ADPN

Adiponectin is an anti-diabetic adipokine whose receptors possess a unique seven-transmembrane topology distinct from G-protein-coupled receptors. This study demonstrates that adiponectin activates adiponectin receptor 1 (AdipoR1) to induce extracellular Ca2? influx, which is essential for subsequent activation of Ca2?/calmodulin-dependent protein kinase kinase beta (CaMKKβ), AMP-activated protein kinase (AMPK), and SIRT1. This signaling cascade increases the expression and deacetylation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), thereby enhancing mitochondrial biogenesis in myocytes. Muscle-specific disruption of AdipoR1 abolishes adiponectin-induced Ca2? influx, suppresses CaMKK, AMPK, and SIRT1 activation, and reduces PGC-1α expression and mitochondrial content. This impairment leads to decreased oxidative type I muscle fibers, diminished oxidative stress detoxification, insulin resistance, and reduced exercise endurance. The findings suggest that decreased adiponectin and AdipoR1 levels in obesity may contribute to mitochondrial dysfunction and insulin resistance in diabetes, highlighting AdipoR1 as a potential therapeutic target for metabolic disorders.