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健康長寿のための普遍的代謝調節経路の包括的研究

Research Project

Project/Area Number 25221307
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field Metabolomics
Research InstitutionThe 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 *help
¥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。

Report

(3 results)
  • 2014 Annual Research Report
  • 2013 Abstract ( PDF )   Annual Research Report
  • Research Products

    (32 results)

All 2014 2013 Other

All Journal Article (18 results) (of which Peer Reviewed: 18 results,  Open Access: 4 results,  Acknowledgement Compliant: 1 results) Presentation (10 results) (of which Invited: 10 results) Book (4 results)

  • [Journal Article] Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility2014

    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • 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 Countries2014

    • Author(s)
      Sacks FM, ..., Kadowaki T, ..., Carey VJ
    • Journal Title

      Circulation

      Volume: 122 Issue: 9 Pages: 999-1008

    • DOI

      10.1161/circulationaha.113.002529

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adiponectin and its receptors: Implications for obesity-associated diseases and longevity2014

    • 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

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adiponectin receptors: A review of their structure, function and how they work2014

    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Genome-wide association study identifies three novel loci for type 2 diabetes2014

    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2014 Annual Research Report
    • 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
    • Related Report
      2014 Annual Research Report
    • 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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Dysregulation of signal transduction systems underlying intractable disorders

    • Author(s)
      Takashi Kadowaki
    • Organizer
      40th IMSUT Founding Commemorative Symposium
    • Place of Presentation
      Tokyo
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Diet Therapy in Diabetes

    • Author(s)
      Takashi Kadowaki
    • Organizer
      8th Asia Pacific conference on Clinical Nutrition
    • Place of Presentation
      Chiba
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Adiponectin in the development of type 2 diabetes

    • Author(s)
      Takashi Kadowaki
    • Organizer
      World Diabetes Congress 2013
    • Place of Presentation
      Melbourne, Australia
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Book] Islet Equality2014

    • 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
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report

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Published: 2013-06-20   Modified: 2019-07-29  

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