Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1

• Published in: Nature (London) 2010-04, Vol.464 (7293), p.1313-1319
• Main Authors: Iwabu, Masato, Yamauchi, Toshimasa, Okada-Iwabu, Miki, Sato, Koji, Nakagawa, Tatsuro, Funata, Masaaki, Yamaguchi, Mamiko, Namiki, Shigeyuki, Nakayama, Ryo, Tabata, Mitsuhisa, Ogata, Hitomi, Kubota, Naoto, Takamoto, Iseki, Hayashi, Yukiko K., Yamauchi, Naoko, Waki, Hironori, Fukayama, Masashi, Nishino, Ichizo, Tokuyama, Kumpei, Ueki, Kohjiro, Oike, Yuichi, Ishii, Satoshi, Hirose, Kenzo, Shimizu, Takao, Touhara, Kazushige, Kadowaki, Takashi
• Format: Article
• Language: English
• Subjects: 631/208/200; 631/45/127; 631/80/86; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Humanities and Social Sciences; Medical sciences; Miscellaneous; multidisciplinary; Pharmacology. Drug treatments; Science
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08991

Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca 2+ influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca 2+ concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1α expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes. Adiponectin and obesity The fat-derived hormone adiponectin is involved in the regulation of glucose and fatty acid metabolism, showing both antidiabetic and anti-atherogenic properties. Work in mice lacking the adiponectin receptor AdipoR1 in muscle cells shows them to be insulin resistant and less able to endure exercise than wild-type animals. Adiponectin induces extracellular Ca 2+ influx in skeletal muscle via AdipoR1, a prerequisite for various downstream signalling steps implicated in mitochondrial function and oxidative stress. This suggests that strategies designed to stimulate AdipoR1 receptors or to increase AdipoR1 receptor numbers in skeletal muscle may be useful for the treatment of mitochondrial dysfunction, insulin resistance and type 2 diabetes linked to obesity. Adiponectin is a protein with anti-diabetic properties; its levels are decreased in obesity, insulin resistance and type 2 diabetes. It is shown here that mice with a muscle-specific disruption of adiponectin receptor 1 (AdipoR1) are insulin resistant and less able to endure exercise. The pathway downstream of receptor activation is delineated; the findings suggest that the decreased levels of adiponectin and AdipoR1 seen in obesity may