Molecular Basis and Disorders of Control of Appetite and Fat Accumulation

• Project Area: Molecular Basis and Disorders of Control of Apetite and Fat Accumulation
• Project/Area Number: 22126012
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: HOSODA KIMINORI 京都大学, 医学(系)研究科(研究院), 教授 (40271598)
• Co-Investigator(Renkei-kenkyūsha): MORI Kiyoshi 京都大学, 医学研究科, 准教授 (60343232) ; TOMITA Tsutomu 京都大学, 医学研究科, 助教 (50402897)
• Project Period (FY): 2010-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥150,670,000 (Direct Cost: ¥115,900,000、Indirect Cost: ¥34,770,000); Fiscal Year 2014: ¥25,350,000 (Direct Cost: ¥19,500,000、Indirect Cost: ¥5,850,000); Fiscal Year 2013: ¥26,650,000 (Direct Cost: ¥20,500,000、Indirect Cost: ¥6,150,000); Fiscal Year 2012: ¥28,080,000 (Direct Cost: ¥21,600,000、Indirect Cost: ¥6,480,000); Fiscal Year 2011: ¥27,690,000 (Direct Cost: ¥21,300,000、Indirect Cost: ¥6,390,000); Fiscal Year 2010: ¥42,900,000 (Direct Cost: ¥33,000,000、Indirect Cost: ¥9,900,000)
• Keywords: GPR40 / 脂質異常症 / インスリン抵抗性 / GPCR / インスリン分泌 / レプチン / 膵臓 / 肥満 / 脂肪蓄積 / 脂肪毒性 / レプチン抵抗性 / 脳内報酬系 / 脂肪細胞 / 脂肪萎縮症 / iPS細胞 / 細胞治療 / ミトコンドリア遺伝子変異 / インスリン

Outline of Final Research Achievements

We demonstrated that the increase of triglyceride accumulation and the decrease of GPR40 gene expression in the pancreas of genetically obese rats deficient in leption receptor gene.We created GPR40 KO rat and now investigate the abnormalities in glucose and lipid metabolism.We established leptin gene deficient rats as a new genetically obese animal model.We succeeded in differentiation of human iPS cells into adipocyte for the first time in the world. We also established iPS cell lines from congenital lipodystrophy patients, and established a tool for the elucidation of pathogenesis and pathophysiology.

Research Products

• [Journal Article] The G-Protein-Coupled Long-Chain Fatty Acid Receptor GPR40 and Glucose Metabolism. (2014)
  • Author(s): T. Tomita, K. Hosoda, J. Fujikura, N. Inagaki, K. Nakao
  • Journal Title: Front Endocrinol Volume: 5:152 Pages: 152-152
  • DOI: 10.3389/fendo.2014.00152
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Leptin restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet. (2014)
  • Author(s): T. Sakai, T. Kusakabe, K. Ebihara, D. Aotani, S. Yamamoto-Kataoka, Z. Mingming, VM. Gumbilai, C. Ebihara, M. Aizawa-Abe, Y. Yamamoto, M. Noguchi, J. Fujikura, K. Hosoda, N. Inagaki, K. Nakao
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 307 Pages: 712-719
  • DOI: 10.1152/ajpendo.00272.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production. (2014)
  • Author(s): S. H. Chew, Y. Okazaki, H. Nagai, N. Misawa, S. Akatsuka, K. Yamashita, L. Jiang, Y. Yamashita, M. Noguchi, K. Hosoda, Y. Sekido, T. Takahashi, S. Toyokuni
  • Journal Title: Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production Volume: 35(1) Pages: 164-172
  • DOI: 10.1093/carcin/bgt267
