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Bone marrow provides progenitors of several types of cells, including muscle and white adipocytes, ensuring peripheral tissue homeostasis. However, the role of bone marrow-derived cells (BMCs) in induction of thermogenic adipocytes is unresolved. The purpose of this study is to examine whether BMCs are involved in the emergence of thermogenic adipocytes through adrenergic activation. Irradiation of mice with 8 Gy of X-ray-depleted BMCs and peripheral blood mononucleated cells (PBMCs), which in turn impaired induction of uncoupling protein 1 (UCP1) through administration of β3 adrenergic receptor agonist, CL 316,243 (CL), in inguinal white adipose tissue (iWAT). In contrast, CL-induced UCP1 induction in brown adipose tissue was unaffected by BMC depletion. Transplantation of normal BMCs into mice depleted of BMCs recovered PBMC levels and rescued the ability of iWAT browning by CL. Furthermore, analyses of mice transplanted with green fluorescent protein (GFP)-labeled BMCs revealed that the number of GFP-positive BMCs and PBMCs were significantly decreased by CL and that GFP-positive stromal cells and GFP-positive UCP1-expressing multilocular adipocytes appeared in iWAT after CL administration, demonstrating differentiation of BMC-derived preadipocytes into UCP1-expressing thermogenic adipocytes. These results unveiled a crucial role of the BMC as a nonresident origin for a subset of thermogenic adipocytes, contributing to browning of white adipose tissue.-Yoneshiro, T., Shin, W., Machida, K., Fukano, K., Tsubota, A., Chen, Y., Yasui, H., Inanami, O., Okamatsu-Ogura, Y., Kimura, K. Differentiation of bone marrow-derived cells toward thermogenic adipocytes in white adipose tissue induced by the β3 adrenergic stimulation.

Interaction of Nerve Growth Factor β with Adiponectin and SPARC Oppositely Modulates its Biological Activity.
Okura Y, Imao T, Murashima S, Shibata H, Kamikavwa A, Okamatsu-Ogura Y, Saito M, Kimura K
International journal of molecular sciences, 20, 7, 2019年03月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Both adiponectin and secreted protein, acidic and rich in cysteine (SPARC) inhibit platelet-derived growth factor-BB (PDGF-BB)-induced and basic fibroblast growth factor (FGF2)-induced angiogenic activities through direct and indirect interactions. Although SPARC enhances nerve growth factor (NGF)-dependent neurogenesis, the physical interaction of NGFβ with adiponectin and SPARC remains obscure. Therefore, we first examined their intermolecular interaction by surface plasmon resonance method. NGFβ bound to immobilized SPARC with the binding constant of 59.4 nM, comparable with that of PDGF-BB (24.5 nM) but far less than that of FGF2 (14.4 µM). NGFβ bound to immobilized full length adiponectin with the binding constant of 103 nM, slightly higher than those of PDGF-BB (24.3 nM) and FGF2 (80.2 nM), respectively. Treatment of PC12 cells with SPARC did not cause mitogen-activated protein kinase (MAPK) activation and neurite outgrowth. However, simultaneous addition of SPARC with NGFβ enhanced NGFβ-induced MAPK phosphorylation and neurite outgrowth. Treatment of the cells with adiponectin increased AMP-activated protein kinase (AMPK) phosphorylation but failed to induce neurite outgrowth. Simultaneous treatment with NGFβ and adiponectin significantly reduced cell size and the number of cells with neurite, even after silencing the adiponectin receptors by their siRNA. These results indicate that NGFβ directly interacts with adiponectin and SPARC, whereas these interactions oppositely regulate NGFβ functions.

Linking pathways and processes: Retinoic acid and glucose
Shinya Matsuoka, Jussiaea Valente Bariuan, Shohei Nakagiri, Mabrouk Attia Abd Eldaim, Yuko Okamatsu-Ogura, Kazuhiro Kimura
Molecular Nutrition Carbohydrates, 247, 264, Elsevier, 2019年01月01日
英語, 論文集(書籍)内論文, This chapter focuses on the interplay between retinoids and carbohydrate metabolisms. Retinoic acid (RA), an active retinoid, is intracellularly synthesized by two-step conversion of retinol and activates transcription of target genes mainly through retinoic acid receptor (RAR). On the other hand, glucose is oxidized to produce ATP, but if in excess, it is stored effectively as triacylglycerol by activating nutrient-sensing transcription factors (TFs) such as carbohydrate response element-binding protein (ChREBP), sterol response element-binding protein (SREBP), and liver X receptor (LXR). Expression of these TFs is induced by hepatocyte nuclear factor (HNF)4α and peroxisome proliferator-activated receptor (PPAR)γ. It is reported that RA represses expression of HNF4α directly and of PPARγ indirectly. RA also induces small heterodimer partner expression that inhibits activity of TFs such as HNF4α and LXR. Therefore RA may control carbohydrate metabolism through repressing upstream TFs (nuclear receptors) that activate expression of the nutrient-sensing TFs.

Cold Exposure Increases Circulating miR-122 Levels via UCP1-Dependent Mechanism in Mice.　　　　　　　　　　　　　　　
Bariuan JV, Okamatsu-Ogura Y, Tsubota A, Matsuoka S, Saito M, Kimura K
Japanese Journal of Veterinary Research, 68, 3, 187, 195, 2019年, ［責任著者］

Melinjo (Gnetum gnemon L.) seed extract induces uncoupling protein 1 expression in brown fat and protects mice against diet-induced obesity, inflammation, and insulin resistance.
Takeshi Yoneshiro, Ryuji Kaede, Kazuki Nagaya, Manami Saito, Julia Aoyama, Mohamed Elfeky, Yuko Okamatsu-Ogura, Kazuhiro Kimura, Akira Terao
Nutrition research (New York, N.Y.), 58, 17, 25, 2018年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Dietary supplementation with melinjo (Gnetum gnemon L.) seed extract (MSE) has been proposed as an anti-obesity strategy. However, it remains unclear how MSE modulates energy balance. We tested the hypothesis that dietary MSE reduces energy intake and/or increases physical activity and metabolic thermogenesis in brown and white adipose tissue (BAT and WAT) in mice. Twenty-four C57BL/6 J mice were provided with normal diet, high-fat diet (HFD), or HFD with 1% MSE added, for 17 weeks. Food intake, spontaneous locomotor activity, hepatic triglyceride (TG) content, and blood parameters were examined. Mitochondrial thermogenesis-associated molecule and inflammatory marker expression levels in BAT and WAT were examined by quantitative PCR and western blotting. Dietary MSE did not affect energy intake or spontaneous locomotor activity, but significantly suppressed HFD-induced fat accumulation, hyperglycemia, and hyperinsulinemia. Homeostasis model assessment of insulin resistance score and hepatic TG content were both lower in the MSE-supplemented HFD-fed group than in the HFD-fed group, indicating reduced insulin resistance and a less fatty liver. Dietary MSE upregulated thermogenic uncoupling protein 1 (UCP1) and mitochondrial marker cytochrome c oxidase subunit IV protein expression in BAT; this was closely associated with sirtuin 1 mRNA induction. mRNAs of adipose inflammatory markers, such as monocyte chemotactic 1 and interleukin-1, were induced by HFD but suppressed by MSE. Considering that UCP1 protein expression is the most physiologically relevant parameter to assess the thermogenic capacities of BAT, our results indicate that dietary MSE supplementation induces BAT thermogenesis and reduces obesity-associated adipose tissue inflammation, hepatic steatosis, and insulin resistance.

Fasting-dependent Vascular Permeability Enhancement in Brown Adipose Tissues Evidenced by Using Carbon Nanotubes as Fluorescent Probes.
Masako Yudasaka, Yohei Yomogida, Minfang Zhang, Masako Nakahara, Norihiko Kobayashi, Takeshi Tanaka, Yuko Okamatsu-Ogura, Kumiko Saeki, Hiromichi Kataura
Scientific reports, 8, 1, 14446, 14446, 2018年09月27日, ［国際誌］
英語, 研究論文（学術雑誌）, Brown adipose tissue (BAT), which is composed of thermogenic brown adipocytes (BA) and non-parenchymal components including vasculatures and extracellular matrix, contribute to the maintenance of body temperature. BAT distribution is detected by positron emission tomography-computed tomography (PET/CT) using 18F-fluorodeoxy glucose (18F-FDG) or single-photon-emission computed tomography-computed tomography (SPECT/CT) using [123/125I]-beta-methyl-p-iodophenyl-pentadecanoic acid. Although sympathetic nerve activity and thermogenic capacity of BA is downregulated under fasting conditions in mice, fasting-dependent structural changes and fluid kinetics of BAT remain unknown. Here we show that the fasting induces fine and reversible structural changes in the non-parenchymal region in murine BAT with widened intercellular spaces and deformed collagen bands as revealed by electron microscopy. Interestingly, a newly introduced near infrared fluorescent probe of single-walled carbon nanotubes (CNTs) coated with phospholipid polyethylene glycol (PLPEG) easily demonstrated enhanced vascular permeability in BAT by the fasting. PLPEG-CNTs extravasated and remained in intercellular spaces or further redistributed in parenchymal cells in fasted mice, which is a previously unknown phenomenon. Thus, PLPEG-CNTs provide a powerful tool to trace fluid kinetics in sub-tissue levels.

Effect of ambient temperature on the proliferation of brown adipocyte progenitors and endothelial cells during postnatal BAT development in Syrian hamsters
Kazuki Nagaya, Yuko Okamatsu-Ogura, Junko Nio-Kobayashi, Shohei Nakagiri, Ayumi Tsubota, Kazuhiro Kimura
Journal of Physiological Sciences, 1, 8, Springer Tokyo, 2018年04月02日, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, In Syrian hamsters, brown adipose tissue (BAT) develops postnatally through the proliferation and differentiation of brown adipocyte progenitors. In the study reported here, we investigated how ambient temperature influenced BAT formation in neonatal hamsters. In both hamsters raised at 23 or 30 °C, the interscapular fat changed from white to brown coloration in an age-dependent manner and acquired the typical morphological features of BAT by day 16. However, the expression of uncoupling protein 1, a brown adipocyte marker, and of vascular endothelial growth factor α were lower in the group raised at 30 °C than in that raised at 23 °C. Immunofluorescent staining revealed that the proportion of Ki67-expressing progenitors and endothelial cells was lower in the 30 °C group than in the 23 °C group. These results indicate that warm ambient temperature suppresses the proliferation of brown adipocyte progenitors and endothelial cells and negatively affects the postnatal development of BAT in Syrian hamsters.

Adiponectin suppression of late inflammatory mediator, HMGB1-induced cytokine expression in RAW264 macrophage cells
Mohamed Elfeky, Takeshi Yoneshiro, Yuko Okamatsu-Ogura, Kazuhiro Kimura
Journal of Biochemistry, 163, 2, 143, 153, Oxford University Press, 2018年02月01日, ［査読有り］
英語, 研究論文（学術雑誌）, High-mobility group protein B1 (HMGB1) is a late inflammatory mediator released from inflammatory cells when stimulated, resulting in exaggerating septic symptoms. We recently demonstrated that full-length adiponectin, a potent anti-inflammatory adipokine, inhibits lipopolysaccharide-induced HMGB1 release. However, the effects of adiponectin on HMGB1-induced exaggerating signals currently remain unknown. This study aimed to investigate the effects of adiponectin on the pro-inflammatory function of HMGB1 in RAW264 macrophage cells. The treatment of RAW264 cells with HMGB1 significantly up-regulated the mRNA expression of tumour necrosis factor-α, interleukin-1β and C-X-C motif chemokine 10. HMGB1-induced cytokine expression was markedly suppressed by a toll-like receptor 4 (TLR4) antagonist and slightly suppressed by an antagonist of the receptor for advanced glycation end products. A prior treatment with full-length or globular adiponectin dose-dependently suppressed all types of HMGB1-induced cytokine expression, and this suppression was abolished by compound C, an AMPK inhibitor, but not by the haem oxygenase (HO)-1 inhibitor, zinc protoporphyrin IX. Both forms of adiponectin also reduced the mRNA expression of TLR4. These results suggest that full-length and globular adiponectin suppress HMGB1-induced cytokine expression through an AMPK-mediated HO-1-independent pathway.

Brown adipocytes postnatally arise through both differentiation from progenitors and conversion from white adipocytes in Syrian hamster
Yuko Okamatsu-Ogura, Junko Nio-Kobayashi, Kazuki Nagaya, Ayumi Tsubota, Kazuhiro Kimura
Journal of Applied Physiology, 124, 1, 99, 108, American Physiological Society, 2018年01月01日, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌）, To investigate the postnatal development of brown adipose tissue (BAT) in Syrian hamsters, we histologically examined interscapular fat tissue from 5-16-day-old pups, focusing on how brown adipocytes arise. Interscapular fat of 5-day-old hamsters mainly consisted of white adipocytes containing large unilocular lipid droplets, as observed in typical white adipose tissue (WAT). On day 7, clusters of small, proliferative nonadipocytes with a strong immunoreactivity for Ki67 appeared near the edge of the interscapular fat tissue. The area of the Ki67-positive regions expanded to ~50% of the total tissue area by day 10.The interscapular fat showed the typical BAT feature by day 16. A brown adipocyte-specific marker, uncoupling protein-1, was clearly detected on day 10 and thereafter, while not detected on day 7. During conversion of interscapular fat from WAT to BAT, unilocular adipocytes completely and rapidly disappeared without obvious apoptosis. Dual immunofluorescence staining for Ki67 and monocarboxylate transporter 1 (MCT1), another selective marker for brown adipocytes, revealed that most of the proliferating cells were of the brown adipocyte lineage. Electron microscopic examination showed that some of the white adipocytes contained small lipid droplets in addition to the large droplet and expressed MCT1 as do progenitor and mature brown adipocytes, implying a direct conversion from white to brown adipocytes. These results suggest that BAT of Syrian hamsters develops postnatally through two different pathways: The proliferation and differentiation of brown adipocyte progenitors and the conversion of unilocular adipocytes to multilocular brown adipocytes.

