Adiponectin, Adiponectin Receptors, and Epigenetic Regulation of Adipogenesis

Abstract

We studied the molecular mechanism of obesity-induced insulin resistance and adipogenesis. Plasma adiponectin and adiponectin receptor (AdipoR1) in muscle are down-regulated in obesity. Analysis of muscle-specific AdipoR1 knockout mice revealed the pivotal role of adiponectin/AdipoR1 in the regulation of mitochondrial biogenesis via AMPK- and SIRT1-mediated PGC-1α activation as well as Ca²⁺-dependent up-regulation of PGC-1α expression. Reduced adiponectin/AdipoR1 signals in muscle in obesity appear to cause PGC-1α inactivation as well as down-regulation and consequently impaired mitochondrial biogenesis and insulin resistance. In the epigenetic analysis of adipogenesis, we demonstrated that adipocyte-specific formaldehyde-assisted isolation of regulatory elements (FAIRE) peaks are associated with genes up-regulated by adipogenesis, whereas preadipocyte-specific FAIRE peaks are associated with genes down-regulated by adipogenesis. Computational motif analyses of adipocyte-specific FAIRE peaks confirmed PPARγ and CCAAT-enhancer binding proteins (C/EBPs) on the top list, consistent with their crucial roles in adipogenic transcription, and also revealed NFIA and NFIB to be important regulators of proper adipocyte differentiation.