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Generation of leptin deficient Lepmkyo/Lepmkyo rats and identification of leptin responsive genes in the liver. (2013)
  • Author(s): M. Aizawa-Abe, K. Ebihara, C. Ebihara, T. Mashimo, A. Takizawa, T. Tomita, T. Kusakabe, Y. Yamamoto, D. Aotani, S. Yamamoto-Kataoka, T. Sakai, K. Hosoda, T. Serikawa, K. Nakao
  • Journal Title: Physiol Genomics Volume: 45(17) Pages: 786-793
  • DOI: 10.1152/physiolgenomics.00040.2013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cell transplantation therapy for diabetes mellitus: endocrine pancreas and adipocyte [Review] (2013)
  • Author(s): J. Fujikura, K. Hosoda, K. Nakao
  • Journal Title: Endocr J Volume: 60(6) Issue: 6 Pages: 697-708
  • DOI: 10.1507/endocrj.EJ13-0162
  • NAID: 10031184538
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In Vitro Characterization and Engraftment of Adipocytes Derived from Human Induced Pluripotent Stem Cells and Embryonic Stem Cells. (2013)
  • Author(s): M. Noguchi, K. Hosoda, E. Mori, M. Nakane, K. Nakao, D. Taura, Y. Yamamoto, T. Kusakabe, M. Sone, H. Sakurai, J. Fujikura, K. Ebihara, K. Nakao
  • Journal Title: Stem Cells Dev Volume: 22(21) Pages: 2895-2905
  • DOI: 10.1089/scd.2013.0113
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Early changes of abdominal adiposity detected with weekly dual bioelectrical impedance analysis during calorie restriction. (2013)
  • Author(s): M. Ida, M. Hirata, S. Odori, E. Mori, E. Kondo, J. Fujikura, T. Kusakabe, K. Ebihara, K. Hosoda, K. Nakao.
  • Journal Title: Obesity Volume: 21(9)
  • DOI: 10.1002/oby.20300
  • Peer Reviewed
• [Journal Article] Intracerebroventricular administration of C-Type natriuretic peptide suppresses food intake via activation of the melanocortin system in mice (2013)
  • Author(s): N. Yamada-Goto, G. Katsuura, K. Ebihara, M. Inuzuka, Y. Ochi, Y. Yamashita, T. Kusakabe, A. Yasoda, N. Asahara-Satoh, H. Ariyasu, K. Hosoda, K. Nakao.
  • Journal Title: Diabetes Volume: 62(5) Pages: 1500-1504
  • DOI: 10.2337/db12-0718
  • NAID: 120005244943
  • Peer Reviewed
• [Journal Article] GPR119 expression in normal human tissues and islet cell tumors : evidence for its isletgastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function. (2013)
  • Author(s): Odori S, Nakao K, et al
  • Journal Title: Metabolism. Volume: 62 Pages: 70-78
  • DOI: 10.1016/j.metabol.2012.06.010
  • NAID: 120005242664
  • Peer Reviewed
• [Journal Article] Induced pluripotent stem cells generated from diabetic patients with mitochondrial DNAA3243G mutation. (2012)
  • Author(s): J.Fujikura, M.Sone, K.Hosoda, K.Nakao, et al
  • Journal Title: Diabetologia. Volume: (in press) Pages: 1689-1698
  • DOI: 10.1007/s00125-012-2508-2
  • Peer Reviewed
• [Journal Article] Leptin activates hepatic 5' AMP-Activated Protein Kinase through sympathetic nervous system and α1 adrenergic receptor: Apotential mechanism for improvement of fatty liver in lipodystrophy by leptin. (2012)