Role of macrophages in depot-dependent browning of white adipose tissue.　　　　　　　　　　　　　　　
Machida K, Okamatsu-Ogura Y, Shin W, Matsuoka S, Tsubota A, Kimura K
J Physiol Sci, 68, 5, 601, 608, 2018年, ［査読有り］, ［責任著者］

Royal jelly ameliorates diet-induced obesity and glucose intolerance by promoting brown adipose tissue thermogenesis in mice
Yoneshiro T, Kaede R, Nagaya K, Aoyama J, Saito M, Okamatsu-Ogura Y, Kimura K, Terao A
Obes Res Clin Prac, 12, 1, 127, 137, 2018年01月, ［査読有り］
英語, 研究論文（学術雑誌）

Species-specific control of hepatocyte growth factor expression and production in adipocytes in a differentiation-dependent manner.
Yamaji, D, Soliman, M.M, Kamikawa, A, Ito, T, Ahmed, M.M, Okamatsu-Ogura, Y, Saito, M, Kimura, K
Domestic Animal Endocrinology, 62, 39, 48, 2018年, ［査読有り］
英語, 研究論文（学術雑誌）

Cell-cycle arrest in mature adipocytes impairs BAT development but not WAT browning, and reduces adaptive thermogenesis in mice
Yuko Okamatsu-Ogura, Keigo Fukano, Ayumi Tsubota, Junko Nio-Kobayashi, Kyoko Nakamura, Masami Morimatsu, Hiroshi Sakaue, Masayuki Saito, Kazuhiro Kimura
SCIENTIFIC REPORTS, 7, 1, 6648, NATURE PUBLISHING GROUP, 2017年07月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌）, We previously reported brown adipocytes can proliferate even after differentiation. To test the involvement of mature adipocyte proliferation in cell number control in fat tissue, we generated transgenic (Tg) mice over-expressing cell-cycle inhibitory protein p27 specifically in adipocytes, using the aP2 promoter. While there was no apparent difference in white adipose tissue (WAT) between wild-type (WT) and Tg mice, the amount of brown adipose tissue (BAT) was much smaller in Tg mice. Although BAT showed a normal cellular morphology, Tg mice had lower content of uncoupling protein 1 (UCP1) as a whole, and attenuated cold exposure-or beta 3-adrenergic receptor (AR) agonist-induced thermogenesis, with a decrease in the number of mature brown adipocytes expressing proliferation markers. An agonist for the beta 3-AR failed to increase the number of proliferating brown adipocytes, UCP1 content in BAT, and oxygen consumption in Tg mice, although the induction and the function of beige adipocytes in inguinal WAT from Tg mice were similar to WT mice. These results show that brown adipocyte proliferation significantly contributes to BAT development and adaptive thermogenesis in mice, but not to induction of beige adipocytes.

Retinoic acid modulates lipid accumulation glucose concentration dependently through inverse regulation of SREBP-1 expression in 3T3L1 adipocytes
Mabrouk Attia Abd Eldaim, Shinya Matsuoka, Yuko Okamatsu-Ogura, Akihiro Kamikawa, Mohamed Mohamed Ahmed, Akira Terao, Kei-ichi Nakajima, Kazuhiro Kimura
GENES TO CELLS, 22, 6, 568, 582, WILEY, 2017年06月, ［査読有り］
英語, 研究論文（学術雑誌）, It is well known that retinoic acid (RA) suppresses adipogenesis, although there are some contradicting reports. In this study, we examined the effect of extracellular glucose on RA-induced suppression of adipogenesis in 3T3L1 cell culture. When the cells were cultured in normal glucose medium (NG), the addition of RA suppressed lipid accumulation. However, when cultured in high glucose medium (HG), addition of RA to the cells enhanced lipid accumulation. These changes were accompanied by parallel alterations in fatty acid synthase (FAS) and sterol regulatory element-binding protein (SREBP)-1 gene expression. Transfection of SREBP-1 siRNA suppressed RA-induced enhancement of lipid accumulation and FAS expression in the cells cultured with HG. Transfection of the nuclear form of SREBP-1a cDNA into the cells cultured with NG inhibited RA-induced suppression of lipid accumulation and FAS expression. Moreover, RA- and HG-induced SREBP-1a expression occurred at the early phase of adipogenesis and was dependent on glucocorticoid to induce liver X receptor (LXR) , peroxisomal proliferator-activated receptor (PPAR) and retinoid X receptor (RXR), the key nuclear factors influencing the SREBP-1a gene expression. These results suggest that RA suppresses and enhances lipid accumulation through extracellular glucose concentration-dependent modulation of SREBP-1 expression.

Near-Infrared Photoluminescent Carbon Nanotubes for Imaging of Brown Fat
Masako Yudasaka, Yohei Yomogida, Minfang Zhang, Takeshi Tanaka, Masako Nakahara, Norihiko Kobayashi, Yuko Okamatsu-Ogura, Ken Machida, Kazuhiko Ishihara, Kumiko Saeki, Hiromichi Kataura
Scientific Reports, 7, Nature Publishing Group, 2017年03月20日, ［査読有り］
英語, 研究論文（学術雑誌）, Near-infrared photoluminescent single-walled carbon nanotubes (CNTs) are expected to provide effectual bio-imaging tools, although, as yet, only limited applications have been reported. Here, we report that CNTs coated with an amphiphilic and biocompatible polymer, poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate
PMB), generate high-quality images of brown fat. Brown fat is a heat-productive adipose tissue, which is attracting increasing attention as a new therapeutic target for obesity-associated metabolic disorders. Its brown colour is mainly attributed to densely packed capillaries, which facilitate its high heat-exchanging efficiency. Currently, positron emission tomography-computed tomography is the only practical technique to identify brown fat distribution in the living body
however, it is expensive to use. By virtue of their high affinity to apolipoproteins and exemption from macrophage phagocytosis, PMB-CNTs selectively accumulate on capillary endothelial cells but not larger vessels in adipose tissue. Therefore, the image brightness of adipose tissue can directly reflect the capillary density, and indirectly the thermogenic capability and brownness. PMB-CNTs provide clearer images than conventional organic dyes, as the high level of transmitted light passes through the body with less light scattering. Thus, PMB-CNT-based imaging methods could open a new phase in thermogenic adipose tissue research.

Impaired Adrenergic Agonist-Dependent Beige Adipocyte Induction in Aged Mice
Woongchul Shin, Yuko Okamatsu-Ogura, Ken Machida, Ayumi Tsubota, Junko Nio-Kobayashi, Kazuhiro Kimura
OBESITY, 25, 2, 417, 423, WILEY, 2017年02月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, Objective: There are two types of thermogenic adipocytes expressing uncoupling protein ( UCP)-1: the brown adipocyte activated by adrenergic stimulation and the beige adipocyte that appears within the white adipose tissue ( WAT) in response to chronic adrenergic stimulation. This study examined age-related changes in responses of both types of adipocytes to adrenergic stimulation in mice.
Methods: Aged ( age 20 months) and young ( 4 months) mice were injected daily with either saline or beta 3-adrenergic receptor agonist CL316,243 ( CL; 0.1 mg/kg, once a day) for 1 week.
Results: The body and WAT weight tended to be higher in aged mice. CL treatment increased UCP-1 protein amounts in both brown adipose tissue and inguinal WAT, suggesting activation of brown and beige adipocytes. However, induction of beige adipocytes was impaired in aged mice, whereas brown adipocyte activation was comparable to young mice. The number of platelet-derived growth factor receptor alpha-expressing progenitor cells, which were reported to differentiate into beige adipocytes, significantly decreased in inguinal WAT of aged mice compared with that of young mice.
Conclusions: Inductive ability of beige adipocytes in WAT declines with aging in mice. It may be partly because of a decreased number of progenitor cells associated with aging.

エネルギー代謝調節における視床下部MCH神経の役割
伊澤 俊太郎, 中桐 匠平, 米代 武司, 岡松 優子, 寺尾 晶, 山中 章弘, 木村 和弘
日本内分泌学会雑誌, 92, 3, 736, 736, (一社)日本内分泌学会, 2017年01月
日本語

Progesterone dose-dependently modulates hepatocyte growth factor production in 3T3-L1 mouse preadipocytes
Tomoki Ito, Daisuke Yamaji, Akihiro Kamikawa, Mabrouk Attia Abd Eldaim, Yuko Okamatsu-Ogura, Akira Terao, Masayuki Saito, Kazuhiro Kimura
ENDOCRINE JOURNAL, 64, 8, 777, 785, JAPAN ENDOCRINE SOC, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, It is well documented that estrogen is predominant inducer of hepatocyte growth factor (HGF) in a variety of cell types. However, the effect of progesterone (P) remains to be elusive. Thus, in the present study, we examined the effect of P and combined effect of P and 17 beta-estradiol (E2) on HGF expression and production in 3T3-L1 fibroblastic preadipocytes and mature adipocytes, as a model of stromal cells. Northern blot analysis showed that hgf mRNA expressed in preadipocytes was notably higher than that of mature adipocytes, and increased by treatment of preadipocytes with E2 or 10 nM P, but not with 1,000 nM P. The E2-induced hgf mRNA expression was enhanced by 10 nM P, but suppressed by 1,000 nM P. Western blot analysis revealed that biological active forms of HGF protein was found in the preadipocyte culture medium, while the lesser amount of HGF precursor protein was detected in the mature adipocyte culture medium. The amounts of HGF were changed dependently on the hgf mRNA expression levels. These results indicate that HGF production is intricately regulated by E2 and P at the transcriptional levels in 3T3-L1 cells, and may explain the changes in the HGF production during the mammary gland development, especially decrease in HGF expression during pregnancy when P concentration is high.

Cold Exposure Induces Proliferation of Mature Brown Adipocyte in a beta 3-Adrenergic Receptor-Mediated Pathway
Fukano Keigo, Okamatsu-Ogura Yuko, Tsubota Ayumi, Nio-Kobayashi Junko, Kimura Kazuhiro
PLOS One, 11, 11, e0166579, e0166579, PLOS, 2016年11月15日, ［責任著者］
英語, 研究論文（学術雑誌）, Hyperplasia of brown adipose tissue (BAT) is a fundamental mechanism for adaptation to survive in the cold environment in rodents. To determine which cell types comprising BAT contribute to tissue hyperplasia, immunohistochemical analysis using a proliferative marker Ki67 was performed on the BAT from 6-week-old C57BLJ6J mice housed at 23 degrees C (control) or 10 degrees C (cold) for 5 days. Interestingly, in the control group, the cell proliferative marker Ki67 was detected in the nuclei of uncoupling protein 1-positive mature brown adipocytes (7.2% +/- 0.4% of brown adipocyte), as well as in the non-adipocyte stromal-vascular (SV) cells (19.6% +/- 2.3% of SV cells), which include preadiopocytes. The percentage of Ki67-positive brown adipocytes increased to 25.6% +/- 1.8% at Day 1 after cold exposure and was significantly higher than the non-cold acclimated control until Day 5 (21.8%+/- 1.7%). On the other hand, the percentage of Ki67-positive SV cells gradually increased by a cold exposure and peaked to 42.1%+/- 8.3% at Day 5. Injection of a beta 3-adrenergic receptor (beta 3-AR) agonist for continuous 5 days increased the number of Ki67-positive brown adipocytes even at Day 1 but not that of SV cells. In addition, the beta 3-AR antagonist, but not beta 1-AR antagonist, attenuated the cold exposure-induced increase in the number of Ki67-positive brown adipocytes. These results suggest that mature brown adipocytes proliferate immediately after cold exposure in a beta 3-AR-mediated pathway. Thus, proliferation of mature brown adipocytes as well as preadipocytes in SV cells may contribute to cold exposure-induced BAT hyperplasia.

Adiponectin Inhibits LPS-Induced HMGB1 Release through an AMP Kinase and Heme Oxygenase-1-Dependent Pathway in RAW 264 Macrophage Cells
Mohamed Elfeky, Ryuji Kaede, Yuko Okamatsu-Ogura, Kazuhiro Kimura
MEDIATORS OF INFLAMMATION, HINDAWI PUBLISHING CORP, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, High mobility group protein B1 (HMGB1) is a late inflammatory mediator that exaggerates septic symptoms. Adiponectin, an adipokine, has potent anti-inflammatory properties. However, possible effects of adiponectin on lipopolysaccharide-(LPS-) induced HMGB1 release are unknown. The aim of this study was to investigate effects of full length adiponectin on HMGB1 release in LPS-stimulated RAW 264 macrophage cells. Treatment of the cells with LPS alone significantly induced HMGB1 release associated with HMGB1 translocation from the nucleus to the cytosol. However, prior treatment with adiponectin suppressed LPS-induced HMGB1 release and translocation. The anti-inflammatory cytokine interleukin-(IL-) 10 similarly suppressed LPS-induced-HMGB1 release. Adiponectin treatment decreased toll-like receptor 4 (TLR4) mRNA expression and increased heme oxygenase-(HO-) 1 mRNA expression without inducing IL-10 mRNA, while IL-10 treatment decreased TLR2 and HMGB1 mRNA expression and increased the expression of IL-10 andHO-1mRNA. Treatment with the HO-1 inhibitor ZnPP completely prevented the suppression of HMGB1 release by adiponectin but only partially inhibited that induced by IL-10. Treatment with compound C, an AMP kinase (AMPK) inhibitor, abolished the increase in HO-1 expression and the suppression of HMGB1 release mediated by adiponectin. In conclusion, our results indicate that adiponectin suppresses HMGB1 release by LPS through an AMPK-mediated and HO-1-dependent IL-10-independent pathway.

