Roles of Hypothalamic Akt on Food Intake and Glucose Metabolism

• Project/Area Number: 15K09398
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Chiba University (2017); Saitama Medical University (2015-2016)
• Principal Investigator: Ono Hiraku 千葉大学, 大学院医学研究院, 講師 (10570616)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: Akt / 視床下部 / 摂食 / インスリン感受性 / インスリン / インスリン抵抗性 / 摂食調節 / インスリン情報伝達 / グルコースクランプ法 / 阻害薬 / 糖尿病 / PTEN

Outline of Final Research Achievements

Insulin is known to function in the arcuate nucleus of the hypothalamus to suppress food intake as well as suppress hepatic glucose production indirectly, via PI 3-kinase pathway. The most important molecule downstream of PI 3-kinase is Akt, while its role in the hypothalamus is unclear. In this study we bidirectionally modified Akt activity specifically in the arcuate nucleus of rats and investigated effects on food intake and glucose metabolism.
Overexpression of constitutively-active Akt or dominant-negative Akt in the arcuate nucleus unexpectedly did not significantly change food intake or body weight. On the other hand, hypothalamic constitutive activation of Akt ameliorated high fat diet-induced hepatic insulin resistance, suggesting a divergence of pathway toward regulation of food intake and that toward glucose metabolism exist downstream of PI 3-kinase, only latter of which is what Akt is responsible.

