ANP-ing Up Diabetes: Impaired Natriuretic Peptide Action in Muscle Forms a Mechanistic Link Between Obesity and Diabetes

A growing body of work concerns the role of natriuretic peptides (NPs) in metabolism and insulin sensitivity, the latest addition to which is published in this issue of Diabetes (1). Three principal structurally related NPs exist in mammals: atrial natriuretic peptide (ANP), produced primarily by the cardiac atria; brain/B-type natriuretic peptide (BNP), secreted by the ventricle and brain; and C-type natriuretic peptide (CNP), originating from the vascular endothelium, central nervous system, and kidney. They were originally shown to possess potent natriuretic, diuretic, and vasodilatory activity, thus playing a significant role in the prevention of circulatory volume overload and hypertension. These peptides use plasma membrane–situated natriuretic peptide receptors (NPRs) A and B, with the A receptor showing a preference for ANP and BNP and the B receptor being specific for CNP, while a distinct C receptor is responsible for peptide clearance in tissues. Binding of peptides to NPRA leads to the activation of intracellular cyclic guanosine monophosphate (cGMP)-dependent signaling cascades involving cGMP-dependent protein kinases, phosphodiesterases, and ion channels that mediate the physiological effects of NPs (reviewed in ref. 2). Recently, parallel metabolic actions of NPs have been demonstrated in adipose tissue, with selective effects in the visceral adipose depot, expansion of which is most associated with insulin resistance (IR). ANP-stimulated cGMP-mediated phosphorylation of hormone-sensitive lipase results in lipolysis in primates/humans that is independent of β-adrenergic stimulation (3–5), thereby inhibiting visceral adipocyte hypertrophy (6). In addition, ANP treatment causes reduced adipose secretion of proinflammatory cytokines and …