Capsinoids suppress diet-induced obesity through uncoupling protein 1-dependent mechanism in mice
Yuko Okamatsu-Ogura, Ayumi Tsubota, Kana Ohygma, Yoshihito Nogusa, Masayuki Saito, Kazuhiro Kimura
JOURNAL OF FUNCTIONAL FOODS, 19, 1, 9, ELSEVIER SCIENCE BV, 2015年12月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌）, Capsinoids are less pungent capsaicin analogues that increase whole body energy expenditure and hence reduce fat. Several studies have suggested that capsinoids activate brown adipose tissue (BAT), a major site of adaptive thermogenesis, but the actual contribution of BAT and uncoupling protein 1 (UCP1), a thermogenic protein expressed in BAT, to the fat-reducing effect of capsinoids has not yet been determined. Here, we investigated the effect of capsinoids on high-fat diet (HFD)-induced obesity using wild-type (WT) and UCP1-deficient (KO) mice. Capsinoids feeding potently suppressed HFD-induced increase in body weight, adiposity, and fatty liver development in WT mice. In contrast, such effects of capsinoids were completely abolished in UCP1-KO mice. Moreover, capsinoids significantly increased UCP1 protein expression in BAT without its apparent induction in white adipose tissue (WAT) in WT mice. These results indicate that capsinoids suppress diet-induced obesity of mice through the UCP1 function in BAT but not in WAT. (C) 2015 Elsevier Ltd. All rights reserved.

Brown adipose tissue expresses uncoupling protein 1 in newborn harbor seals (Phoca vitulina)
Yuta Sakurai, Yuko Okamatsu-Ogura, Masayuki Saito, Kazuhiro Kimura, Ryo Nakao, Aiko Ohnuma, Mari Kobayashi
MARINE MAMMAL SCIENCE, 31, 2, 818, 827, WILEY-BLACKWELL, 2015年04月, ［査読有り］
英語, 研究論文（学術雑誌）

Organ-specific changes in norepinephrine turnover against various stress conditions in thermoneutral mice
Yasufumi Teramura, Akira Terao, Yuko Okada, Junichi Tomida, Yuko Okamatsu-Ogura, Kazuhiro Kimura
JAPANESE JOURNAL OF VETERINARY RESEARCH, 62, 3, 117, 127, HOKKAIDO UNIV, 2014年08月, ［査読有り］
英語, 研究論文（学術雑誌）, The effects of three stressors of different categories, namely cold exposure, immobilization, and lipopolysaccharide (LPS) treatment, on sympathetic nerve activity were examined by assessing its biochemical index norepinephrine (NE) turnover in peripheral organs of C57BL/6 mice. NE turnover was assessed by measuring the decrease in the organ NE concentration 3 h after inhibition of catecholamine biosynthesis with alpha-methyl-p-tyrosine. NE turnover in brown adipose tissue (BAT) in the room temperature (23 degrees C) control group was as high as that in the cold exposure (4 degrees C) group. Similarly, the mRNA level of the thermogenic marker uncoupling protein 1 (UCP1) in the room temperature control group was as high as that in the cold exposure group. As sympathetic stimulation upregulates the UCP1 mRNA level, we thought that sympathetic nerve tonus in BAT was already accelerated at room temperature. To exclude factors affecting basal sympathetic nerve activity, mice housed at thermoneutral temperature (30 degrees C) were used as controls for the subsequent experiments. In this condition, cold exposure accelerated NE turnover in the BAT, as well as heart and pancreas. The corticosterone level showed a higher trend in the cold exposure group in comparison to the control group. Immobilization accelerated NE turnover in the spleen, pancreas, and white adipose tissue and elevated the corticosterone level. LPS (3 mg/kg, i.p.) did not affect NE turnover in all peripheral organs but elevated the corticosterone level. In summary, the sympathetic nervous and adrenocortical responses to three stressors differed greatly. In particular, sympathetic responses showed clear organ-specific acceleration patterns. This important feature may improve our understanding of the multiplicity of biological responses.

Temperature changes in brown adipocytes detected with a bimaterial microcantilever
Masaaki K. Sato, Masaya Toda, Naoki Inomata, Hisataka Maruyama, Yuko Okamatsu-Ogura, Fumihito Arai, Takahito Ono, Akihiko Ishijima, Yuichi Inoue
Biophysical Journal, 106, 11, 2458, 2464, 2014年06月03日, ［査読有り］
研究論文（学術雑誌）, Mammalian cells must produce heat to maintain body temperature and support other biological activities. Methods to measure a cell's thermogenic ability by inserting a thermometer into the cell or measuring the rate of oxygen consumption in a closed vessel can disturb its natural state. Here, we developed a noninvasive system for measuring a cell's heat production with a bimaterial microcantilever. This method is suitable for investigating the heat-generating properties of cells in their native state, because changes in cell temperature can be measured from the bending of the microcantilever, without damaging the cell and restricting its supply of dissolved oxygen. Thus, we were able to measure increases in cell temperature of <1 K in a small number of murine brown adipocytes (n = 4-7 cells) stimulated with norepinephrine, and observed a slow increase in temperature over several hours. This long-term heat production suggests that, in addition to converting fatty acids into heat energy, brown adipocytes may also adjust protein expression to raise their own temperature, to generate more heat. We expect this bimaterial microcantilever system to prove useful for determining a cell's state by measuring thermal characteristics. © 2014 Biophysical Society.

Characteristics of Sleep and Wakefulness in Wild-Derived Inbred Mice.
HIYOSHI Hideyuki, TERAO Akira, OKAMATSU-OGURA Yuko, KIMURA Kazuhiro
Experimental Animals, 62, 2, 205, 213, Japanese Association for Laboratory Animal Science, 2014年, ［査読有り］
英語, 研究論文（学術雑誌）, Genetic variations in the wild-derived inbred mouse strains are more diverse than that of classical laboratory inbred mouse strains, including C57BL/6J (B6). The sleep/wake and monoamine properties of six wild-derived inbred mouse strains (PGN2, NJL, BLG2, KJR, MSM, HMI) were characterized and compared with those of B6 mice. All examined mice were nocturnal and had a polyphasic sleep pattern with a "main sleep period" identified during the light period. However, there were three sleep/wake phenotypic differences between the wild-derived mouse strains and B6 strain. First, the amount of sleep during the dark phase was comparable with that of B6 mice. However, the amount of sleep during the light phase was more varied among strains, in particular, NJL and HMI had significantly less sleep compared with that of B6 mice. Second, PGN2, NJL, BLG2, and KJR mice showed a "highly awake period" (in which the hourly total sleep time was <10%) immediately after the onset of the dark period, which was not seen in B6 mice. Third, relative to that of B6 mice, PGN2 and KJR mice showed longer duration of wakefulness episodes during the 12-h dark phase. Differences in whole brain noradrenaline, dopamine, and 5-hydroxy-tryptamine contents between the wild-derived mouse strains and B6 strain were also found. These identified phenotypes might be potentially under strong genetic control. Hence, wild-derived inbred mice could be useful for identifying the genetic factors underlying the regulation of sleep and wakefulness.

Evodiamine Inhibits Insulin-Stimulated mTOR-S6K Activation and IRS1 Serine Phosphorylation in Adipocytes and Improves Glucose Tolerance in Obese/Diabetic Mice
Ting Wang, Tatsuya Kusudo, Tamaki Takeuchi, Yukari Yamashita, Yasuhide Kontani, Yuko Okamatsu, Masayuki Saito, Nozomu Mori, Hitoshi Yamashita
PLOS ONE, 8, 12, PUBLIC LIBRARY SCIENCE, 2013年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Evodiamine, an alkaloid extracted from the dried unripe fruit of the tree Evodia rutaecarpa Bentham (Rutaceae), reduces obesity and insulin resistance in obese/diabetic mice; however, the mechanism underlying the effect of evodiamine on insulin resistance is unknown. This study investigated the effect of evodiamine on signal transduction relating to insulin resistance using obese/diabetic KK-Ay mice and an in vitro adipocyte culture. There is a significant decrease in the mammalian target of rapamycin (mTOR) and ribosomal S6 protein kinase (S6K) signaling in white adipose tissue (WAT) in KK-Ay mice treated with evodiamine, in which glucose tolerance is improved. In addition, reduction of insulin receptor substrate 1 (IRS1) serine phosphorylation, an indicator of insulin resistance, was detected in their WAT, suggesting suppression of the negative feedback loop from S6K to IRS1. As well as the stimulation of IRS1 and Akt serine phosphorylation, insulin-stimulated phosphorylation of mTOR and S6K is time-dependent in 3T3-L1 adipocytes, whereas evodiamine does not affect their phosphorylation except for an inhibitory effect on mTOR phosphorylation. Moreover, evodiamine inhibits the insulin-stimulated phosphorylation of mTOR and S6K, leading to down-regulation of IRS1 serine phosphorylation in the adipocytes. Evodiamine also stimulates phosphorylation of AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, which may cause down-regulation of mTOR signaling in adipocytes. A similar effect on AMPK, mTOR and IRS1 phosphorylation was found in adipocytes treated with rosiglitazone. These results suggest evodiamine improves glucose tolerance and prevents the progress of insulin resistance associated with obese/diabetic states, at least in part, through inhibition of mTOR-S6K signaling and IRS1 serine phosphorylation in adipocytes.

Thermogenic Ability of Uncoupling Protein 1 in Beige Adipocytes in Mice
Yuko Okamatsu-Ogura, Keigo Fukano, Ayumi Tsubota, Akihiro Uozumi, Akira Terao, Kazuhiro Kimura, Masayuki Saito
PLOS ONE, 8, 12, e84229, PUBLIC LIBRARY SCIENCE, 2013年12月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌）, Chronic adrenergic activation leads to the emergence of beige adipocytes in some depots of white adipose tissue in mice. Despite their morphological similarities to brown adipocytes and their expression of uncoupling protein 1 (UCP1), a thermogenic protein exclusively expressed in brown adipocytes, the beige adipocytes have a gene expression pattern distinct from that of brown adipocytes. However, it is unclear whether the thermogenic function of beige adipocytes is different from that of classical brown adipocytes existing in brown adipose tissue. To examine the thermogenic ability of UCP1 expressed in beige and brown adipocytes, the adipocytes were isolated from the fat depots of C57BL/6J mice housed at 24 degrees C (control group) or 10 degrees C (cold-acclimated group) for 3 weeks. Morphological and gene expression analyses revealed that the adipocytes isolated from brown adipose tissue of both the control and cold-acclimated groups consisted mainly of brown adipocytes. These brown adipocytes contained large amounts of UCP1 and increased their oxygen consumption when stimulated with norepinephirine. Adipocytes isolated from the perigonadal white adipose tissues of both groups and the inguinal white adipose tissue of the control group were white adipocytes that showed no increase in oxygen consumption after norepinephrine stimulation. Adipocytes isolated from the inguinal white adipose tissue of the cold-acclimated group were a mixture of white and beige adipocytes, which expressed UCP1 and increased their oxygen consumption in response to norepinephrine. The UCP1 content and thermogenic ability of beige adipocytes estimated on the basis of their abundance in the cell mixture were similar to those of brown adipocytes. These results revealed that the inducible beige adipocytes have potent thermogenic ability comparable to classical brown adipocytes.

Hypothalamic prepro-orexin mRNA level is inversely correlated to the non-rapid eye movement sleep level in high-fat diet-induced obese mice
Tanno S, Terao A, Okamatsu-Ogura Y, Kimura K
Obes Res Clin Pract, 7, 4, e251, e257, Elsevier, 2013年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Orexins are hypothalamic neuropeptides, which play important roles in the regulation and maintenance of sleep/wakefulness states and energy homeostasis. To evaluate whether alterations in orexin system is associated with the sleep/wakefulness abnormalities observed in obesity, we examined the mRNA expression of prepro-orexin, orexin receptor type 1 (orexin 1r), and orexin receptor type 2 (oxexin 2r) in the hypothalamus in mice fed with a normal diet (ND) and high-fat diet (HFD)-induced obese mice. We also compared their relationships with sleep/wakefulness. Twenty-four, 4-week-old, male C57BL/6J mice were divided randomly into three groups, which received the following: (1) ND for 17 weeks; (2) HFD for 17 weeks; and (3) ND for 7 weeks and HFD for a further 10 weeks. The body weights of mice fed the HFD for 10-17 weeks were 112-150% of the average body weight of the ND group. The daily amount of non-rapid eye movement (NREM) sleep increased significantly in HFD-fed mice. These changes were accompanied by increases in the number but decreases in the duration of each NREM sleep episode. In addition, brief awakenings (<20 s epoch) during NREM sleep was nearly 2-fold more frequent. The mRNA level of prepro-orexin in the hypothalamus was significantly reduced in HFD-induced obese mice, whereas the levels of orexin 1r and orexin 2r were unaffected. The daily amount of NREM sleep was negatively correlated with the hypothalamic prepro-orexin mRNA level, so these results suggest that the increased NREM sleep levels in HFD-induced obese mice are attributable to impaired orexin activity. (C) 2013 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Extracellular signal-regulated kinase in the ventromedial hypothalamus mediates leptin-induced glucose uptake in red-type skeletal muscle.
Toda C, Shiuchi T, Kageyama H, Okamoto S, Coutinho EA, Sato T, Okamatsu-Ogura Y, Yokota S, Takagi K, Tang L, Saito K, Shioda S, Minokoshi Y
Diabetes, 62, 7, 2295, 2307, 2013年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal-regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle.

