Diabetes and Obesity Drug Discovery & Therapy
(Track)
cGMP-dependent Protein Kinase Cascades Increase Muscle Mitochondrial Content and Prevent Obesity and Diabetes
Kazutoshi Miyashita
Department of Internal Medicine, School of Medicine, Keio University, Japan
Abstract:
Natriuretic peptides (NP) have been characterized as vascular hormones which regulate vascular tone via cyclic GMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in persons with the metabolic syndrome. Our study was aimed to elucidate the roles for NP/cGK cascades in energy metabolism. We used BNP transgenic (BNP-Tg) and cGK-Tg mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NP in cultured myocytes. BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance; and cGK-Tg mice had reduced body weight even on standard chow with giant mitochondria densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through up-regulation of PGC-1 and PPAR. The functional NP-receptors, GCA and GCB, were down-regulated by feeding high-fat diet; while GCA+/- mice showed increases in body weight and glucose intolerance when fed on high-fat diet. NP directly increased the expression of PGC-1alpha and PPARdelta and mitochondrial content in cultured myocytes. The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. Thus, the vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and utilization.