  • Author(s): Miyamoto L, Nakao K, et al
  • Journal Title: J Biol Chem Volume: 287 Pages: 40441-40447
  • DOI: 10.1074/jbc.m112.384545
  • Peer Reviewed
• [Journal Article] Functional magnetic resonance imaging analysis of food-related brain activity in patients with lipodystrophy undergoing leptin-replacement therapy. (2012)
  • Author(s): Aotani D, Nakao K, et al
  • Journal Title: J Clin Endocrinol Metab Volume: 97 Pages: 3663-3671
  • DOI: 10.1210/jc.2012-1872
  • Peer Reviewed
• [Journal Article] Impairment of fear-conditioning responses and changes of brain neurotrophic factors in diet-induced obese mice. (2012)
  • Author(s): N.Yamada-Goto, K.Ebihara, K.Hosoda, K.Nakao, et al
  • Journal Title: Journal of Neuroendocrinology Volume: (in press) Pages: 1120-1125
  • DOI: 10.1111/j.1365-2826.2012.02327.x
  • Peer Reviewed
• [Journal Article] Amylin improves the effect of leptin on i nsul in sensitivity in leptinresistant diet-induced obese mice. (2012)
  • Author(s): T.Kusakabe, K.Ebihara, K.Nakao, et al
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 302
  • DOI: 10.1152/ajpendo.00198.2011
  • Peer Reviewed
• [Journal Article] Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo. (2012)
  • Author(s): Bando M, Nakao K, et al
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 302 Pages: 403-408
  • DOI: 10.1152/ajpendo.00341.2011
  • Peer Reviewed
• [Journal Article] Intra-abdominal fat area is a predictor for new onset of individual components of metabolic syndrome: MEtabolic syndRome and abdominaL ObesiTy (MERLOT study) (2012)
  • Author(s): YM. Nakao, K. Hosoda, et al
  • Journal Title: Proc Jpn Acad Ser B Phys Biol Sci. Volume: 88(8) Pages: 454-61
  • NAID: 130001924760
  • Peer Reviewed
• [Journal Article] Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo (2012)
  • Author(s): M.Bando, K.Hosoda, et al
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 302(4)
  • Peer Reviewed
• [Journal Article] Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice (2011)
  • Author(s): M.Naito, K.Ebihara, M.Mukoyama, K.Hosoda, K.Nakao, et al
  • Journal Title: Diabetes Volume: 60(9) Pages: 2265-2273
  • DOI: 10.2337/db10-1795
  • Peer Reviewed
• [Journal Article] Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats (2011)
  • Author(s): M. Zhao, K. Ebihara(8人中4番目)
  • Journal Title: Diabetes Obes Metab. Volume: 12 Pages: 1123-1129
  • DOI: 10.1111/j.1463-1326.2011.01471.x
  • Peer Reviewed
• [Journal Article] Oxytocin and dopamine stimulate ghrelin secretion by the ghrelin-producing cell line, MGN3-1 in vitro. (2011)
  • Author(s): H. Iwakura, K. Hosoda, et al
  • Journal Title: Endocrinology. Volume: 152 (7) Pages: 2619-25
  • DOI: 10.1210/en.2010-1455
  • NAID: 120004397870
  • URL: http://repository.kulib.kyoto-u.ac.jp/dspace/handle/2433/158372
  • Peer Reviewed