Miglitol prevents diet-induced obesity by stimulating brown adipose tissue and energy expenditure independent of preventing the digestion of carbohydrates
Tsutomu Sasaki, Mayumi Shimpuku, Tomoya Kitazumi, Haruna Hiraga, Yuko Nakagawa, Hiroshi Shibata, Yuko Okamatsu-Ogura, Osamu Kikuchi, Hye-Jin Kim, Yuki Fujita, Jun Maruyama, Vina Yanti Susanti, Hiromi Yokota-Hashimoto, Masaki Kobayashi, Masayuki Saito, Tadahiro Kitamura
Endocrine Journal, 60, 10, 1117, 1129, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alphaglucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented dietinduced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol's effect on brown adipose tissue could lead to a novel anti-obesity drug. © The Japan Endocrine Society.

Proinsulin C-peptide activates α-enolase: implications for C-peptide--cell membrane interaction.
Ishii T, Fukano K, Shimada K, Kamikawa A, Okamatsu-Ogura Y, Terao A, Yoshida T, Saito M, Kimura K
Journal of biochemistry, 152, 1, 53, 62, 1, 2012年07月, ［査読有り］
英語, Proinsulin C-peptide shows beneficial effects on microvascular complications of type 1 diabetes. However, the possible occurrence of membrane C-peptide receptor(s) has not been elucidated. The aim of this study was to identify and characterize membrane proteins to which C-peptide binds. The enzyme α-enolase was co-immunoprecipitated with C-peptide after chemical cross-linking to HL-60 cell surface proteins, and identified by mass spectrometry. Recombinant α-enolase activity was modulated by C-peptide, with a significant decrease in Km for 2-phosphoglycerate without affecting Vmax. The enzyme modulation by C-peptide was abolished when C-terminal basic lysine residue (K434) of the enzyme was replaced by neutral alanine or acidic glutamate, but not with basic arginine. The enzyme modulation by C-peptide was reproduced with the C-peptide fragments containing glutamate corresponding to position 27 (E27) of the full-length C-peptide. Addition of a lysine analogue to the assay and A31 cell culture abrogated the enzyme modulation and MAP kinase activation by C-peptide, respectively. The results indicate that C-peptide has the capacity to activate α-enolase via a specific interaction between E27 of the peptide and K434 of the enzyme. Since α-enolase plays a role as a cell surface receptor for plasminogen, it may conceivably also serve as a receptor for C-peptide in vivo.

Neuropeptide Y activates phosphorylation of ERK and STAT3 in stromal vascular cells from brown adipose tissue, but fails to affect thermogenic function of brown adipocytes
Kohei Shimada, Yuta Ohno, Yuko Okamatsu-Ogura, Masahiro Suzuki, Akihiro Kamikawa, Akira Terao, Kazuhiro Kimura
PEPTIDES, 34, 2, 336, 342, ELSEVIER SCIENCE INC, 2012年04月, ［査読有り］
英語, 研究論文（学術雑誌）, The thermogenic function of brown adipose tissue (BAT) is increased by norepinephrine (NE) released from sympathetic nerve endings, but the roles of NPY released along with NE are poorly elucidated. Here, we examined effect of NPY on basal and NE-enhanced thermogenesis in isolated brown adipocytes that express Y1 and Y5 receptor mRNA. Treatment of cells with NPY did not influence the basal and NE-enhanced rates of oxygen consumption and cAMP accumulation. Treatment with NPY also failed to induce ERK (Thr202/Tyr204) phosphorylation in the brown adipocytes. In contrast, treatment with NPY increased ERK phosphorylation in cultured stromal vascular cells from the BAT that express Y1 receptor mRNA. In the latter treatment with NPY also increased STAT3 (Ser727) phosphorylation. These results suggest that NPY mainly acts on stromal vascular cells in BAT and plays roles in the regulation of their gene transcription through ERK and STAT3 pathways, while NPY does not affect the thermogenic function of brown adipocytes. (C) 2012 Elsevier Inc. All rights reserved.

Possible involvement of uncoupling protein 1 in appetite control by leptin
Yuko Okamatsu-Ogura, Junko Nio-Kobayashi, Toshihiko Iwanaga, Akira Terao, Kazuhiro Kimura, Masayuki Saito
EXPERIMENTAL BIOLOGY AND MEDICINE, 236, 11, 1274, 1281, ROYAL SOC MEDICINE PRESS LTD, 2011年11月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌）, Leptin reduces body fat by decreasing food intake and increasing energy expenditure. Uncoupling protein (UCP) 1, a key molecule for brown adipose tissue (BAT) thermogenesis, was reported to contribute to the stimulatory effect of leptin on energy expenditure. To clarify whether UCP1 is also involved in the anorexigenic effect of leptin, in this study we examined the effect of leptin on food intake using wild-type (WT) and UCP1-deficient (UCP1-KO) mice. Repeated injection of leptin decreased food intake more markedly in WT mice than in UCP1-KO mice, while a single injection of leptin showed similar effects in the two groups of mice. As chronic leptin stimulation induces UCP1 expression in BAT and ectopically in white adipose tissue (WAT), we mimicked the UCP1 induction by repeated injection of CL316,243 (CL), a highly specific beta 3-adrenoceptor agonist, and measured food intake in response to a single injection of leptin. Two-week treatment with CL enhanced the anorexigenic effect of leptin in WT mice, but not in UCP1-KO mice. Three-day treatment with CL in WT mice also enhanced the anorexigenic effect of leptin and leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the arcuate nucleus of the hypothalamus, without any notable change in adiposity. These results indicate that UCP1 enhances leptin action at the hypothalamus level, suggesting UCP1 contributes to the control of energy balance not only through the regulation of energy expenditure but also through appetite control by modulating leptin action.

Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation.
Shimba S, Ogawa T, Hitosugi S, Ichihashi Y, Nakadaira Y, Kobayashi M, Tezuka M, Kosuge Y, Ishige K, Ito Y, Komiyama K, Okamatsu-Ogura Y, Kimura K, Saito M
PloS one, 6, 9, e25231, 9, 2011年09月22日, ［査読有り］

Age-Related Decrease in Cold-Activated Brown Adipose Tissue and Accumulation of Body Fat in Healthy Humans
Takeshi Yoneshiro, Sayuri Aita, Mami Matsushita, Yuko Okamatsu-Ogura, Toshimitsu Kameya, Yuko Kawai, Masao Miyagawa, Masayuki Tsujisaki, Masayuki Saito
OBESITY, 19, 9, 1755, 1760, NATURE PUBLISHING GROUP, 2011年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with X-ray computed tomography (CT) in adult humans. The objective of this study was to clarify the relationship between BAT and adiposity in healthy adult humans, particularly to test the idea that decreased BAT activity may be associated with body fat accumulation with age. One hundred and sixty-two healthy volunteers aged 20-73 years (103 males and 59 females) underwent FDG-PET/CT after 2-h cold exposure at 19 degrees C with light clothing. Cold-activated BAT was detected in 41% of the subjects (BAT-positive). Compared with the BAT-negative group, the BAT-positive group was younger (P < 0.01) and showed a lower BMI (P < 0.01), body fat content (P < 0.01), and abdominal fat (P < 0.01). The incidence of cold-activated BAT decreased with age (P < 0.01), being more than 50% in the twenties, but less than 10% in the fifties and sixties. The adiposity-related parameters showed some sex differences, but increased with age in the BAT-negative group (P < 0.01), while they remained unchanged from the twenties to forties in the BAT-positive group, in both sexes. These results suggest that decreased BAT activity may be associated with accumulation of body fat with age.

Effects of retinoic acid and hydrogen peroxide on sterol regulatory element-binding protein-1a activation during adipogenic differentiation of 3T3-L1 cells.
Abd Eldaim MA, Okamatsu-Ogura Y, Terao A, Kimura K
The Japanese journal of veterinary research, 58, 3-4, 149, 154, 3-4, 2010年11月, ［査読有り］
英語, Both retinoic acid (RA) and oxidative stress (H2O2) increased transcription and cleavage ofmembrane-bound sterol regulatory element-binding protein (SREBP)-1, leading toenhanced transcription of fatty acid synthase (FAS) in hepatoma cells. On the other hand,RA and H2O2 decreased and increased lipogenesis in adipocytes, respectively, althoughroles of SREBP-1 activation in these effects remain to be elucidated. To elucidate itsinvolvement, we examined the activation of SREBP-1a, expression of FAS genes and lipidaccumulation in 3T3-L1 cells in the presence of RA and/or H2O2. RA (1 μM) treatmentsuppressed expression of SREBP-1a and FAS genes and lipid accumulation. H2O2 (2 μM)treatment induced increased cleavage of SREBP-1a, without affecting amounts ofSREBP-1a mRNA and precursor protein, and enhanced expression of FAS gene and lipidaccumulation. Increased cleavage of SREBP-1a by H2O2 was also observed even in thepresence of RA. These results suggest that H2O2 enhances a cleavage of SREBP-1aprecursor protein, which independently occurs with the RA suppression of SREBP-1a geneexpression, and that RA itself has no role in the SREBP-1a activation in adipocytes.

Perilipin Overexpression in White Adipose Tissue Induces a Brown Fat-Like Phenotype
Takashi Sawada, Hideaki Miyoshi, Kohei Shimada, Akira Suzuki, Yuko Okamatsu-Ogura, James W. Perfield, Takuma Kondo, So Nagai, Chikara Shimizu, Narihito Yoshioka, Andrew S. Greenberg, Kazuhiro Kimura, Takao Koike
PLOS ONE, 5, 11, e14006, PUBLIC LIBRARY SCIENCE, 2010年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Perilipin A (PeriA) exclusively locates on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Previously, we reported that adipocyte specific overexpression of PeriA caused resistance to diet-induced obesity and resulted in improved insulin sensitivity. In order to better understand the biological basis for this observed phenotype, we performed additional studies in this transgenic mouse model.
Methodology and Principal Findings: When compared to control animals, whole body energy expenditure was increased in the transgenic mice. Subsequently, we performed DNA microarray analysis and real-time PCR on white adipose tissue. Consistent with the metabolic chamber data, we observed increased expression of genes associated with fatty acid beta-oxidation and heat production, and a decrease in the genes associated with lipid synthesis. Gene expression of Pgc1a, a regulator of fatty acid oxidation and Ucp1, a brown adipocyte specific protein, was increased in the white adipose tissue of the transgenic mice. This observation was subsequently verified by both Western blotting and histological examination. Expression of RIP140, a regulator of white adipocyte differentiation, and the lipid droplet protein FSP27 was decreased in the transgenic mice. Importantly, FSP27 has been shown to control gene expression of these crucial metabolic regulators. Overexpression of PeriA in 3T3-L1 adipocytes also reduced FSP27 expression and diminished lipid droplet size.
Conclusions: These findings demonstrate that overexpression of PeriA in white adipocytes reduces lipid droplet size by decreasing FSP27 expression and thereby inducing a brown adipose tissue-like phenotype. Our data suggest that modulation of lipid droplet proteins in white adipocytes is a potential therapeutic strategy for the treatment of obesity and its related disorders.

Retinol binding protein 4 in dairy cows: its presence in colostrum and alteration in plasma during fasting, inflammation, and the peripartum period.
Abd Eldaim MA, Kamikawa A, Soliman MM, Ahmed MM, Okamatsu-Ogura Y, Terao A, Miyamoto T, Kimura K
The Journal of dairy research, 77, 1, 27, 32, 1, 2010年02月, ［査読有り］
英語, Retinol-binding protein 4 (RBP4) is a plasma protein involved in retinol transportation, and recent evidence in rodents suggests that RBP4 is also a metabolic regulator that modifies insulin sensitivity. To assess how RBP4 levels are regulated in ruminants, we determined the RBP4 concentrations in bovine plasma and milk using Western blot analysis. Plasma RBP4 levels in non-pregnant non-lactating (control) cows were around 45 μg/ml, which were sustained during 60-h fasting, but decreased significantly 4 h after lipopolysaccharide (LPS) administration. Basal plasma retinol concentration was around 30 μg/dl, but this decreased to approximately one-third and one-half of these values during fasting and 8 h after LPS challenge, respectively. Plasma RBP4 and retinol levels in cows 3-6 d before parturition were comparable to those of the controls. However, on the day of parturition both were significantly decreased and had returned to basal levels by two weeks after calving. Interestingly, RBP4 was clearly detected in colostrum (16.4 ± 5.6 μg/ml) but was only faintly detected in milk from cows at 7 d and 15 d after calving. Retinol concentrations in colostrum were almost 10-fold higher than those in plasma, while those in milk were comparable to those in plasma. These results suggest that RBP4 and retinol levels are independently regulated under physiological and pathophysiological conditions and that RBP4, like retinol, is transferred from maternal stores to calves through colostrum.

