Crosstalk between sirtuins and endocrine system in regulation of brown adipose tissue function.

• Project/Area Number: 24659451
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Endocrinology
• Research Institution: Nagoya University
• Principal Investigator: Hayashi Yoshitaka 名古屋大学, 環境医学研究所, 准教授 (80420363)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: グルカゴン / 褐色脂肪 / 熱産生 / 脱共役蛋白質 / 交感神経 / サーチュイン / ニコチンアミド代謝 / 線維芽細胞成長因子21 / 寒冷曝露 / ニコチンアミド / 甲状腺ホルモン / 寒冷暴露 / 内分泌代謝学 / カロリー制限 / 肥満

Outline of Final Research Achievements

Brown adipose tissue (BAT) plays important roles in adaptive thermogenesis. It is well known that function of BAT is regulated by sympathetic nerve system and thyroid hormones. We have established animal models deficient in glucagon gene and have shown that glucagon plays important roles not only in glucose homeostasis but also in regulation of amino acid metabolism and nicotinamide metabolism.
In this study, BAT function in glucagon-deficient mice was analyzed, as the animal showed cold intolerance. Expression of genes involved in thermogenesis, such as uncoupling protein 1 and deiodinase 2, was lower in BAT in glucagon-deficient mice than in the controls. Administration of glucagon to glucagon-deficient mice restored gene expression patterns in BAT and ameliorated cold intolerance. Involvement of FGF21 was suggested, as its serum concentration was markedly increased by glucagon administration.

Research Products

• [Journal Article] Chronic hyponatremia causes neurologic and psychologic impairments (2016)
  • Author(s): Fujisawa H, Sugimura Y, Takagi H, Mizoguchi H, Takeuchi H, Izumida H, Nakashima K, Iwama S, Takagishi Y, Hayashi Y, Arima H, Komatsu Y, Murata Y, Oiso Y
  • Journal Title: Journal of the American Society of Nephrology Volume: 27 Issue: 3 Pages: 766-780
  • DOI: 10.1681/asn.2014121196
  • Peer Reviewed
• [Journal Article] グルカゴンの全身作用「新時代の臨床糖尿病学（上） –より良い血糖管理をめざして-」 (2016)
  • Author(s): 林 良敬, 高野悠子, 前川龍也, 清野祐介
  • Journal Title: 日本臨床 Volume: 74（増1） Pages: 68-71
• [Journal Article] Pancreatic Neuroendocrine Tumors in Mice Deficient in Proglucagon-Derived Peptides. (2015)
  • Author(s): Takano Y, Kasai K, Takagishi Y, Kikumori T, Imai T, Murata Y, Hayashi Y.
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0133812-e0133812
  • DOI: 10.1371/journal.pone.0133812
  • Peer Reviewed / Open Access
• [Journal Article] Mice deficient in proglucagon-derivek peptides exhibit glucose intolerance on a high-fat diet but are resistant to obesity (2015)
  • Author(s): Takagi Y, Kinoshita K, Ozaki N, Seino Y, Murata Y, Oshida Y, Hayashi Y
  • Journal Title: PLoS One Volume: 10 Issue: 9 Pages: e0138322-e0138322
  • DOI: 10.1371/journal.pone.0138322
  • Peer Reviewed / Open Access
• [Journal Article] グルカゴンの真の特異的作用は何か？グルカゴン作用欠損モデルの表現型. (2015)
  • Author(s): 林 良敬
  • Journal Title: 実験医学 Volume: 33(6) Pages: 897-902
• [Journal Article] グルカゴンの生合成とα細胞増殖の制御機構 (2015)
  • Author(s): 林 良敬
  • Journal Title: Islet Equality Volume: 4(3) Pages: 20-22
• [Journal Article] Fatty acid binding protein 5 (FABP5) regulates diet-induced obesity (DIO) via GIP secretion from enteroendocrine K-cells in response to fat ingestion. (2015)