• [Journal Article] Impaired CNS Leptin Action Is Implicated in Depression Associated with Obesity (2011)
  • Author(s): N.Yamada, K.Ebihara, K.Hosoda, K.Nakao, et al
  • Journal Title: Endocrinology Volume: 152(7) Pages: 2634-2643
  • DOI: 10.1210/en.2011-0004
  • Peer Reviewed
• [Journal Article] Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice (2011)
  • Author(s): M.Naito, K.Hosoda, et al
  • Journal Title: Diabetes Volume: 60(9) Pages: 2265-73
  • Peer Reviewed
• [Journal Article] Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats (2011)
  • Author(s): M.Zhao, K.Hosoda, et al
  • Journal Title: Diabetes Obes Metab Volume: 13(12) Pages: 1123-9
  • Peer Reviewed
• [Journal Article] Oxytocin and Dopamine Stimulate Ghrelin Secretion by the Ghrelin-Producing Cell Line, MGN3-1 in Vitro (2011)
  • Author(s): H.Iwakura, K.Hosoda, et al
  • Journal Title: Endocrinology Volume: 152(7) Pages: 2619-2625
  • NAID: 120004397870
  • Peer Reviewed
• [Journal Article] Establishment of a Novel Ghrelin-Producing Cell Line (2010)
  • Author(s): H.Iwakura, K.Hosoda, et al
  • Journal Title: Endocrinology Volume: 151(6) Pages: 695-705
  • Peer Reviewed
• [Journal Article] Relevant use of Klotho in FGF19 subfamily signaling system in vivo (2010)
  • Author(s): K.Tomiyama, K.Hosoda, et al
  • Journal Title: Proc Natl Acad Sci U S A Volume: 26;107(4) Pages: 1666-71
  • Peer Reviewed
• [Journal Article] Adipose Tissue-Specific Regulation of Angiotensinogen in Obese Humans and Mice : Impact of Nutritional Status and Adipocyte Hypertrophy (2010)
  • Author(s): S.Yasue, K.Hosoda, et al
  • Journal Title: Am J Hypertens Volume: 23(4) Pages: 425-31
  • Peer Reviewed
• [Journal Article] Adipose tissue-specific dysregulation of angiotensinogen by oxidative stress in obesity (2010)
  • Author(s): S.Okada, K.Hosoda, et al
  • Journal Title: Metabolism Volume: 59(9) Pages: 1241-51
  • Peer Reviewed
• [Presentation] 遺伝性肥満モデルmkyo/mkyoラット膵島での脂質受容体GPR40の遺伝子発現調節 (2016)
  • Author(s): 吉良由里、冨田努、細田公則、藤倉純二、海老原千尋、阿部恵、海老原健、中尾一和、稲垣暢也
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 国立京都国際会館(京都府京都市)
  • Year and Date: 2016-04-21
• [Presentation] 新規の遺伝性肥満モデルmkyo/mkyoラット膵島における脂肪酸受容体GPR40の遺伝子発現調節 (2015)
  • Author(s): 吉良友里、冨田 努、細田公則、藤倉純二、海老原千尋、阿部 恵、海老原健、中尾一和、稲垣暢也
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-10-02
• [Presentation] 新規の遺伝性肥満モデルmkyo/mkyoラット膵島における脂質受容体のGPR40の遺伝子発現調節 (2015)
  • Author(s): 吉良友里、冨田努、細田公則、藤倉純二、海老原千尋、阿部 恵、海老原健、中尾一和、稲垣暢也
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 海峡メッセ下関(山口県下関市)
  • Year and Date: 2015-05-23
• [Presentation] GPR40の分子構造およびGPR40作動薬 (2015)
  • Author(s): 冨田 努、細田公則、中尾一和、稲垣暢也
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 日本科学未来館(東京都江東区)
  • Year and Date: 2015-05-15
• [Presentation] GPR40の遺伝子肥満・耐糖能異常モデルKoletskyラット膵島における発現調節の検討 (2015)
  • Author(s): 冨田努、細田公則、小鳥真司、藤倉純二、中尾一和、稲垣暢也
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2015-04-23
• [Presentation] 第35回日本肥満学会 (2014)