High Incidence of Metabolically Active Brown Adipose Tissue in Healthy Adult Humans Effects of Cold Exposure and Adiposity
Masayuki Saito, Yuko Okamatsu-Ogura, Mami Matsushita, Kumiko Watanabe, Takeshi Yoneshiro, Junko Nio-Kobayashi, Toshihiko Iwanaga, Masao Miyagawa, Toshimitsu Kameya, Kunihiro Nakada, Yuko Kawai, Masayuki Tsujisaki
DIABETES, 58, 7, 1526, 1531, AMER DIABETES ASSOC, 2009年07月, ［査読有り］
英語, 研究論文（学術雑誌）, OBJECTIVE-The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity.
RESEARCH DESIGN AND METHODS-In vivo 2-[ (18)F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23-65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT).
RESULTS-When exposed to cold (19 C) for 2 h, 17 of 32 younger subjects (aged 23-35 years) and 2 of 24 elderly subjects (aged 38-65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27 C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level.
CONCLUSIONS-Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity. Diabetes 58:1526-1531, 2009

Diet-Induced Obesity Disrupts Ductal Development in the Mammary Glands of Nonpregnant Mice
Akihiro Kamikawa, Osamu Ichii, Daisuke Yamaji, Takeshi Imao, Chihairu Suzuki, Yuko Okamatsu-Ogura, Akira Terao, Yasuhiro Kon, Kazuhiro Kimura
DEVELOPMENTAL DYNAMICS, 238, 5, 1092, 1099, WILEY-LISS, 2009年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Mammary glands develop postnatally in response to the hypothalamic-pituitary-gonadal axis. Obesity-induced changes in the local environment, however, retard mammary gland development during late pregnancy and lactation. To clarify the effects of obesity on fundamental duct development, we compared the mammary glands of nulliparous nonpregnant obese mice fed a high-fat diet with those of lean mice fed a normal diet. Obese mice had enlarged mammary glands, reflecting fat pad size, whereas the ducts in obese mice showed a less dense distribution with less frequent branching. Additionally, the ducts were surrounded by thick collagen layers, and were incompletely lined with myoepithelium. Because leptin receptors were localized in the epithelium region and leptin that was highly expressed in the obese glands suppressed mammary epithelial cell proliferation in vitro, the present results suggest that obesity disrupts mammary ductal development, possibly by remodeling the mammary microenvironment and promoting the expression of such paracrine factors as leptin. Developmental Dynamics 238:1092-1099, 2009. (C) 2009 Wiley-Liss, Inc.

Leptin inhibits mitogen-induced proliferation of peripheral T lymphocytes from Holstein cows.
Ahmed M, Kimura K, Soliman M, Yamaji D, Okamatsu-Ogura Y, Ishioka K, Makondo K, Hagiwara K, Saito M
Veterinary journal (London, England : 1997), 176, 3, 361, 8, 2008年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study examined the mitogenic response of bovine peripheral T lymphocytes to leptin, a pleiotropic hormone regulating food intake and energy expenditure. Leptin alone slightly suppressed proliferation of T lymphocytes in the presence of concanavalin A (ConA). Leptin also inhibited proliferation of T lymphocytes induced by anti-CD3 antibody. ConA treatment activated some protein kinases, including p44/p42(MAPK) and Akt/PKB, while anti-CD3 antibody treatment increased mRNA expression of suppressor of cytokine signalling (SOCS) 3, interferon (IFN)gamma, interleukin (IL) 2 and IL4 in T lymphocytes. Leptin alone increased only SOCS3 mRNA expression. Simultaneous treatment with mitogens and leptin enhanced IFNgamma mRNA expression but decreased IL2 mRNA expression, without any synergistic effect on phosphorylation of protein kinases or mRNA expression of SOCS3 and IL4. These results suggest that leptin modulates bovine T lymphocyte functions.

Uncoupling protein 1 contributes to fat-reducing effect of leptin
Yuko Okamatsu-Ogura, Akihiro Uozumi, Chitoku Toda, Kazuhiro Kimura, Hitoshi Yamashita, Masayuki Saito
OBESITY RESEARCH & CLINICAL PRACTICE, 1, 4, 233, 241, ELSEVIER SCI LTD, 2007年12月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, Leptin is proposed to reduce body fat by increasing energy expenditure, in addition to decreasing food intake, through the activation of brown adipose tissue (BAT) thermogenesis. To confirm this, we investigated the effects of leptin on whole body energy expenditure, BAT functions and adiposity in wild-type (WT) mice, and compared with those in mice deficient in uncoupling protein 1 (UCP1), a key molecule for BAT thermogenesis. Chronic hyperleptinemia induced by adenovirus gene transfer reduced food intake in both WT and UCP1-KO mice. WT mice with hyperleptinemia, compared to pair-fed controls, showed increased oxygen consumption, elevated UCP1 expression in BAT, ectopic UCP1 induction in white adipose tissue (WAT), and reduced body fat content. These effects of chronic hyperleptinemia were not observed in UCP1-KO mice. It was concluded that the fat-reducing effect of leptin is due to not only decreased food intake, but also increased UCP1-dependent energy expenditure. (c) 2007 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Inverse regulation of leptin mRNA expression by short- and long-chain fatty acids in cultured bovine adipocytes
Mohamed Soliman, Kazuhiro Kimura, Mohamed Ahmed, Daisuke Yamaji, Yukiko Matsushita, Yuko Okamatsu-Ogura, Kennedy Makondo, Masayuki Saito
DOMESTIC ANIMAL ENDOCRINOLOGY, 33, 4, 400, 409, ELSEVIER SCIENCE INC, 2007年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Leptin is an adipose tissue-derived cytokine plays key roles in the regulation of food intake and energy expenditure. However, regulatory mechanisms of leptin gene expression are not fully elucidated in ruminants that utilize short-chain fatty acids (SCFA), known as volatile fatty acids, as principal energy sources. In this study, we determined effects of SCFA and long-chain fatty acids (LCFA) on leptin expression in bovine adipocytes. Bovine stromal vascular cells isolated from subcutaneous adipose tissue of Holstein cows were cultured to confluence and treated sequentially with dexamethasone and isobutylmethylxanthine for 2 days and insulin and troglitazone for 12 days to achieve full differentiation to adipocytes. The cells started to accumulate lipids 4 days after the onset of treatment, with increased mRNA expression of leptin, as well as aP2, adiponectin, and PPAR-gamma. Removal of fetal calf serum and reduction of glucose in the culture medium of differentiated adipocytes decreased leptin mRNA expression. Subsequent addition of acetate, butyrate, or propionate dose-dependently restored and rather increased leptin expression, while addition of LCFA suppressed it. The stimulatory effect of acetate was abolished by prior treatment of the cells with pertussis toxin and by addition of LCFA. Furthermore, cows fasted for 48 h and fed thereafter, elaborate reduced and increased plasma leptin levels, respectively. Thus. these results suggest that plasma leptin levels in cows are inversely controlled at the transcription level by VFA and LCFA, and that the effects of SCFA possibly act through a G protein-coupled receptor for SCFA.
(c) 2006 Elsevier Inc. All rights reserved.

Molecular cloning and tissue distribution of uncoupling protein 1 (UCP1) in plateau pika (Ochotona dauurica).
Naoya Kitao, Takahiro Yahata, Takaaki Matsumoto, Yuko Okamatsu-Ogura, Asako Omachi, Kazuhiro Kimura, Masayuki Saito
The Journal of veterinary medical science, 69, 10, 1065, 8, 2007年10月, ［査読有り］, ［国内誌］
英語, Uncoupling protein 1 (UCP1) is present exclusively in brown adipose tissue, and contributes to body temperature control during cold exposure. We cloned UCP1 cDNA of plateau pika (Ochotona dauurica), a small, non-hibernating, diurnal lagomorph that inhabits in relatively cold climates and at high altitudes in Mongolia and in northern China. The nucleotide sequence of pika UCP1 was highly homologous to UCP1 of other species, and the deduced amino acid sequence had some common domains for UCP, including six mitochondrial carrier protein motifs and a putative purine-nucleotide binding site. RT-PCR and Western blot analyses revealed that both UCP1 mRNA and protein were expressed exclusively in the interscapular adipose tissue. These results suggest that pika UCP1 contributes to heat production in brown adipose tissue, as do those in other species.

Minor role of brown fat thermogenesis in IL-1beta-induced fever
Yuko Okamatsu-Ogura, Naoya Kitao, Kazuhiro Kimura, Masayuki Saito
INTERNATIONAL JOURNAL OF OBESITY, 31, S58, S58, NATURE PUBLISHING GROUP, 2007年05月, ［査読有り］, ［筆頭著者］
英語

Induction of proinflammatory cytokines and caspase-1 by leptin in monocyte/macrophages from holstein cows.
Ahmed M, Shaban Z, Yamaji D, Okamatsu-Ogura Y, Soliman M, Abd Eldaim M, Ishioka K, Makondo K, Saito M, Kimura K
The Journal of veterinary medical science / the Japanese Society of Veterinary Science, 69, 5, 509, 514, 5, 2007年05月, ［査読有り］
英語, 脂肪細胞分泌因子,レプチンは摂食やエネルギー消費のみならず,免疫細胞機能を修飾することが知られる.ウシ単核球(PBMC)をレプチン単独あるいはT細胞マイトージェンCon Aと同時に刺激すると,レプチンはPBMCの増殖を10-40%増大させた.一方,PBMCからTリンパ球を分離し,同様に刺激すると,レプチンはTリンパ球の増殖を抑制したので,レプチンはPBMCに含まれる単球マクロファージなどに作用してTリンパ球増殖因子を産生させる可能性を示した.次に単球マクロファージを分離してサイトカイン遺伝子の発現を調べたところ,多寡はあるものの腫瘍壊死因子TNF-α,インターロイキン(IL)-1β,IL-12p35,IL-12p40,IL-18遺伝子の恒常的な発現が見られた.レプチンを作用させるとTNF-αとIL-12p40mRNAの発現が増大したが,他の遺伝子の発現は変化しなかった.TNF-αの分泌量を調べると,実際に培養液中の濃度が増加した.また培養液中のIL-1β濃度が増大した.そこで伏在性のpro-IL-1βやpro-IL-18を活性型に分解させるタンパク分解酵素caspase-1の発現について調べたところ,レプチンによってその遺伝子の発現が増大した.これらの結果より,レプチンは単球マクロファージに作用しIL-12p35/p40の複合体形成や活性型IL-1β/IL-18を分泌させTリンパ球の増殖を促進すると考えられた.

Brown fat UCP1 is not involved in the febrile and thermogenic responses to IL-1ß in mice.
Okamatsu-Ogura Y, Kitao N, Kimura K, Saito M
Am J Physiol Endocrinol Metab, 292, 4, E1135, E1139, AMER PHYSIOLOGICAL SOC, 2007年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Brown fat UCP1 is not involved in the febrile and thermogenic responses to IL-1 beta in mice. Am J Physiol Endocrinol Metab 292: E1135-E1139, 2007. First published December 12, 2006; doi:10.1152/ajpendo.00425.2006. - The activity of brown adipose tissue (BAT), a site of nonshivering metabolic thermogenesis, has been reported to increase after interleukin (IL)-1 beta/lipopolysaccharide injection. To clarify the possible contribution of BAT thermogenesis to whole body febrile response, we investigated febrile and thermogenic response to IL-1 beta using mice deficient in uncoupling protein-1 (UCP1), a key molecule for BAT thermogenesis. In wild-type (WT) mice, IL-1 beta injection (5 mu g/kg ip) increased body temperature (+1.82 degrees C at 20 min), decreased physical activity (-37% at 1 h), and produced a slight and insignificant rise (+15% at 1 h) in oxygen consumption (V-O2). V-O2 dependent on metabolic thermogenesis (Delta V-O2 thermogenesis) calculated by correcting the effect of physical activity was increased after IL-1 beta injection (726 +/- 200 ml center dot h(-1)center dot kg(-1) at 1 h). Almost the same responses were observed in UCP1-deficient mice, showing 638 +/- 87 ml center dot h(-1)center dot kg(-1) of Delta V-O2 (thermogenesis) at 1 h. In contrast, CL316,243, a selective activator of BAT thermogenesis, increased body temperature, decreased physical activity, and produced a significant rise in V-O2 in WT mice, showing 1,229 +/- 35 ml center dot h(-1)center dot kg(-1) of Delta V-O2 thermogenesis at 1 h. These changes were not observed in UCP1-deficient mice. These results, conflicting with a previously proposed idea of a role of BAT in fever, suggest a minor contribution of BAT thermogenesis to IL-1 beta-induced fever. In support of this, we found no effect of IL-1 beta on triglyceride content and UCP1 mRNA level in BAT, in contrast with apparent effects of CL316,243.