  • Author(s): Shibue, K., Yamane, S., Harada, N., Hamasaki, A., Suzuki, K., Joo, E., Iwasaki, K., Nasteska, D., Harada, T., Hayashi, Y., Adachi, Y., Owada, Y., Takayanagi, R. and Inagaki, N.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 308 Issue: 7 Pages: 583-591
  • DOI: 10.1152/ajpendo.00543.2014
  • Peer Reviewed / Open Access
• [Journal Article] KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state (2014)
  • Author(s): Ogata H, Seino Y, Harada N, Iida A, Suzuki K, Izumoto T, Ishikawa K, Uenishi E, Ozaki N, Hayashi Y, Miki T, Inagaki N, Tsunekawa S, Hamada Y, Seino S, Oiso Y
  • Journal Title: J Endocrinol Volume: 222 Issue: 2 Pages: 191-200
  • DOI: 10.1530/joe-14-0161
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Glucagon is essential for adaptive thermongenesis in brown adipose tissue. (2014)
  • Author(s): Kinoshita K, Ozaki N, Takagi Y, Murata Y, Oshida Y, Hayashi Y
  • Journal Title: Endocrinology Volume: 155 Issue: 9 Pages: 3484-3492
  • DOI: 10.1210/en.2014-1175
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells. (2014)
  • Author(s): Ichijo S, Furuya F, Shimura H, Hayashi K, Kobayashi T, Kitamura K.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e116252-e116252
  • DOI: 10.1371/journal.pone.0116252
  • Peer Reviewed / Open Access
• [Journal Article] Low temperature-induced circulating triiodothyronine accelerates seasonal testicular regression. (2014)
  • Author(s): K. Ikegami, Y. Atsumi, E. Yorinaga, H. Ono, I. Murayama1, Y. Nakane, W. Ota, N. Arai, A. Tega, M. Iigo, V. M. Darras, K. Tsutsui, Y. Hayashi, S. Yoshida and T. Yoshimura
  • Journal Title: Endocrinology Volume: 56 Issue: 2 Pages: 647-659
  • DOI: 10.1210/en.2014-1741
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sensory and motor physiological functions are impaired in gastric inhibitory polypeptide receptor deficient mice. (2014)
  • Author(s): Okawa T, Kamiya H, Himeno T, Seino Y, Tsunekaw S, Hayashi Y, Harada N, Yamada Y, Inagarki N, Seino Y, Oiso Y, Nakamura J
  • Journal Title: Journal of Diabetes Investigation Volume: 5(1) Issue: 1 Pages: 31-37
  • DOI: 10.1111/jdi.12129
  • Peer Reviewed
• [Journal Article] Aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet α-like cells in mice deficient in proglucagon-derived peptides (2013)
  • Author(s): Xu S, Hayashi Y, Takagishi Y, Itoh M, Murata Y
  • Journal Title: PLoS ONE Volume: 8 Issue: 5 Pages: e64415-e64415
  • DOI: 10.1371/journal.pone.0064415
  • Peer Reviewed
• [Journal Article] Hyperthyroidism due to thyroid stimulating hormone secretion after surgery for Cushing’s syndrome: a novel cause of the syndrome of inappropriate secretion of thyroid stimulating hormone. (2013)
  • Author(s): Tamada D, Onodera T, Kitamura T, Yamamoto Y, Hayashi Y, Murata Y, Otsuki M, Shimomur I
  • Journal Title: Journal of Clinical Endocrinology and Metabolism Volume: 98(7) Issue: 7 Pages: 2656-62
  • DOI: 10.1210/jc.2013-2135
  • Peer Reviewed
• [Journal Article] 膵島とグルカゴンシグナル―グルカゴンKOマウスによる解析―. (2013)
  • Author(s): 林 良敬、清野祐介、尾崎信暁
  • Journal Title: Diabetes Frontier Volume: 5(24) Pages: 550-554
• [Journal Article] Ectopic expression of GIP in pancreatic β-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides. (2013)
  • Author(s): Fukami A, Seino Y, Ozaki N, Yamamoto M, Sugiyama C, Sakamoto-Miura E, Himeno T, Takagishi Y, Tsunekawa S, Ali S, Drucker DJ, Murata Y, Seino Y, Oiso Y, Hayashi Y.
