Adiponectin, a hormone released from adipose tissue that has antidiabetic activity, signals through seven-transmembrane receptors (AdipoR1 and AdipoR2) that are structurally and functionally distinct from the more familiar seven-transmembrane G protein–coupled receptors. Noting that adiponectin deficiency promotes insulin resistance and that insulin resistance is associated with mitochondrial dysfunction, Iwabu et al. looked for a link between adiponectin-AdipoR1 signaling and mitochondria. Phenotypic analyses of mice that lacked muscle Adipor1 (muscle-R1KO mice) revealed decreased phosphorylation of muscle adenosine monophosphate–activated protein kinase (AMPK) compared with control littermates; moreover, unlike their littermates, muscle-R1KO mice failed to show increased muscle AMPK phosphorylation in response to adiponectin. Their skeletal muscle showed decreased abundance of mRNAs encoding proteins involved in various aspects of mitochondrial function, notably peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, which was itself decreased in abundance), decreased mitochondrial DNA (a marker for mitochondrial content), and decreased mitochondrial function (as assessed by enzymatic activity). Muscle-R1KO mice had decreased muscle endurance and a phenotype consistent with a decrease in type I fibers, and, after glucose administration, their plasma glucose and insulin concentrations were higher than those of control mice, in association with insulin resistance. Having explored the phenotypic effects of a loss of adiponectin signaling through AdipoR1, the authors investigated the underlying pathway. Consistent with the decrease in muscle mitochondria in the muscle-R1KO mice, adiponectin caused an increase in mitochondrial DNA in C2C12 myocytes. Analyses of the effects of short-interfering RNA (siRNA) implicated AdipoR1, the AMPK kinase CaMKKβ (Ca2+/calmodulin-dependent protein kinase kinase β), AMPK, SIRT1, and PGC-1α in this response. Adiponectin signaling through AdipoR1 appeared to increase the abundance of the mRNA encoding PGC-1α through a CaMKKβ-dependent pathway that did not require AMPK and to stimulate PGC-1α deacetylation by SIRT1, and thereby its activation, through an AMPK-dependent pathway. Adiponectin also elicited an AdipoR1-dependent increase in Ca2+ influx, which played a critical role in the pathway leading to increased PGC-1α expression and also contributed to adiponectin-mediated AMPK phosphorylation. Thus, the authors conclude that adiponectin signaling through AdipoR1 plays a crucial role in the regulation of mitochondrial function and glucose metabolism.
M. Iwabu, T. Yamauchi, M. Okada-Iwabu, K. Sato, T. Nakagawa, M. Funata, M. Yamaguchi, S. Namiki, R. Nakayama, M. Tabata, H. Ogata, N. Kubota, I. Takamoto, Y. K. Hayashi, N. Yamauchi, H. Waki, M. Fukayama, I. Nishino, K. Tokuyama, K. Ueki, Y. Oike, S. Ishii, K. Hirose, T. Shimizu, K. Touhara, T. Kadowaki, Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313–1319 (2010). [PubMed]