Effects of leptin and tumor necrosis factor-alpha on degranulation and superoxide production of polymorphonuclear neutrophils from Holstein cows.
Ahmed M, Kimura K, Soliman M, Yamaji D, Okamatsu-Ogura Y, Makondo K, Inanami O, Saito M
The Journal of veterinary medical science, 69, 2, 125, 131, 社団法人 日本獣医学会(The Japanese Society of Veterinary Science), 2007年02月, ［査読有り］
英語, Leptin, a pleiotropic hormone regulating food intake and energy expenditure, has been shown to directly modulate human polymorphonuclear neutrophil (PMN) functions or indirectly through the action of tumor necrosis factor-α (TNF-α). Bovine PMN have considerable different characteristics from human PMN. For example, it does not respond to N-formyl-Methionyl-Leucyl-phenylalanine, a well known human PMN activator. In the present study, we tested the effects of leptin and TNF-α on superoxide production and degranulation of bovine peripheral PMN, in which both long isoform of leptin receptor (Ob-Rb) and TNF receptor 1 were expressed. Human leptin, human TNF-α, phorbol myristate acetate (PMA) and opsonized zymosan particles (OZP) did not stimulate degranulation responses, while zymosan-activated serum (ZAS) did. Neither leptin nor TNF-α enhanced the ZAS-induced degranulation responses. TNF-α, PMA, OZP and ZAS increased superoxide production in different magnitudes, whereas leptin did not. TNF-α, but not leptin, enhanced OZP- and ZAS-induced superoxide production, possibly, in part due to facilitating translocation of p47phox, a component of NADPH oxidase. These results indicate that, unlike in human PMN, leptin does not have any direct effect on degranulation and superoxide production in bovine PMN, although TNF-α influences superoxide production.

Day-Night difference in ß3-adrenoceptor agonist-induced energy expenditure: Contribution of brown fat thermognesis and physical activity.
Okamatsu-Ogura Y, Uozumi A, Kitao N, Kimura K, Saito M
Obes Res Clin Prac, 1, 1, 61, 67, ELSEVIER SCI LTD, 2007年01月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, beta 3-adrenergic receptor (beta 3-AR) agonist, a drug that reduces body fat, stimulates lipomobilization from white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). To test the day-night difference in the effects of beta 3-AR agonist, in the present study, we examined the responses of lipomobitization and energy expenditure to CL316,243 (CL) during the daytime at 10:00 and nighttime at 22:00 in mice kept in a 12 h light-dark cycle with lights on from 07:00. CL injection increased plasma free fatty acid to the same extent at 10:00 and 22:00. In contrast, CL injection increased total oxygen consumption more markedly at 10:00 than 22:00. Physical activity was suppressed by CL injection especially at 22:00. Correcting total oxygen consumption by the suppressive effect on physical activity, oxygen consumption dependent on BAT thermogenesis was estimated. This revealed that the effect of CL on BAT thermogenesis was not different between 10:00 and 22:00. Thus, we concluded that there is no day-night difference in the CL effects on lipomobilization from WAT and thermogenesis in BAT. The stronger effect of CL on total energy expenditure in the daytime was largely due to a more suppressive effect on physical activity in the nighttime. (C) 2006 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Indispensable role of mitochondrial UCP1 for antiobesity effect of ß3-adrenergic stimulation.
Inokuma K, Okamatsu-Ogura Y, Omachi A, Matsushita Y, Kimura K, Yamashita H, Saito M
Am J Physiol Endocrinol Metab, 290, 5, E1014, E1021, AMER PHYSIOLOGICAL SOC, 2006年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Mitochondrial uncoupling protein-1 ( UCP1) has been thought to be a key molecule for thermogenesis during cold exposure and spontaneous hyperphagia and thereby in the autonomic regulation of energy expenditure and adiposity. However, UCP1 knockout ( KO) mice were reported to be cold intolerant but unexpectedly did not get obese even after hyperphagia, implying that UCP1 may not be involved in the regulation of adiposity. Treatment of obese animals with beta(3)-adrenergic agonists is known to increase lipid mobilization, induce UCP1, and, finally, reduce body fat content. To obtain direct evidence for the role of UCP1 in the anti-obesity effect of beta(3)-adrenergic stimulation, in the present study, UCP1-KO and wild-type ( WT) mice were fed on cafeteria diets for 8 wk and then given a beta(3)-adrenergic agonist, CL-316,243 ( CL), or saline for 2 wk. A single injection of CL increased whole body oxygen consumption and brown fat temperature in WT mice but not in KO mice, and it elicited almost the same plasma free fatty acid response in WT and KO mice. WT and KO mice increased similarly their body and white fat pad weights on cafeteria diets compared with those on laboratory chow. Daily treatment with CL resulted in a marked reduction of white fat pad weight and the size of adipocytes in WT mice, but not in KO mice. Compared with WT mice, KO mice expressed increased levels of UCP2 in brown fat but decreased levels in white fat and comparable levels of UCP3. It was concluded that the anti-obesity effect of beta(3)-adrenergic stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and thereby to UCP1-dependent degradation of fatty acids released from white adipose tissue.

Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue
K Inokuma, Y Ogura-Kamatsu, C Toda, K Kimura, H Yamashita, M Saito
DIABETES, 54, 5, 1385, 1391, AMER DIABETES ASSOC, 2005年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Sympathetic stimulation activates glucose utilization in parallel with fatty acid oxidation and thermogenesis in brown adipose tissue (BAT) through the beta-adrenergic receptors. To clarify the roles of the principal thermogenic molecule mitochondrial uncoupling protein 1 (UCP1) in the sympathetically stimulated glucose utilization, we investigated the uptake of 2-deoxyglucose (2-DG) into BAT and some other tissues of UCP1-knockout (KO) mice in vivo. In wild-type (WT) mice, administration of norepinephrine (NE) accelerated the disappearance of plasma 2-DG and increased 2-DG uptake into BAT and heart without any rise of plasma insulin level. In UCP1-KO mice, the stimulatory effect of NE on 2-DG uptake into BAT, but not into heart, disappeared completely. Insulin administration increased 2-DG uptake into BAT and also heart similarly in WT and UCP1-KO mice. NE also increased the activity of AMP-activated protein kinase (AMP kinase) in BAT of WT but not UCP1-KO mice. Our results, together with reports that the activation of AMP kinase increases glucose transport in myocytes, suggest that the sympathetically stimulated glucose utilization in BAT is due to the serial activation of UCP1 and AMP kinase.

UCP1レポーター脂肪細胞株を用いたβ-アドレナリンシグナル調節遺伝子の探索　　　　　　　　　　　　　　　
川原崎 聡子, 瀬尾 茂人, 岡松 優子, 高橋 春弥, 野村 亘, 神戸 大朋, 木村 和弘, 斉藤 昌之, 松田 秀雄, 井上 和生, 後藤 剛, 日本栄養・食糧学会大会講演要旨集, 77回, 267, 267, 2023年03月
(公社)日本栄養・食糧学会, 日本語

母親のビタミンA欠乏食摂取は子のベージュ脂肪細胞の出現を抑制する
加藤美羅, 岡松優子, 塚田杏樹, 二川瑛実, 稲波修, 木村和弘, 日本獣医学会学術集会講演要旨集, 166th, 2023年

レポーター脂肪細胞株を用いたβ-アドレナリン刺激応答性UCP1発現誘導調節遺伝子の探索　　　　　　　　　　　　　　　
川原崎 聡子, 瀬尾 茂人, 岡松 優子, 高橋 春弥, 野村 亘, 神戸 大朋, 木村 和弘, 斉藤 昌之, 松田 秀雄, 井上 和生, 後藤 剛, 肥満研究, 28, Suppl., 318, 318, 2022年11月
(一社)日本肥満学会, 日本語

イソプレノイド合成経路の褐色脂肪細胞分化制御機構の検討　　　　　　　　　　　　　　　
Kwon Jungin, Yeh Yu-Sheng, 川原崎 聡子, 南野 寛人, 藤田 義人, 岡松 優子, 野村 亘, 高橋 春弥, 木村 和弘, 斉藤 昌之, 稲垣 暢也, 井上 和生, 河田 照雄, 後藤 剛, 肥満研究, 27, Suppl., 338, 338, 2022年03月
(一社)日本肥満学会, 日本語

腹内側視床下部におけるプロスタグランジンは低血糖症におけるグルコース産生を調節する【JST・京大機械翻訳】
徐書誠, 早坂孝宏, 杉浦悠毅, 岡松優子, 木村和弘, 戸田知得, 日本獣医学会学術集会講演要旨集, 165th (CD-ROM), 2022年

食と栄養による脂肪組織の機能制御　　　　　　　　　　　　　　　
岡松優子, 生化学, 93, 1, 22, 34, 2021年, ［招待有り］

肥満における視床下部の細胞膜リン脂質代謝と全身糖代謝の関係
戸田知得, 李明亮, 松永洋和, 杉浦悠毅, 早坂孝宏, 北沢泉, 岡松優子, 木村和弘, 日本肥満学会・日本肥満症治療学会合同学術集会プログラム・抄録集, 40th-37th, 2019年

絶食によるマウス褐色脂肪組織による血管外漏出性亢進
湯田坂雅子, 蓬田陽平, 張民芳, 中原正子, 小林徳彦, 田中丈士, 岡松優子, 佐伯久美子, 片浦弘道, 日本肥満学会・日本肥満症治療学会合同学術集会プログラム・抄録集, 40th-37th, 2019年

齧歯類モデルにおけるネオニコチノイド殺虫剤と高脂肪食2型糖尿病発症促進シグナルの相互作用
NIMAKO Collins, IKENAKA Yoshinori, IKENAKA Yoshinori, OKAMATSU-OGURA Yuko, KOBAYASHI Atsushi, NAKAYAMA Shouta M.M., ISHIZUKA Mayumi, 環境化学討論会要旨集(CD-ROM), 28th, 2019年

Differentiation of Japanese Black Bears' Adipose-Derived Stem Cells to Osteoblasts
Alireza Nasoori, Yuko Okamatsu-Ogura, Woongchul Shin, Michito Shimozuru, Mohamed Abdallah Mohamed Moustafa, Toshio Tsubota, JOURNAL OF BONE AND MINERAL RESEARCH, 33, 224, 224, 2018年11月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

視床下部エイコサノイドは血糖値の調節に関与する
戸田知得, 李明亮, 松永洋和, 早坂孝宏, 北沢泉, 岡松優子, 木村和弘, 肥満研究, 24, Supplement, 2018年

褐色脂肪細胞によるエネルギー代謝調節　　　　　　　　　　　　　　　
岡松優子, FOOD STYLE 21, 21, 8, 60, 63, 2017年, ［招待有り］

膵臓の内分泌生理　　　　　　　　　　　　　　　
岡松優子, SURGEON 129, 22, 3, 12, 19, 2016年, ［招待有り］

犬と猫の肥満研究の最前線「摂食と栄養代謝」
岡松優子, J-VET, 29, 10, 8, 18, 2016年, ［招待有り］
インターズー, 日本語

視床下部メラニン凝集ホルモン産生神経の長期記憶における役割
伊澤俊太郎, 寺尾晶, 寺尾晶, 上野貴文, 岡松優子, 大村優, 吉岡充弘, 山中章弘, 木村和弘, 日本獣医学会学術集会講演要旨集, 158th, 2015年

脂肪燃焼組織・褐色脂肪の食品成分による活性化と抗肥満効果　　　　　　　　　　　　　　　
岡松優子, New Food Industry, 58, 10, 21, 25, 2015年, ［招待有り］

褐色脂肪組織の低形成を示すaP2-p27 Tgマウスにおける白色脂肪組織の褐色化　　　　　　　　　　　　　　　
深野 圭伍, 岡松 優子, 坪田 あゆみ, 阪上 浩, 寺尾 晶, 木村 和弘, 肥満研究, 20, Suppl., 205, 205, 2014年10月
(一社)日本肥満学会, 日本語

実験動物を用いたエネルギー代謝研究 最近のトピックから 肥満対策のターゲットとしての褐色脂肪組織 実験動物を用いた検討　　　　　　　　　　　　　　　
岡松 優子, 深野 圭伍, 坪田 あゆみ, 大山 夏奈, 野草 義人, 寺尾 晶, 阪上 浩, 木村 和弘, 日本獣医学会学術集会講演要旨集, 157回, 301, 301, 2014年08月
(公社)日本獣医学会, 日本語

aP2-p27トランスジェニックマウスにおける褐色脂肪組織低形成のメカニズムの解析　　　　　　　　　　　　　　　
深野 圭伍, 岡松 優子, 阪上 浩, 寺尾 晶, 木村 和弘, 日本獣医学会学術集会講演要旨集, 157回, 506, 506, 2014年08月
(公社)日本獣医学会, 日本語

褐色脂肪組織は新生ゼニガタアザラシの体温保持に寄与するか
櫻井裕太, 岡松優子, 中尾亮, 大沼愛子, 斉藤昌之, 小林万里, 小林万里, 木村和弘, 日本獣医学会学術集会講演要旨集, 157th, 2014年

褐色脂肪細胞の増殖とその生理的意義　　　　　　　　　　　　　　　
岡松優子, 深野圭吾, 医学のあゆみ, 250, 9, 822, 826, 2014年, ［招待有り］

褐色/ベージュ脂肪細胞の発生機構と生理的役割　　　　　　　　　　　　　　　
岡松優子, 木村和弘, バイオインダストリー, 30, 11, 4, 10, 2013年, ［招待有り］