  • Journal Title: Diabetes Volume: 62 Issue: 2 Pages: 510-518
  • DOI: 10.2337/db12-0294
  • Peer Reviewed
• [Journal Article] Fertility and pregnancy-associated β-cell proliferation in mice deficient in proglucagon-derived peptides. (2012)
  • Author(s): Sugiyama C, Yamamoto M, Kotani T, Kikkawa F, Murata Y, Hayashi Y.
  • Journal Title: Plos One Volume: 7(8) Issue: 8 Pages: e43745-e43745
  • DOI: 10.1371/journal.pone.0043745
  • Peer Reviewed
• [Journal Article] グルカゴンによる代謝制御 (2012)
  • Author(s): 林 良敬
  • Journal Title: Diabetes Journal:糖尿病と代謝 Volume: 40(3) Pages: 1-8
• [Presentation] グルカゴンによる代謝とα細胞増殖の制御 (2016)
  • Author(s): 林 良敬
  • Organizer: 第5回Diabetes Experrts Forum in Oita
  • Place of Presentation: 大分
  • Year and Date: 2016-02-29
  • Invited
• [Presentation] グルカゴンによるアミノ酸代謝とアルファ細胞増殖の制御、ワークショップ「アミノ酸研究の新展開：細胞シグナルとしての動的制御機構」 (2015)
  • Author(s): 林 良敬
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] アミノ酸代謝制御ホルモンとしてのグルカゴン (2015)
  • Author(s): 林 良敬
  • Organizer: グルカゴンルネッサンス研究会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-28
  • Invited
• [Presentation] 細胞増殖と代謝の制御におけるグルカゴンの特異的作用 (2015)
  • Author(s): 林 良敬
  • Organizer: 第一回生体調節研究所内分泌代謝シンポジウム
  • Place of Presentation: 前橋
  • Year and Date: 2015-11-12
  • Invited
• [Presentation] グルカゴンの真の特異的作用を探る (2015)
  • Author(s): 林 良敬
  • Organizer: 長野県糖尿病懇話会
  • Place of Presentation: 長野
  • Year and Date: 2015-10-31
  • Invited
• [Presentation] Glucose-dependent insulinotropic polypeptide (GIP) preserves insulin secretion and contrib.utes to good-glycemic control in proglucagon-deficient mice treated with streptozotocin (2015)
  • Author(s): Seine Y, Iida A, Fukami A, Maekawa R, Ozaki N, Tsunekawa S, Hamada Y, Hayashi Y, Oiso Y
  • Organizer: Incretin 2015: A Symposium Celebrating the 45th Anniversary of the Discovery of GIP
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-07-29
  • Int'l Joint Research / Invited
• [Presentation] Glycemic control by islet-derived GIP: Analysis of mice deficient in the glucagon gene (2015)
  • Author(s): Seine Y, Iida A, Fukami A, Ozaki N, Hayashi Y
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-21
  • Invited
• [Presentation] GIPはグルカゴン遺伝子欠損マウスにおいて膵β細胞障害時の血糖値改善に関与する (2015)
  • Author(s): 飯田淳史、清野祐介、前川龍也、丹羽靖浩、細川香里、泉本貴子、木下佳大、高木祐輔、緒方秀忠、尾崎信暁、恒川 新、濱田洋司、林 良敬、大磯ユタカ
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-21
• [Presentation] Visualization of pancreatic islets using a decolorization technique. (2015)
  • Author(s): Hayashi Y
  • Organizer: 2nd International Symposium 2015, Neuro-Vascular Wiring.
