title: Perspective of Small-Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity.
abstract: Obesity associated with unhealthy diet and lack of exercise is shown to contribute to the onset and/or aggravation of the metabolic syndrome and diabetes, thus placing affected individuals at increased risk of cardiovascular disease and cancer. Plasma adiponectin levels are decreased in obesity, which causes insulin resistance and diabetes. Therefore, we identified adiponectin receptors (AdipoRs) as the therapeutic target. It was suggested that, similarly to caloric restriction and exercise, activation of the AdipoRs may have the potential not only to improve lifestyle-related diseases but to contribute to prolonged the shortened lifespan on a high caloric unhealthy diet. To this end, we have identified "AdipoRon" as an adiponectin receptor agonist. Indeed, AdipoRon ameliorated diabetes associated with obesity as well as to increase exercise endurance, thus prolonging shortened lifespan of obese mice fed on a high fat diet. Additionally, we have recently determined the crystal structures of the human AdipoRs. The seven-transmembrane helices of AdipoRs are structurally distinct from those of G-protein coupled receptors. It is expected that these findings will contribute not only to the elucidation of the AdipoR-related signal transduction but to the development and optimization of AdipoR-targeted therapeutics for obesity-related diseases such as diabetes.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Okada-Iwabu
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ; PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Iwabu
authors.affiliation: Department of Molecular Sciences on Diabetes, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ; Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ; CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
keywords: AdipoR; Adiponectin; Agonist; Crystal structure; Diabetes mellitus; Obesity