健康長寿のための普遍的代謝調節経路の包括的研究

• Project/Area Number: 25221307
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: 門脇 孝 東京大学, 医学部附属病院, 教授 (30185889)
• Project Period (FY): 2013-05-31 – 2015-03-31
• Project Status: Discontinued (Fiscal Year 2014)
• Budget Amount: ¥136,110,000 (Direct Cost: ¥104,700,000、Indirect Cost: ¥31,410,000); Fiscal Year 2014: ¥44,200,000 (Direct Cost: ¥34,000,000、Indirect Cost: ¥10,200,000); Fiscal Year 2013: ¥91,910,000 (Direct Cost: ¥70,700,000、Indirect Cost: ¥21,210,000)
• Keywords: 糖尿病 / 寿命 / カロリー制限 / AdipoR活性化薬

Outline of Annual Research Achievements

過食・運動不足による肥満を基盤病態とするメタボリックシンドローム・糖尿病・心血管疾患・癌・アルツハイマー病が激増している。そのような現状に対し、栄養状態に対する生体反応を適切にコントロールすることによって寿命の延長や若さを維持することが可能 だと考えられ、健康長寿を実現する方法が待望されている。我々はごく最近、抗糖尿病ホルモンであるアディポネクチン/アディポネクチン受容体（AdipoR）シグナルが新規の寿命決定に深く関わる重要なシグナルであることを明らかにし、その活性化低分子化合物（AdipoRon）の取得にも成功している。本研究課題では、それらのシーズを活かし、下記の（１）から（３）を目的とし、研究を推進した。
（１）「寿命延長効果をもたらす高等生物に適したカロリー制限の科学と方法（栄養素の量と質）を明らかにする 」 カロリー制限を 一定とした上で、炭水化物、タンパク質、脂質の割合を変動させ、様々な栄養条件下におけるマウスの寿命を検討する実験を開始し、定期的に全身の糖・脂質代謝への影響に関するデータを取得し、寿命に対する観察を継続している。
（２）「健康長寿を制御する普遍的シグナルを同定する」 AdipoR 各種遺伝子改変マウスとAdipoR活性化低分子化合物（AdipoRon）投与を組み合わせ、それぞれの代謝に重要な組織におけるメタボローム解析、トランスクリプトーム解析を開始し、候補分子の絞り込みを行った。
（３）「代謝制御経路を基盤とした健康長寿実現に向けた科学と方略を確立する」昨年度Natureに報告したAdipoRonを展開し、さらに新たなAdipoR活性化低分子化合物を取得・選抜した。また、ヒトAdipoR発現マウスにAdipoRonを実際に投与し、抗生活習慣病の効果を検討し、ヒトへの有効性について確認した（未発表データ）。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility (2014)
  • Author(s): DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
  • Journal Title: Nat Genet Volume: 46 Issue: 3 Pages: 234-246
  • DOI: 10.1038/ng.2897
  • Peer Reviewed / Open Access
• [Journal Article] Empagliflozin Monotherapy in Japanese Patients with Type 2 Diabetes Mellitus: a Randomized, 12-Week, Double-Blind, Placebo-Controlled, Phase II Trial. (2014)
  • Author(s): Kadowaki T, Haneda M, Inagaki N, Terauchi Y, Taniguchi A, Koiwai K, Rattunde H, Woerle HJ, Broedl UC
  • Journal Title: Advances in Therapy Volume: 31 Issue: 6 Pages: 621-638
  • DOI: 10.1007/s12325-014-0126-8
  • Peer Reviewed
• [Journal Article] Vagal hyperactivity due to ventromedial hypothalamic lesions increases adiponectin production and release. (2014)
  • Author(s): Suzuki Y, Shimizu H, Ishizuka N, Kubota N, Kubota T, Senoo A, Kageyama H, Osaka T, Hirako S, Kim HJ, Matsumoto A, Shioda S, Mori M, Kadowaki T, Inoue S.