UCP1の機能と比較生物学　　　　　　　　　　　　　　　
岡松 優子, The Lipid, 25, 1, 29, 35, 2013年, ［招待有り］
日本語

褐色脂肪細胞によるエネルギー代謝制御におけるPGC-1 の役割　　　　　　　　　　　　　　　
岡松優子, 木村和弘, 内分泌・糖尿病科, 29, 2, 109, 116, 2009年, ［招待有り］

脱共役タンパク質UCP1によるレプチン感受性の調節
岡松 優子, 斉藤 昌之, 肥満研究 : 日本肥満学会誌 = Journal of Japan Society for the Study of Obesity, 14, 3, 265, 267, 2008年12月25日
日本肥満学会, 日本語

レプチンの体脂肪減少効果にUCP1は貢献しているのか？　　　　　　　　　　　　　　　
岡松優子, 斉藤昌之, 肥満研究, 12, 73, 75, 2006年, ［招待有り］

褐色脂肪細胞の起源と分化制御　　　　　　　　　　　　　　　
岡松優子, 斉藤昌之, The Lipid, 17, 65, 71, 2006年, ［招待有り］

褐色脂肪の機能と分化機構　　　　　　　　　　　　　　　
岡松優子, 斉藤昌之, 細胞, 38, 14, 18, 2006年, ［招待有り］

褐色脂肪によるエネルギー代謝の調節　　　　　　　　　　　　　　　
岡松優子, 斉藤昌之, Clinical Neuroscience, 24, 914, 916, 2006年, ［招待有り］

褐色脂肪と白色脂肪：エネルギー代謝における役割　　　　　　　　　　　　　　　
岡松優子, 大町麻子, 斉藤昌之, 分子細胞治療, 5, 28, 34, 2006年, ［招待有り］

獣医生化学　　　　　　　　　　　　　　　
11章「代謝の臓器特異性とその相関」
朝倉書店, 2014年, ［分担執筆］

ここまでわかった燃える褐色脂肪の不思議　　　　　　　　　　　　　　　
岡松 優子, いろいろな動物の褐色脂肪組織とその役割
有限会社ナップ, 2013年, ［分担執筆］

体と温度の辞典　　　　　　　　　　　　　　　
岡松優子, 斉藤昌之, 熱産生機構2 褐色脂肪組織
朝倉書店, 2010年, ［分担執筆］

肥満と脂肪エネルギー代謝　　　　　　　　　　　　　　　
岡松優子, 斉藤昌之, 褐色脂肪と肥満･メタボリックシンドローム：実験動物からヒトへ
建帛社, 2008年, ［分担執筆］

糖尿病カレントライブラリー７ 脂肪細胞と脂肪組織　　　　　　　　　　　　　　　
岡松優子, 斉藤昌之, 辻崎正幸, 白色脂肪と褐色脂肪の代謝特性
文光堂, 2007年, ［分担執筆］

別冊医学の歩み『糖尿病・代謝症候群ﾑstate of arts 2004-2006』　　　　　　　　　　　　　　　
小倉優子, 猪熊健一, エネルギー消費における脱共役蛋白質UCP1の役割
医歯薬出版, 2004年, ［分担執筆］

冬眠動物ハムスターにおける褐色脂肪組織の形成プログラミング機構　　　　　　　　　　　　　　　
岡松優子
日本獣医学会学術集会（第162回大会）生理学・生化学分科会シンポジウム, 2018年
［招待講演］

母マウスへの高脂肪食の給餌が乳仔期のベージュ脂肪細胞誘導に与える影響　　　　　　　　　　　　　　　
岡松優子
日本栄養・食糧学会北海道支部（第48回大会）・東北支部（第52回大会）合同支部大会公開シンポジウム, 2016年
［招待講演］

褐色脂肪細胞の増殖と適応熱産生adaptive thermogenesisにおける役割　　　　　　　　　　　　　　　
岡松優子
第37回日本肥満学会, 2016年
［招待講演］

肥満対策のターゲットとしての褐色脂肪組織：実験動物を用いた検討　　　　　　　　　　　　　　　
岡松 優子
第157回日本獣医学会, 2014年09月, 日本語, シンポジウム・ワークショップパネル（指名）
［招待講演］, ［国内会議］

食品成分カプシノイドの抗肥満作用　　　　　　　　　　　　　　　
岡松 優子
第34回日本肥満学会, 2013年10月, 日本語, シンポジウム・ワークショップパネル（指名）
［招待講演］, ［国内会議］

褐色脂肪細胞の増殖とその病態生理学的意義　　　　　　　　　　　　　　　
岡松 優子
第18回アディポサイエンス・シンポジウム, 2013年08月, 日本語, シンポジウム・ワークショップパネル（指名）
［招待講演］, ［国内会議］

褐色脂肪細胞の増殖と意義　　　　　　　　　　　　　　　
岡松 優子
第33回日本肥満学会, 2012年10月, 日本語, シンポジウム・ワークショップパネル（指名）
［招待講演］, ［国内会議］

Roles of UCP1 in the regulation of energy metabolism　　　　　　　　　　　　　　　
岡松 優子
Brown Adipose Tissue 2011 Update, 2011年03月, 日本語, シンポジウム・ワークショップパネル（指名）
［招待講演］, ［国内会議］

Protective roles of brown adipose tissue against age-related development of obesity　　　　　　　　　　　　　　　
岡松 優子
14th International Congress of Endocrinology Official Satellite Symposium, 2010年03月, 英語, シンポジウム・ワークショップパネル（指名）
［招待講演］, ［国際会議］

冬眠発動を支える組織リモデリング制御
科学研究費助成事業
2023年04月01日 - 2028年03月31日
岡松 優子, 山内 彩加林
日本学術振興会, 学術変革領域研究(A), 北海道大学, 23H04942

冬眠生物学2.0 総括班
科学研究費助成事業
2023年04月01日 - 2028年03月31日
山口 良文, 榎木 亮介, 田中 和正, 清成 寛, 黒田 真也, 桜井 武, 砂川 玄志郎, 金 尚宏, 岡松 優子
日本学術振興会, 学術変革領域研究(A), 北海道大学, 23H04939

熱産生する褐色脂肪細胞に新規H+チャネルが高発現する生理的意義の解明
科学研究費助成事業
2022年04月01日 - 2026年03月31日
山口 聡一郎, 岡松 優子
日本学術振興会, 基盤研究(C), 北海道大学, 22K06825

食事誘導熱産生における褐色脂肪組織の役割と神経・内分泌機構の解明
科学研究費助成事業
2022年04月01日 - 2025年03月31日
斉藤 昌之, 松下 真美, 岡松 優子
日本学術振興会, 基盤研究(C), 北海道大学, 22K11772

新規動物モデルを用いた脂肪組織リモデリング機構の解明
科学研究費助成事業
2022年04月01日 - 2025年03月31日
岡松 優子
日本学術振興会, 基盤研究(C), 北海道大学, 22K08641

がん特異的代謝システムを標的とした新規セノリティックテラピー開発のための基盤研究
科学研究費助成事業
2020年04月01日 - 2025年03月31日
稲波 修, 平岡 和佳子, 安井 博宣, 平田 拓, 滝口 満喜, 岡松 優子
本年度はインビトロの培養細胞の系の実験で、以下の四つの結果が明らかとなった。
1）グルタミン要求性の強いヒト肺がんA549細胞やH460細胞では、放射線照射により、これらの細胞でのグルタミンの取り込みの増大とグルタメートの増大、すなわちグルタミナーゼの活性化を起こす事を明らかにした。さらに、グルタミン代謝阻害剤添加あるいはグルタミン欠乏培地下で培養すると治療線量レベルの放射線照射によって多くの老化様細胞死とSASPの培養液中への分泌を増強させることが可能である事が明らかとなった。
2）グルタミノリシス阻害条件下で放射線による老化様細胞死の誘発機構には活性酸素種の生成量、グルタチオン量の変化DNA損傷の量、さらにはDNA損傷に伴う伴うp53やp21、p16の発現変化などの既知のメカニズムの関与は殆ど無く、未知の機構の関与が示唆されている。
3）更にグルタミノリシス阻害条件下で放射線誘発する老化様細胞死を起こす条件で、Bcl-XL阻害剤ABT-737によって、この増大した老化様細胞死の多くはアポトーシスに変換できること、いわゆるセノリシスを起こせることを明らかにした。
4）一方では、同じ肺がん由来細胞でも786-o細胞ではグルタミン代謝阻害が老化様細胞の増強を起こさず、A549やH460細胞と同様の現象は観察されず、全ての肺がん細胞に於いて同様の機構が働いていない事も明らかとなった。また、脂質代謝阻害剤は老化様細胞増強には関与しなかった。
以上の結果はグルタミン要求性の強い肺がん細胞を中心にその亜致死レベルのグルタミノリシス阻害条件下で治療線量レベルの放射線照射をすると、多量の老化様細胞死の増大が起こす事を示しており、さらに、アポトーシス抑制因子の阻害剤で効率よく老化様細胞死をアポトーシスに変換できることが明確になった。
日本学術振興会, 基盤研究(A), 北海道大学, 20H00443

褐藻由来フコキサンチンの代謝疾患予防機構における免疫細胞の機能制御の解明
科学研究費助成事業
2021年04月01日 - 2024年03月31日
細川 雅史, 岡松 優子, 高谷 直己
2021年度の研究において、以下の研究成果を得た。
(1)フコキサンチンを投与した肥満マウスの脂肪組織では、これまで報告しているように活性化マクロファージマーカーのF4/80およびM1マクロファージマーカーのCD11cのmRNA発現量の低下が確認された。さらに、M1マーカー(CD11c)/M2マーカー(Arg1)比も低下したことから、フコキサンチンがマクロファージの脂肪組織への浸潤を抑制するとともに、極性変化にも関わることが推察された。一方、T細胞マーカーを解析した結果、CD8に加えCD25およびCD4のmRNA発現量が低下し、T細胞サブセットへの影響が示唆された。(2)非アルコール性脂肪肝炎を誘導したマウスの肝臓では、フコキサンチンの投与によりCD8およびCD25のmRNA発現量が低下傾向を示した。(3)肝細胞およびマクロファージ株をフコキサンチン代謝物のフコキサンチノールで処理し、各オルガネラにおける蓄積をHPLCにて定量した。細胞膜、ミトコンドリア、ミクロソーム画分でフコキサンチノールが検出されたことから、細胞膜を通過しオルガネラへの移行することが推察された。特に、ミトコンドリア画分での蓄積が多いことが示唆された。(4)フコキサンチノールがミトコンドリア画分に蓄積していた点に着目し、ミトコンドリア機能に関わるミトコンドリアDNA量の測定を行った。NASHモデルマウスの肝臓からDNAを抽出し測定を行った結果、普通食群と比較してNASH誘導色群でみられたミトコンドリアDNA量の低下が、フコキサンチンにより抑制された。(5)エネルギー代謝に関わる白色脂肪組織から褐色脂肪組織への転換メカニズムとして分泌因子を介した細胞間コミュニケーションについて調べた。その結果、BMPを介した組織転換制御の可能性が認められた。
日本学術振興会, 基盤研究(B), 北海道大学, 21H02276

mlAOPコンセプトによる化学物質感受性多様性評価と殺虫剤中毒解明に向けた応用
科学研究費助成事業
2018年04月01日 - 2022年03月31日
池中 良徳, 星 信彦, 川合 佑典, 石塚 真由美, 小林 篤史, 久保田 彰, 水川 葉月, 有薗 幸司, 平野 哲史, 加藤 恵介, 宮原 裕一, 市川 剛, 岡松 優子, 中山 翔太
本研究では、毒性影響の種による多様性を評価するため、新しい評価コンセプトであるmlAOPを検証した。モデル化合物として、ネオニコチノイド（NN）に着目し、マウスとゼブラフィッシュ、およびゼノパスに対する神経毒性影響を比較した結果、いずれの種においても無毒性量（NOAEL）以下の曝露で行動異常や神経伝達物質の撹乱が観察された。更に、本研究では広範な野生動物種の感受性評価のため、皮膚線維芽細胞に着目した評価系の構築を行い、多様な種におけるNNの影響評価を実施した。
ヒトへの曝露評価・健康影響評価のために実施した臨床研究では、世界に先駆け、ネオニコチノイドの曝露源を明らかにすることが出来た。
日本学術振興会, 基盤研究(A), 北海道大学, 18H04132

海洋性カロテノイドの代謝物解析と臓器・細胞連関制御を介した生活習慣病予防の新展開
科学研究費助成事業
2018年04月01日 - 2021年03月31日
細川 雅史, 岡松 優子
生活習慣病予防効果が期待されるフコキサンチンの新たな体内代謝物としてパラセントロンを同定した。また、肥満やNASHの発症に関わる活性化マクロファージに対し炎症因子産生を抑制することを見出した。さらに、アポ-10’-フコキサンチナール等にもIκBのリン酸化阻害を介した炎症因子の産生抑制効果を認めた。一方、β-アポ-8’-カロテナールは効果を示さず、フコキサンチンの部分構造をもつアポフコキサンチノイドの機能性を示した。また、炎症誘導した肝細胞に対し、フコキサンチン代謝物がケモカインのmRNA発現を抑制するのみならずマクロファージの遊走を抑制し、慢性炎症に関わる細胞間作用を制御することを見出した。
日本学術振興会, 基盤研究(B), 北海道大学, 18H02274

