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 beta (CaMKKbeta), AMPK and

SIRT1, increased expression and decreased acetylation of peroxisome

proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), 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-1alpha

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.

Iwabu M, et al. Nature. 2010 Mar 31. [Epub ahead of print]