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.

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Acknowledgements

We thank N. Kubota, K. Hara, I. Takamoto, Y. Hada, T. Kobori, H. Umematsu, S. Odawara, T. Aoyama, Y. Jing, S. Wei, K. Soeda and H. Waki for technical help and support; and K. Miyata, Y. Nishibaba, M. Yuasa and A. Hayashi for technical assistance and support. This work was supported by a Grant-in-aid for Scientific Research (S) (20229008, 25221307) (to T.K.), Grant-in-aid for Young Scientists (A) (23689048) (to M.I.), Targeted Proteins Research Program (to T.K.), the Global COE Research Program (to T.K.), Translational Systems Biology and Medicine Initiative (to T.K.) and Translational Research Network Program (to M.O.-I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Funding Program for Next Generation World-Leading Researchers (NEXT Program) (to T.Y.) from Cabinet Office, Government of Japan.

Author information

Author notes

    • Miki Okada-Iwabu
    • , Toshimasa Yamauchi
    •  & Masato Iwabu

    These authors contributed equally to this work.

Affiliations

  1. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

    • Miki Okada-Iwabu
    • , Toshimasa Yamauchi
    • , Masato Iwabu
    • , Ken-ichi Hamagami
    • , Koichi Matsuda
    • , Mamiko Yamaguchi
    • , Kohjiro Ueki
    •  & Takashi Kadowaki
  2. Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan

    • Miki Okada-Iwabu
    • , Toshimasa Yamauchi
    • , Masato Iwabu
    •  & Takashi Kadowaki
  3. Department of Molecular Medicinal Sciences on Metabolic Regulation, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan

    • Miki Okada-Iwabu
    • , Toshimasa Yamauchi
    •  & Takashi Kadowaki
  4. RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan

    • Teruki Honma
    • , Hiroaki Tanabe
    • , Tomomi Kimura-Someya
    • , Mikako Shirouzu
    • , Akiko Tanaka
    •  & Shigeyuki Yokoyama
  5. Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8577, Japan

    • Hitomi Ogata
    •  & Kumpei Tokuyama
  6. Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

    • Tetsuo Nagano
    •  & Akiko Tanaka
  7. Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

    • Shigeyuki Yokoyama

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Contributions

M.O.-I., M.I., T.Y., T.H., K.-i.-H., K.M., M.Y., H.T., T.K-S., M.S., H.O., K.T. and A.T. performed experiments. T.K., T.Y., M.O.-I. and M.I. conceived the study. T.K., A.T., T.Y. and S.Y. supervised the study. T.Y., T.K., M.O.-I. and M.I. wrote the paper. All authors interpreted data.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Toshimasa Yamauchi or Takashi Kadowaki.

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DOI

https://doi.org/10.1038/nature12656

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