  • Journal Title: Diabetes. Volume: 63(5) Issue: 5 Pages: 1637-1648
  • DOI: 10.2337/db13-0636
  • Peer Reviewed
• [Journal Article] Residual macrovascular risk in 2013: what have we learned? (2014)
  • Author(s): Fruchart JC, ..., Kadowaki T, ..., Zimmet P
  • Journal Title: Cardiovasc. Diabetol. Volume: 13 Issue: 1 Pages: 26-26
  • DOI: 10.1186/1475-2840-13-26
  • Peer Reviewed
• [Journal Article] Association Between Plasma Triglycerides and High-Density Lipoprotein Cholesterol and Microvascular Kidney Disease and Retinopathy in Type 2 Diabetes Mellitus : A Global Case–Control Study in 13 Countries (2014)
  • Author(s): Sacks FM, ..., Kadowaki T, ..., Carey VJ
  • Journal Title: Circulation Volume: 122 Issue: 9 Pages: 999-1008
  • DOI: 10.1161/circulationaha.113.002529
  • Peer Reviewed
• [Journal Article] Adiponectin and its receptors: Implications for obesity-associated diseases and longevity (2014)
  • Author(s): Kadowaki T, Yamauchi T, Okada-Iwabu M, Iwabu M
  • Journal Title: Lancet Diabetes Endocrinol. Volume: 2 Issue: 1 Pages: 8-9
  • DOI: 10.1016/s2213-8587(13)70120-7
  • Peer Reviewed
• [Journal Article] Adiponectin receptors: A review of their structure, function and how they work (2014)
  • Author(s): Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T
  • Journal Title: Best Pract. Res. Clin. Endocrinol. Metab. Volume: 28 Issue: 1 Pages: 15-23
  • DOI: 10.1016/j.beem.2013.09.003
  • Peer Reviewed
• [Journal Article] TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass. (2014)
  • Author(s): Takamoto I, Kubota N, Nakaya K, Kumagai K, Hashimoto S, Kubota T, Inoue M, Kajiwara E, Katsuyama H, Obata A, Sakurai Y, Iwamoto M, Kitamura T, Ueki K, Kadowaki T
  • Journal Title: Diabetologia Volume: 57 Issue: 3 Pages: 542-553
  • DOI: 10.1007/s00125-013-3131-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genome-wide association study identifies three novel loci for type 2 diabetes (2014)
  • Author(s): Hara K, Fujita H, Johnson TA, Yamauchi T, Yasuda K, Horikoshi M, Peng C, Hu C, Ma RC, Imamura M, et al
  • Journal Title: Hum Mol Genet Volume: 23 Issue: 1 Pages: 239-246
  • DOI: 10.1093/hmg/ddt399
  • Peer Reviewed / Open Access
• [Journal Article] A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. (2013)
  • Author(s): Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T, Shirouzu M, Ogata H, Tokuyama K, Ueki K, Nagano T, Tanaka A, Yokoyama S and Kadowaki T.
  • Journal Title: Nature Volume: 503 Issue: 7477 Pages: 493-499
  • DOI: 10.1038/nature12656
  • Peer Reviewed
• [Journal Article] The role of endothelial insulin signaling in the regulation of glucose metabolism. (2013)
  • Author(s): Kubota T, Kubota N, Kadowaki T
  • Journal Title: Rev. Endocr. Metab. Disord. Volume: 14 Issue: 2 Pages: 207-216
  • DOI: 10.1007/s11154-013-9242-z
  • Peer Reviewed
• [Journal Article] Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet. (2013)
  • Author(s): Nakaya K, Kubota N, Takamoto I, Kubota T, Katsuyama H, Sato H, Tokuyama K, Hashimoto S, Goto M, Jomori T, Ueki K, Kadowaki T
  • Journal Title: Metabolism Volume: 62 Issue: 7 Pages: 939-951
  • DOI: 10.1016/j.metabol.2013.01.010
  • Peer Reviewed
• [Journal Article] Glycogen shortage during fasting triggers liver-brain-adipose neurocircuitry to facilitate fat utilization. (2013)
  • Author(s): Izumida Y, Yahagi N, Takeuchi Y, Nishi M, Shikama A, Takarada A, Masuda Y, Kubota M, Matsuzaka T, Nakagawa Y, Iizuka Y, Itaka K, Kataoka K, Shioda S, Niijima A, Yamada T, Katagiri H, Nagai R, Yamada N, Kadowaki T, Shimano H
  • Journal Title: Nat Commun. Volume: 4 Issue: 1 Pages: 2316-2316
  • DOI: 10.1038/ncomms3316
  • Peer Reviewed / Open Access
• [Journal Article] Apolipoprotein C-II deficiency with no rare variant in the APOC2 gene. (2013)
  • Author(s): Takase S, Osuga J, Fujita H, Hara K, Sekiya M, Igarashi M, Takanashi M, Takeuchi Y, Izumida Y, Ohta K, Kumagai M, Nishi M, Kubota M, Masuda Y, Taira Y, Okazaki S, Iizuka Y, Yahagi N, Ohashi K, Yoshida H, Yanai H, Tada N, Gotoda T, Ishibashi S, Kadowaki T, Okazaki H
