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A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity

Author

Listed:
  • Miki Okada-Iwabu

    (Graduate School of Medicine, The University of Tokyo
    22nd Century Medical and Research Center, The University of Tokyo
    22nd Century Medical and Research Center, The University of Tokyo)

  • Toshimasa Yamauchi

    (Graduate School of Medicine, The University of Tokyo
    22nd Century Medical and Research Center, The University of Tokyo
    22nd Century Medical and Research Center, The University of Tokyo)

  • Masato Iwabu

    (Graduate School of Medicine, The University of Tokyo
    22nd Century Medical and Research Center, The University of Tokyo)

  • Teruki Honma

    (RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan)

  • Ken-ichi Hamagami

    (Graduate School of Medicine, The University of Tokyo)

  • Koichi Matsuda

    (Graduate School of Medicine, The University of Tokyo)

  • Mamiko Yamaguchi

    (Graduate School of Medicine, The University of Tokyo)

  • Hiroaki Tanabe

    (RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan)

  • Tomomi Kimura-Someya

    (RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan)

  • Mikako Shirouzu

    (RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan)

  • Hitomi Ogata

    (Graduate School of Comprehensive Human Sciences, University of Tsukuba)

  • Kumpei Tokuyama

    (Graduate School of Comprehensive Human Sciences, University of Tsukuba)

  • Kohjiro Ueki

    (Graduate School of Medicine, The University of Tokyo)

  • Tetsuo Nagano

    (Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan)

  • Akiko Tanaka

    (RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan
    Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan)

  • Shigeyuki Yokoyama

    (RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan
    Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan)

  • Takashi Kadowaki

    (Graduate School of Medicine, The University of Tokyo
    22nd Century Medical and Research Center, The University of Tokyo
    22nd Century Medical and Research Center, The University of Tokyo)

Abstract

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.

Suggested Citation

  • Miki Okada-Iwabu & Toshimasa Yamauchi & Masato Iwabu & Teruki Honma & Ken-ichi Hamagami & Koichi Matsuda & Mamiko Yamaguchi & Hiroaki Tanabe & Tomomi Kimura-Someya & Mikako Shirouzu & Hitomi Ogata & K, 2013. "A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity," Nature, Nature, vol. 503(7477), pages 493-499, November.
    • Handle: RePEc:nat:nature:v:503:y:2013:i:7477:d:10.1038_nature12656
    DOI: 10.1038/nature12656
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    Cited by:

    1. Wenxia Wang & Swarna Bale & Jun Wei & Bharath Yalavarthi & Dibyendu Bhattacharyya & Jing Jing Yan & Hiam Abdala-Valencia & Dan Xu & Hanshi Sun & Roberta G. Marangoni & Erica Herzog & Sergejs Berdnikov, 2022. "Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yuya Nishida & Sachiko Yanagisawa & Rikuri Morita & Hideki Shigematsu & Kyoko Shinzawa-Itoh & Hitomi Yuki & Satoshi Ogasawara & Ken Shimuta & Takashi Iwamoto & Chisa Nakabayashi & Waka Matsumura & His, 2022. "Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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