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

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-? 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-? 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.

Okada-Iwabu, Miki
Yamauchi, Toshimasa
Iwabu, Masato
Honma, Teruki
Hamagami, Ken-ichi
Matsuda, Koichi
Yamaguchi, Mamiko
Tanabe, Hiroaki
Kimura-Someya, Tomomi
Shirouzu, Mikako
Ogata, Hitomi
Tokuyama, Kumpei
Ueki, Kohjiro
Nagano, Tetsuo
Tanaka, Akiko
Yokoyama, Shigeyuki
Kadowaki, Takashi
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NCBI Published Medical (?)
PMID: 24172895

Turabian/Chicago 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, Kumpei Tokuyama, Kohjiro Ueki, Tetsuo Nagano, Akiko Tanaka, Shigeyuki Yokoyama and Takashi Kadowaki. 11/28/2013. "A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity." Nature 503: 7477: 493-499. 10.1038/nature12656.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1038/nature12656 | issn = 1476-4687 | volume = 503 | pages = 493-499 | last = Okada-Iwabu | first = Miki | coauthors = Yamauchi, Toshimasa, Iwabu, Masato, Honma, Teruki, Hamagami, Ken-ichi, Matsuda, Koichi, Yamaguchi, Mamiko, Tanabe, Hiroaki, Kimura-Someya, Tomomi, Shirouzu, Mikako, Ogata, Hitomi, Tokuyama, Kumpei, Ueki, Kohjiro, Nagano, Tetsuo, Tanaka, Akiko, Yokoyama, Shigeyuki, Kadowaki, Takashi | title = A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity | journal = Nature | date = 11/28/2013 | pmid = | pmc = }} </ref>