Natriuretic Peptides/cGMP/cGMP-dependent Protein Kinase Cascades Promote Muscle Mitochondrial Biogenesis and Prevent Obesity.

Abstract

Objective: Natriuretic peptides (NP) have been characterized as vascular hormones which regulate vascular tone via guanylyl cyclase (GC), cyclic GMP and cyclic GMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in persons with the metabolic syndrome. The present study was aimed to elucidate the roles for NP/cGK cascades in energy metabolism.

Research Design and Methods: We used three types of genetically engineered mice: BNP transgenic (BNP-Tg), cGK-Tg, and GCA-heterozygous knockout (GCA+/−) 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.

Results: 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, and surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through up-regulation of PGC-1α and PPARδ. 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-1α and PPARδ, and mitochondrial content in cultured myocytes.

Conclusions: The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption.