The cardiac natriuretic peptides (NPs) atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are both secreted by the heart in response to myocardial stress and stretch and act via binding to guanylyl cyclase-A (GC-A), with subsequent generation of the second messenger cyclic guanosine monophosphate. GC-A is widely expressed in mammals, e.g., in heart, kidney, vascular smooth muscle, skeletal muscle, adipose tissue, liver, stomach, terminal ileum, lung, adrenals, and brain. Consequently, the NPs have pleiotropic actions, many of which can be considered to unload the heart, specifically vasodilation, natriuresis, and inhibition of the renin-angiotensin-aldosterone system (1). Vila et al. (2) in the current issue of Diabetes present important information on the emerging metabolic actions of GC-A activation, specifically on its hunger and ghrelin suppressing actions (Fig. 1). FIG. 1. Potential effects of GC-A activation on metabolism and energy balance. There is emerging evidence from animal and human studies that GC-A activation by natriuretic peptides may modulate metabolism and energy balance. See text for details and Addisu et al. (21) for a study on gastric emptying. Obesity, insulin resistance, and the metabolic syndrome have all been associated with reduced NP levels (3,4). The low level of NPs seen in obesity is at least in part due to decreased cardiac secretion and, in fact, cardiac NP levels have been shown to increase after bariatric …