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

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, Kumpei Tokuyama, Kohjiro Ueki, Tetsuo Nagano, Akiko Tanaka, Shigeyuki Yokoyama and Takashi Kadowaki ()
Additional contact information
Miki Okada-Iwabu: Graduate School of Medicine, The University of Tokyo
Toshimasa Yamauchi: Graduate School of Medicine, The University of Tokyo
Masato Iwabu: Graduate School of Medicine, 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
Shigeyuki Yokoyama: RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan
Takashi Kadowaki: Graduate School of Medicine, The University of Tokyo

Nature, 2013, vol. 503, issue 7477, 493-499

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12656

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