ツキノワグマにおける冬眠中の体温調節機構の解明－ふるえ産熱か非ふるえ産熱か－
科学研究費助成事業
2017年04月01日 - 2020年03月31日
坪田 敏男, 宮崎 充功, 佐鹿 万里子, 下鶴 倫人, MOHAMED MOUSTAFA, 岡松 優子
冬眠中のツキノワグマにおける体温調節機構を解明することを目指して、とくに体脂肪を使った非ふるえ産熱に着目して研究を行った。飼育下（北秋田市阿仁クマ牧場）のツキノワグマに体温および心拍数測定用データロガーを埋め込み、冬眠期とその前後の期間の体温および心拍数をモニタリングした。その結果、11月下旬にツキノワグマを個室に移動させ、給餌を停止した直後に体温および心拍数が低下し、冬眠に入ったと判断された。その後は、雄と雌とで体温および心拍数の変化に違いが認められ、冬眠時期（雌では繁殖プロセス）によって体温と心拍数の調節機序が異なることが示唆された。非ふるえ産熱に使われる褐色脂肪の存在は認められなかった。
日本学術振興会, 基盤研究(B), 北海道大学, 17H03936

アディポネクチンとCTRP11による前駆脂肪細胞の増殖制御機構の解明
科学研究費助成事業
2016年04月01日 - 2019年03月31日
木村 和弘, 岡松 優子
分化した脂肪細胞が分泌するアディポクチン(AN)は, 主に前駆脂肪細胞を含む分画から産生される神経成長因子NGFと血管内皮細胞増殖因子VEGF165に結合した。ANはNGFの機能を抑制したが、VEGF165による血管内皮細胞の形態変化を阻害しなかった。その後、NGF, VEGFとは異なる二つの因子を前駆脂肪細胞増殖因子として同定した。ANとこの二つの因子の結合は確認したが、機能への影響は現在解析中である。CTRP11の組み換え体も準備できたので、今後、二つの因子との結合および機能への影響を解析する。
日本学術振興会, 基盤研究(C), 北海道大学, 16K08068

カーボンナノチューブによる褐色脂肪組織の近赤外光造影
科学研究費助成事業
2016年04月01日 - 2019年03月31日
湯田坂 雅子, 片浦 弘道, 佐伯 久美子, 岡松 優子
本研究では、近赤外(NIR)蛍光を発する単層カーボンナノチューブ（CNT) の表面を適切に被覆し、NIR蛍光造影剤として用いると、マウスの褐色脂肪組織（BAT)の選択的造影が可能であり、さらに、外的刺激により起こるBATの状態変化をモニターできることを明らかにした。また、近赤外蛍光顕微鏡によりCNTのBAT内での細胞レベルでの分布を明らかにしたところ、絶食させたマウスのBATでは、CNTの血管外漏出が認められた。遺伝子解析から絶食時にはBATでタンパク質分解酵素増産され、それにより細胞外マトリックスを形成するコラーゲンが脆弱化し、血管基底膜も脆弱化し血管外漏洩が促進されたと推定された。
日本学術振興会, 基盤研究(A), 国立研究開発法人産業技術総合研究所, 16H02085

体温制御システム構築の細胞分子基盤：ハムスターの恒温性獲得機構をモデルとして　　　　　　　　　　　　　　　
科学研究費助成事業（科学研究費補助金） 基盤（C）
2017年 - 2019年
岡松 優子
日本学術振興会, 研究代表者, 競争的資金

母乳の質がもたらす乳児期の脂肪組織リモデリングと成長後のメタボリックシンドロームの発症しやすさとの関わりの解明　　　　　　　　　　　　　　　
研究奨励
2019年
岡松 優子
森永奉仕会, 研究代表者, 競争的資金

ヒト褐色脂肪組織に特異的な血中エクソソームmiRNAの探索と評価法への活用
科学研究費助成事業
2016年04月01日 - 2018年03月31日
斉藤 昌之, 松下 真美, 岡松 優子
肥満のターゲットの一つであるヒト褐色脂肪の簡便・低侵襲な評価法を開発する為に、成人血中のエクソソームmiRNAを網羅的に分析・定量し、標準法であるFDG-PET/CT で測定した褐色脂肪活性と比較した。
健常男性40名から得た血清サンプルから得たエクソソームmiRNAを網羅的アレイ解析した所、高活性者と低活性者で1.5倍以上異なる可能性のあるmiRNAが11種選抜されたので、更にPCR法で定量したところ、miRNA122-5p濃度が高活性者では低活性者に比べて有意に低値であることが判明した。
血中エクソソームmiRNA122-5pが褐色脂肪活性を反映するマーカーとなりうることを明らかにした。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 16K15485

自発的な低体温現象トーパーの発現機構の解明
科学研究費助成事業
2015年04月01日 - 2018年03月31日
坂本 健太郎, 岡松 優子
一部の哺乳類と鳥類では、ある条件下において自発的に大きく体温を低下させることが知られており、これを冬眠やトーパーと呼ぶ。本研究では、様々な条件下で実験的にマウスにトーパーを誘導し、その時の体内状態を調べることで、トーパー発現機構を明らかにすることを試みた。トーパー発現の有無には、寒冷順化の度合いが関与する事が示唆された。また、体温が大きく低下しているときでも、マウスは活動可能であることを示唆する結果を得る事が出来た。
日本学術振興会, 基盤研究(C), 北海道大学, 15K07758

睡眠機能を調節する視床下部MCH神経回路の特定
科学研究費助成事業
2015年04月01日 - 2018年03月31日
寺尾 晶, 岡松 優子, 山中 章弘
メラニン凝集ホルモン（MCH）産生神経は、視床下部外側野にその細胞体が局在しており、睡眠調節に関与することが明らかになっている。視床下部外側野からの主要投射部位に海馬が含まれること、睡眠と記憶という事象には関わりがあることから、我々はMCH神経が海馬依存性の長期記憶に対しても影響していると推察した。マウスの長期記憶を新規物体認知試験と恐怖条件付け試験により評価したところ、MCH神経を脱落させたマウスでは長期記憶力は対照群よりも良いことが明らかになった。MCH神経の活動は睡眠時に高いことが報告されており、睡眠中の記憶形成抑制に関わっている可能性が考えられた。
日本学術振興会, 基盤研究(C), 東海大学, 15K07140

海洋性カロテノイドによる脂肪細胞の褐色化を介したメタボリック症候群予防機構の解明
科学研究費助成事業
2015年04月01日 - 2018年03月31日
細川 雅史, 岡松 優子, 勝木 曉美, 大内 裕佳, 田谷 大輔, 立山 莉帆, 秋田 知輝
褐藻中に特徴的に含まれるフコキサンチンは、食餌性肥満誘導マウスの褐色脂肪組織に加え、白色脂肪組織（WAT）においてUCP1(脱共役タンパク質1)を含むミトコンドリア因子の発現増加による褐色化を誘導し、脂質代謝の活性化を伴ってWAT重量の増加を抑制した。フコキサンチン代謝物によるミトコンドリア因子の発現増加は脂肪細胞においても観察され、その調節因子としてPGC-1αの重要性が推察された。一方、褐色化に関わるベージュ脂肪細胞の数が、脂肪組織中のプロジェニター細胞により規定される可能性が高く、その数が加齢に伴い減少することを基礎知見として見出した。
日本学術振興会, 基盤研究(B), 北海道大学, 15H04545

冬眠動物における体温制御システム構築の分子基盤：発熱細胞プロジェニターの同定と局所環境の役割　　　　　　　　　　　　　　　
内藤記念女性研究者研究助成
2015年 - 2017年
岡松 優子
内藤記念科学振興財団, 研究代表者, 競争的資金

乳幼児期のベージュ脂肪細胞の誘導と消失に母乳の摂取が与える影響の解明　　　　　　　　　　　　　　　
一般公募研究
2017年
岡松 優子
糧食研究会, 研究代表者, 競争的資金

生体のエネルギー消費能力を増大させる褐色脂肪由来アディポカインの同定　　　　　　　　　　　　　　　
科学研究費助成事業（科学研究費補助金） 若手研究（B）
2014年 - 2016年
岡松 優子
日本学術振興会, 研究代表者, 競争的資金

冬眠動物の体温を制御する熱産生脂肪細胞の発生・誘導機構の解明　　　　　　　　　　　　　　　
奨励助成
2014年
岡松 優子
秋山記念生命科学振興財団, 研究代表者, 競争的資金

アザラシはどのように脂肪を蓄えるのか —皮下脂肪の重度蓄積と内臓脂肪の欠損の謎に迫る—　　　　　　　　　　　　　　　
研究助成
2012年 - 2013年
岡松 優子
栗林育英学術財団, 研究代表者, 競争的資金

乳腺組織形成における脂肪細胞分泌因子レプチンの役割　　　　　　　　　　　　　　　
研究奨励
2012年
岡松 優子
森永奉仕会, 研究代表者, 競争的資金

食品成分を利用した肥満対策法の開発に向けた褐色脂肪増加機構の解析　　　　　　　　　　　　　　　
フードイノベーション創造支援事業 研究シーズ発掘補助金
2012年
岡松 優子
ノーステック財団, 研究代表者, 競争的資金

乳腺組織形成と乳腺腫瘍におよぼす脂肪細胞の新たな役割とその分子基盤
科学研究費助成事業
2009年 - 2011年
木村 和弘, 岡松 優子
乳腺は皮下脂肪組織内に形成され、脂肪細胞は上皮細胞の栄養支持細胞として機能する。過栄養による脂肪細胞の肥大化に伴い、非妊娠期の乳腺導管形成は脆弱化し、妊娠期においては導管側枝形成が遅れ、その後の腺房形成やその成熟も遅れた。この時、脂肪細胞分泌因子レプチンの血中濃度は異常に高く、レプチンはin vivo, in vitroで乳腺上皮細胞機能を阻害した。よって、肥満による乳腺形成阻害の一部はレプチンを介することが示唆された。
日本学術振興会, 基盤研究(B), 北海道大学, 21380177

白色脂肪の褐色化機構の解明：新規肥満治療法の開発に向けた基礎研究
科学研究費助成事業（科学研究費補助金） 若手研究（B）
2009年 - 2010年
岡松 優子
褐色脂肪は脂肪を燃やして熱を産生する特殊な脂肪組織であり、肥満予防・治療のターゲットとして注目されている。褐色脂肪による抗肥満効果を得るためには、それを活性化する方法と増加させる方法が考えられる。本研究では、増加させる方法について検討した。一般に脂肪細胞は前駆細胞が増殖・分裂し、それらが成熟脂肪細胞に分化することで増加すると考えられている。本研究では、褐色脂肪は成熟分化後にも分裂・増加する可能性を新たに見いだした。
日本学術振興会, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 21780261

褐色脂肪の増殖及び機能におけるp27Kip1の役割　　　　　　　　　　　　　　　
奨励助成
2009年
岡松 優子
秋山記念生命科学振興財団, 研究代表者, 競争的資金

エネルギー消費組織：褐色脂肪の増殖・機能分化機構の解明　　　　　　　　　　　　　　　
公募型プロジェクト研究等支援経費（若手研究者自立支援）
2009年
岡松 優子
北海道大学, 研究代表者, 競争的資金

白色脂肪の褐色化 -太りにくい体質の獲得に向けて-
科学研究費助成事業（科学研究費補助金） （特別研究員奨励費）
2007年 - 2008年
岡松 優子
褐色脂肪は脂肪を燃焼して熱を産生する特殊な脂肪組織であり、その熱産生能を担うのが脱共役蛋白質UCP1である。前年度までの研究により、脂肪細胞から分泌されるレプチンがUCP1を活性化することで全身のエネルギー消費を亢進させ、体脂肪を減少させることが明らかになった。一方、UCP1はレプチンのエネルギー消費亢進作用のみならず、レプチン感受性の調節を介して摂食抑制作用にも関与する可能性が示唆されたので、UCP1によるレプチン感受性の調節機構について解析を行った。
野生型マウスにβ3受容体作動薬を慢性的に投与すると、通常UCP1が存在しない白色脂肪にUCP1が異所性発現する。これらのマウスではレプチンの摂食抑制作用が増強していた。アデノウイルスを用いて、UCP1欠損マウスの白色脂肪に人為的にUCP1を発現させてもレプチン作用の増強が認められたので、白色脂肪の異所性UCP1がレプチン作用の増強、つまりレプチン感受性の増加を引き起こすと考えられた。
レプチンは視床下部の弓状核に作用してJAK2-STAT3経路を活性化し、摂食抑制作用を示すことが知られているので、リン酸化STAT3(活性型STAT3)を指標に中枢でのレプチン感受性を調べた。レプチン投与後の弓状核でのリン酸化STAT3レベルは、対照マウスに比べβ3受容体作動薬慢性投与マウスにおいて増加していた。したがって、β3受容体作動薬慢性投与によるレプチン感受性の増加は中枢レベルで起こっていると考えられた。
以上の結果から、これまで発熱分子として知られてきたUCP1がレプチン感受性の調節を介して摂食調節にも関与する可能性が示唆された。
日本学術振興会, 特別研究員奨励費, 北海道大学, 研究代表者, 競争的資金, 07J04831

レプチンの作用におけるUCP1の役割　　　　　　　　　　　　　　　
海外研究交流助成
2006年
岡松 優子
伊藤医薬学術交流財団, 研究代表者, 競争的資金