  • Author(s): 冨田努、細田公則、小鳥真司、藤倉純二、稲垣暢也、中尾一和
  • Organizer: GPR40の遺伝性肥満・耐糖能異常モデルKoletskyラット膵島における発現調節の検討
  • Place of Presentation: シーガイアコンベンションセンター(宮崎市)
  • Year and Date: 2014-10-24
• [Presentation] G蛋白共役型-脂肪酸受容体GPR40の肥満糖尿病における発現調節と意義 (2014)
  • Author(s): 冨田努、細田公則、小鳥真司、藤倉純二、日下部徹、海老原健、稲垣暢也、中尾一和
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2014-05-23
• [Presentation] 新規のインスリン分泌調節因子GPR40の遺伝子肥満モデルでの発現調節 (2011)
  • Author(s): 冨田努, 細田公則, その他
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 神戸市
  • Year and Date: 2011-04-21
• [Presentation] 膜型脂質受容体GPR40の遺伝性肥満Koletskyラット膵島での発現調節とその意義
  • Author(s): 冨田努、細田公則、小鳥真司、藤倉純二、日下部徹、海老原健、中尾一和
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台国際センター(宮城県)
• [Presentation] G蛋白共役型－脂肪酸受容体GPR40の糖尿病における発現調節と意義
  • Author(s): 冨田努、細田公則、小鳥真司、藤倉純二、日下部徹、海老原健、中尾一和
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: テトリア熊本ビル(熊本県)
• [Presentation] 部分性脂肪萎縮症に対するレプチン補充療法の有効性
  • Author(s): 青谷大介、海老原健、日下部徹、阿部恵、片岡祥子、酒井建、海老原千尋、藤倉純二、細田公則、中尾一和
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本(熊本県)
• [Presentation] ニューロメジンUのインスリン抵抗性における意義
  • Author(s): 青谷大介、海老原健、日下部徹、阿部恵、片岡祥子、酒井建、海老原千尋、藤倉純二、細田公則、中尾一和
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京国際フォーラム(東京都)
• [Presentation] 高脂肪食負荷レプチントランスジェニック(LepTg)マウスにおけるレプチン感受性の検討
  • Author(s): 野村英生、孫徹、後藤伸子、勝浦五郎、野口倫生、冨田努、藤倉純二、海老原健、細田公則、中尾一和
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京国際フォーラム(東京都)
• [Presentation] 膜型脂質受容体GPR40の遺伝性肥満Koletskyラット膵島での発現調節とその意義
  • Author(s): 冨田努、細田公則、小鳥真司、藤倉純二、海老原健、中尾一和
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京国際フォーラム(東京都)
• [Presentation] The Role of Neuromedin U in Glucose Homeostasis
  • Author(s): D. Aotani, K. Ebihara, T. Kusakabe, M. Aizawa-Abe, S. Y. Kataoka, T. Sakai, C. Ebihara, K. Hosoda, K. Nakao
  • Organizer: OBESITY 2013 31th Annual Scientific Meeting of The Obesity Society
  • Place of Presentation: Atlanta,Georgia
• [Presentation] Leptin Transgenic Mice on Short-Term High Fat Diet Show Leptin Resistance without Obesity
  • Author(s): H. Nomura, C. Son, K. Ebihara, K. Hosoda, K. Nakao
  • Organizer: OBESITY 2013 31th Annual Scientific Meeting of The Obesity Society
  • Place of Presentation: Atlanta,Georgia
• [Presentation] ヒトips細胞由来の脂肪細胞の脂肪細胞機能解析と細胞移植
  • Author(s): 野口倫生、細田公則、田浦大輔、森栄作、松原正樹、曽根正勝、藤倉純二、海老原健、中尾一和
  • Organizer: 第109回日本内科学会
  • Place of Presentation: みやこめっせ（京都府）
• [Presentation] 新規のインスリン分泌促進因子GPR40の遺伝性肥満モデルの発現調節と機能的意義
  • Author(s): 冨田努、細田公則、小鳥真司、孫徹、藤倉純二、岩倉浩、野口倫生、日下部徹、海老原健、中尾一和
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県）
• [Patent(Industrial Property Rights)] Mitochondrial Disease-Specific Induced Pluripotent Stem Cells, Method of Producing Same and Use Thereof (2011)
  • Inventor(s): 中尾一和, 藤倉純二, 細田公則, 曽根正勝, 中尾一泰
  • Industrial Property Rights Holder: 中尾一和, 藤倉純二, 細田公則, 曽根正勝, 中尾一泰
  • Industrial Property Rights Type: 特許
  • Filing Date: 2011-06-30
  • Application Year: 2011
  • Overseas