  • Journal Title: J. Atheroscler. Thromb. Volume: 20 Pages: 481-493
  • NAID: 130004444688
  • Peer Reviewed
• [Journal Article] Body composition is main determinant for the difference in Type 2 diabetese pathophysiology between Japanese and Caucasians. (2013)
  • Author(s): Moller J, Pedersen M, Tanaka H, Ohsugi M, Overgaard R, Lynge J Almind K, Vasconcelos Nina-Maria, Poulsen P, Keller C, Ueki K, Ingwersen S, Pedersen B, Kadowaki T
  • Journal Title: Diabetes Care Volume: 37 Issue: 3 Pages: 796-804
  • DOI: 10.2337/dc13-0598
  • Peer Reviewed
• [Journal Article] A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. (2013)
  • Author(s): Nabeno M, Akahoshi F, Kishida H, Miyaguchi I, Tanaka Y, Ishii S, Kadowaki T
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 434 Issue: 2 Pages: 191-196
  • DOI: 10.1016/j.bbrc.2013.03.010
  • Peer Reviewed
• [Journal Article] Sweat gland atrophy of the heel in diabetic patients with angiopathy. (2013)
  • Author(s): Oe M, Sanada H, Nagase T, Minematsu T, Ohashi Y, Kadono T, Ueki K, Kadowaki T
  • Journal Title: J. Clin. Nurs. Volume: 22 Issue: 1-2 Pages: 289-292
  • DOI: 10.1111/j.1365-2702.2012.04267.x
  • Peer Reviewed
• [Journal Article] Morphological pattern classification system for plantar thermography of patients with Diabetes. (2013)
  • Author(s): Mori T, Nagase T, Takehara K, Oe M, Ohashi Y, Amemiya A, Noguchi H, Ueki K, Kadowaki T, Sanada H
  • Journal Title: J. Diabetes Sci. Technol. Volume: 7 Pages: 1102-1112
  • Peer Reviewed
• [Presentation] 理事長声明 (2014)
  • Author(s): 門脇 孝
  • 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
  • Invited
• [Presentation] 医学研究・臨床とエビデンス (2014)
  • Author(s): 門脇 孝
  • Organizer: 第111回日本内科学会総会・講演会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-12
  • Invited
• [Presentation] メタボリックシンドロームとは？ (2014)
  • Author(s): 門脇 孝
  • Organizer: 日本医学会総会2015関西特別企画
  • Place of Presentation: 東京
  • Year and Date: 2014-04-03
  • Invited
• [Presentation] Dysregulation of signal transduction systems underlying intractable disorders
  • Author(s): Takashi Kadowaki
  • Organizer: 40th IMSUT Founding Commemorative Symposium
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] Diet Therapy in Diabetes
  • Author(s): Takashi Kadowaki
  • Organizer: 8th Asia Pacific conference on Clinical Nutrition
  • Place of Presentation: Chiba
  • Invited
• [Presentation] Roles of adiponectin receptors in regulation of nutrient disposal and promising drug target for obesity-linked disease
  • Author(s): Takashi Kadowaki
  • Organizer: 1st Annual Helmholtz-Nature Medicine Diabetes Conference
  • Place of Presentation: Munich, Germany
  • Invited
• [Presentation] 肥満に伴うインスリン抵抗性、2型糖尿病の分子機構に関する研究
  • Author(s): 門脇 孝
  • Organizer: 第34回日本肥満学会年次学術集会
  • Place of Presentation: 東京
  • Invited
• [Presentation] The role of adiponectin receptor in insulin resistance and type 2 diabetes
  • Author(s): Takashi Kadowaki
  • Organizer: Boston Joslin International Symposium on Diabetes 2013
  • Place of Presentation: Boston, USA
  • Invited
• [Presentation] Impaired adiponectin receptor signaling in obesity-linked insulin resistance and shortened lifespan
  • Author(s): Takashi Kadowaki
  • Organizer: International Symposium on Insulin Receptors and Insulin Action
  • Place of Presentation: Barcelona, Spain
  • Invited
• [Presentation] Adiponectin in the development of type 2 diabetes
  • Author(s): Takashi Kadowaki
  • Organizer: World Diabetes Congress 2013
  • Place of Presentation: Melbourne, Australia
  • Invited
• [Book] Islet Equality (2014)
  • Author(s): 門脇 孝、川口 義弥、粂 昭苑、宮島 篤
  • Total Pages: 10
  • Publisher: メディカルレビュー社
• [Book] 医療技術・機器のイノベーションと医療の質の向上 (2013)
  • Author(s): 門脇 孝
  • Total Pages: 11
  • Publisher: 医療機器学
• [Book] 【糖尿病をめぐる話題と治療の現況】 糖尿病の分類と診断基準 (2013)
  • Author(s): 門脇 孝
  • Total Pages: 9
  • Publisher: 医学と薬学
• [Book] 【糖尿病療養のイノベーション 生活習慣病としての糖尿病】 病態に応じた糖尿病治療 糖尿病治療の現状と展望 (2013)
  • Author(s): 門脇 孝
  • Total Pages: 18
  • Publisher: 糖尿病UP-DATE