  • Place of Presentation: 京都
  • Year and Date: 2015-01-28 – 2015-01-30
• [Presentation] グルカゴンによる膵島内分泌細胞の分化増殖制御 シンポジウム「膵内分泌細胞の可塑性を制御するシグナルネットワーク」 (2014)
  • Author(s): 林 良敬
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Glucagon-GFP knock-in mice, a model to analyze development, differentiation and proliferation of isletα-cells and intestinal L-cells. (2014)
  • Author(s): 林 良敬
  • Organizer: 熊本医学・生物化学国際シンポジウム「幹細胞制御と臓器再建」
  • Place of Presentation: 熊本
  • Year and Date: 2014-09-04 – 2014-09-05
• [Presentation] Pancreatic neuroendocrine tumors in mice deficient in glucagon gene. (2014)
  • Author(s): Hayashi Y, Takano Y, Kasai K, Imai T, Murata Y
  • Organizer: ICE/ENDO 2014, The 16th International Congress of Endocrinology/ The 96th Endocrine Society Annual Meeting
  • Place of Presentation: 米国
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] Diabetes in the absence of glucagon. In Symposium “Glucagon Renaissance in Osaka” (2014)
  • Author(s): Ozaki N, Seino Y, Hayashi Y
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
  • Invited
• [Presentation] グルカゴンと代謝制御. -シンポジウム“恒常性維持のためのホルモン分泌調節” (2014)
  • Author(s): 林 良敬
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
  • Invited
• [Presentation] Vascular basement membrane in developing islets of Langerhans in the presence or absence of proglucagon-derived peptides. (2014)
  • Author(s): Hayashi Y
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] 褐色脂肪組織の熱産生におけるグルカゴンの役割の解明－グルカゴン遺伝子欠損マウスの解析－ (2014)
  • Author(s): 木下佳大，尾崎信暁，高木祐輔，村田善晴，押田芳治，林 良敬
  • Organizer: 第28回第日本糖尿病・肥満動物学会年次学術集会
  • Place of Presentation: 宮崎市
• [Presentation] Metabolism and islet “α”-cell hyperplasia in mice deficient in proglucagon-derived peptides. (2013)
  • Author(s): HAYASHI Yoshitaka
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本市
  • Invited
• [Presentation] グルカゴン遺伝子欠損動物モデル相同遺伝性内分泌疾患は存在するか？ (2013)
  • Author(s): 林 良敬
  • Organizer: 第19回Kansai Diabetes Mellitus Federation研究会
  • Place of Presentation: 大阪市
  • Invited
• [Presentation] グルカゴン遺伝子とランゲルハンス島内分泌細胞の増殖 (2013)
  • Author(s): 林 良敬
  • Organizer: 第1回岳南DM Specialist懇話会
  • Place of Presentation: 富士市
  • Invited
• [Presentation] グルカゴン欠損動物モデルにおける膵島内分泌細胞の増殖と神経内分泌腫瘍 (2013)
  • Author(s): 林 良敬
  • Organizer: 第225回 発生研セミナー
  • Place of Presentation: 熊本市
  • Invited
• [Presentation] プログルカゴン由来ペプチドの欠損が高脂肪食による糖代謝異常に及ぼす影響 (2013)
  • Author(s): 木下佳大, 尾崎信暁, 高木祐輔, 清野祐介, 村田善晴, 押田芳治, 林 良敬
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本市
• [Presentation] 褐色脂肪組織における甲状腺ホルモンとグルカゴンのクロストーク (2013)
  • Author(s): 木下佳大, 高木祐輔, 尾崎信暁, 押田芳治, 村田善晴, 林 良敬
  • Organizer: 第56回日本甲状腺学会学術集会
  • Place of Presentation: 和歌山市
• [Presentation] プログルカゴン由来ペプチド欠損下の膵島内分泌細胞と代謝 (2013)
  • Author(s): 林 良敬
  • Organizer: 第200回 発生研セミナー
  • Place of Presentation: 熊本
  • Invited
• [Presentation] Innervation and vascularization into islets of Langerhans in the presence or absence of proglucagon-derived peptides. (2012)
  • Author(s): Yoshitaka Hayashi, Hiroyuki Tanaka, Noriko Sanzen, Kiyotoshi Sekiguchi, Yoshiharu Murata
  • Organizer: 15th International /14th European Congress of Endocrinology
  • Place of Presentation: フィレンツェ（イタリア）
• [Presentation] プログルカゴン欠損下の代謝制御 (2012)
  • Author(s): 林 良敬
  • Organizer: 第2回 Metabolism Scientific Forum
  • Place of Presentation: 東京
  • Invited