Research Products

• [Journal Article] Gut microbiota as a therapeutic target for metabolic disorders. (2018)
  • Author(s): Okubo H, Nakatsu Y, Kushiyama A, Yamamotoya T, Matsunaga Y, Inoue MK, Fujishiro M, Sakoda H, Ohno H, Yoneda M, Ono H, Asano T.
  • Journal Title: Curr Med Chem. Volume: 25 Issue: 9 Pages: 984-1001
  • DOI: 10.2174/0929867324666171009121702
  • Peer Reviewed / Open Access
• [Journal Article] Effects of the activations of three major hepatic Akt substrates on glucose metabolism in male mice. (2017)
  • Author(s): Sakai G, Inoue I, Suzuki T, Sumita T, Inukai K, Katayama S, Awata T, Yamada T, Asano T, Katagiri H, Noda M, Shimada A, Ono H.
  • Journal Title: Endocrinology. Volume: 158 Issue: 8 Pages: 2659-2671
  • DOI: 10.1210/en.2016-1969
  • Peer Reviewed / Open Access
• [Journal Article] The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion (2017)
  • Author(s): Nakatsu Y, Mori K, Matsunaga Y, Yamamotoya T, Ueda K, Inoue Y, Mitsuzaki-Miyoshi K, Sakoda H, Fujishiro M, Yamaguchi S, Kushiyama A, Ono H, Ishihara H, Asano T.
  • Journal Title: J Biol Chem. Volume: 292 Issue: 28 Pages: 11886-11895
  • DOI: 10.1074/jbc.m117.780726
  • Peer Reviewed / Open Access
• [Journal Article] The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice. (2017)
  • Author(s): Yusuke Nakatsu, Hiroki Kokubo, Batmunkh Bumdelger, Masao Yoshizumi, Takeshi Yamamotoya, Yasuka Matsunaga, Koji Ueda, Yuki Inoue, Masa-Ki Inoue, Midori Fujishiro, Akifumi Kushiyama, Hiraku Ono, Hideyuki Sakoda, and Tomoichiro Asano
  • Journal Title: International Journal of Molecular Sciences Volume: 18(8) Issue: 8 Pages: 1704-1717
  • DOI: 10.3390/ijms18081704
  • Peer Reviewed / Open Access
• [Journal Article] Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity. (2017)
  • Author(s): Yamamotoya T, Nakatsu Y, Kushiyama A, Matsunaga Y, Ueda K, Inoue Y, Inoue MK, Sakoda H, Fujishiro M, Ono H, Kiyonari H, Ishihara H, Asano T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-017-13432-x
  • Peer Reviewed / Open Access
• [Journal Article] Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations. (2016)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue Y, Mori K, Sakoda H, Fujishiro M, Ono H, Kushiyama A, Asano T.
  • Journal Title: Int J Mol Sci. Volume: 17 (9) Issue: 9 Pages: 1495-1495
  • DOI: 10.3390/ijms17091495
  • Peer Reviewed / Open Access
• [Journal Article] Role of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis. (2016)
  • Author(s): Kushiyama A, Nakatsu Y, Matsunaga Y, Yamamotoya T, Mori K, Ueda K, Inoue Y, Sakoda H, Fujishiro M, Ono H, Asano T.
  • Journal Title: Mediators Inflamm. Volume: 2016 Pages: 8603164-8603164
  • DOI: 10.1155/2016/8603164
  • Peer Reviewed / Open Access
• [Journal Article] Ezetimibe Promotes Brush Border Membrane-to-Lumen Cholesterol Efflux in the Small Intestine (2016)
  • Author(s): Nakano T, Inoue I, Takenaka Y, Ono H, Katayama S, Awata T, Murakoshi T.
  • Journal Title: Plos One Volume: 11 Issue: 3 Pages: e0152207-e0152207
  • DOI: 10.1371/journal.pone.0152207
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl isomerase Pin1 negatively regulates AMP-activated protein kinase (AMPK) by associating with the CBS domain in the γ subunit (2015)
  • Author(s): Nakatsu Y, Iwashita M, Sakoda H, Ono H, Nagata K, Matsunaga Y, Fukushima T, Fujishiro M, Kushiyama A, Kamata H, Takahashi S, Katagiri H, Honda H, Kiyonari H, Uchida T, Asano T
  • Journal Title: J Biol Chem Volume: 290 Issue: 40 Pages: 24255-24266
  • DOI: 10.1074/jbc.m115.658559
  • Peer Reviewed / Open Access
• [Journal Article] A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals (2015)
  • Author(s): Uno K, Yamada T, Ishigaki Y, Imai J, Hasegawa Y, Sawada S, Kaneko K, Ono H, Asano T, Oka Y, Katagiri H
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 7940-7940
  • DOI: 10.1038/ncomms8940
  • Peer Reviewed / Open Access
• [Journal Article] Influence of Treatment with Extracts of <i>Hypsyzigus marmoreus</i> Mushroom on Body Composition during Obesity Development in KK-A^y Mice (2015)
  • Author(s): Iuchi T, Hosaka T, Shiroishi M, Ono H, Inukai K, Sumita T, Sakai G, Katayama S, Awata T
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 61 Issue: 1 Pages: 96-100
  • DOI: 10.3177/jnsv.61.96
  • NAID: 130005070827
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed / Open Access
• [Presentation] 視床下部弓状核のAktは摂食調節とは独立してインスリン感受性を調節する (2017)
  • Author(s): 小野 啓，横手 幸太郎
  • Organizer: 第38回日本肥満学会
• [Presentation] 肝Foxo1は糖新生律速酵素と独立してインスリンによる糖代謝を制御する (2017)
  • Author(s): 酒井豪太，小野啓，鈴木徳子，犬飼浩一，住田崇，片山茂裕，粟田卓也，井上郁夫，野田光彦，島田朗
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 3種のAkt基質の糖代謝における役割 (2016)
  • Author(s): 小野 啓
  • Organizer: 第30回 日本糖尿病・肥満動物学会 年次学術集会
  • Place of Presentation: 大宮ソニックシティ(埼玉県大宮市）
  • Year and Date: 2016-03-12
  • Invited
• [Presentation] 3種のAkt基質と迷走神経肝臓枝の糖代謝における役割 (2016)
  • Author(s): 酒井豪太，小野啓，鈴木徳子，住田崇，井上郁夫，片山茂裕，粟田卓也，野田光彦，島田朗
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: みやこめっせ（京都）
• [Presentation] DPP-4阻害薬/少量SU薬併用およびSU薬増量の膵β細胞機能に及ぼす影響：3S（Saitama Sitagliptin Study）無作為化比較試験 (2016)
  • Author(s): 小野啓, 栗原進, 松田昌文, 加計正文, 豊島秀男, 犬飼敏彦, 麻生好正, 粟田卓也, 片山茂裕, 3S研究グループ
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: みやこめっせ（京都）
• [Presentation] Differential roles of three Akt substrates in the liver and vagal hepatic branch on insulin sensitivity (2015)
  • Author(s): Gota Sakai, Hiraku Ono, Tokuko Suzuki, Takashi Sumita, Kouichi Inukai, Shigehiro Katayama, Takuya Awata, Ikuo Inoue
  • Organizer: Keystone Symposia's Third Conference in Japan
  • Place of Presentation: ウェスティン都ホテル（京都府京都市）
  • Year and Date: 2015-10-27
  • Int'l Joint Research
• [Presentation] インスリンの血糖低下機序と最新の糖尿病治療 (2015)
  • Author(s): 小野 啓
  • Organizer: 第19回日本適応医学会
  • Place of Presentation: 一橋大学（東京都千代田区）
  • Year and Date: 2015-09-13
  • Invited
• [Presentation] Aｋｔ基質と迷走神経肝臓枝の肝糖代謝における役割 (2015)
  • Author(s): 小野 啓, 酒井 豪太, 住田 崇, 犬飼 浩一, 片山 茂裕, 粟田 卓也, 井上 郁夫
  • 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: 2015-05-21
• [Book] これが知りたかった!糖尿病診療・療養指導Q&A 「インスリン分泌能とインスリン抵抗性はどのように評価し，どのように活用するのですか？」 (2017)
  • Author(s): 小野啓（分担執筆），岩本安彦（監修），吉田洋子（編集）
  • Total Pages: 299
  • Publisher: 中山書店
  • ISBN: 9784521745237