The natriuretic peptide (NP) family is comprised of atrial NP, brain NP, and c-type NP (CNP). These peptides play diverse physiological roles (1–5) by binding to one of two receptors: NP receptor (NPR)-A (for atrial NP and brain NP) or NPR-B (for CNP), both of which signal through the guanylyl cyclase-cyclic GMP (cGMP) pathway (6). Among the physiological systems involving NPs are those controlling circulating blood volume, vascular tone, electrolyte balance, skeletal growth, and whole-body energy expenditure (1–5). In addition to actions in peripheral tissues, NPs are present in brain (7). In the current issue of Diabetes, Yamada-Goto et al. (8) report that central (but not peripheral) administration of CNP reduces food intake and body weight. The underlying mechanism appears to involve activation of the hypothalamic melanocortin pathway, which is also engaged by leptin, serotonin, and several other inputs that favor weight loss. These observations raise intriguing possibilities regarding the role of NPs and, by extension, guanylyl cyclase–cGMP signaling in hypothalamic neurocircuits controlling energy balance. The arcuate nucleus (ARC) is a key hypothalamic area for energy homeostasis. Neurons in this brain area transduce input from hormones such as leptin and insulin as well as from nutrients such as glucose. This results in adaptive changes involving both food intake and energy expenditure. Located within the ARC are pro-opiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons that, when activated, reduce or increase food intake, respectively (Fig. 1A). In response to leptin, the simultaneous activation of POMC and inhibition of NPY/ AgRP neurons reduces food intake, whereas in leptindeficient states such as fasting, the opposite combination of responses serve to drive hyperphagia (9). However, human obesity is typically associated with increased plasma leptin levels, and hypothalamic leptin resistance is present in most rodent models of obesity (10). Consequently, strategies for bypassing leptin resistance are of interest from the standpoint of obesity treatment. The melanocortin-4 receptor subtype (Mc4r) mediates inhibition of food intake by melanocortins such as a-melanocytestimulating hormone. Yamada-Goto et al. (8) report that the ability of intracerebroventricular CNP administration to reduce food intake is blunted by an Mc4r antagonist. Extending this observation, the authors also found that, like leptin, intracerebroventricular CNP activates POMC cells (based on induction of c-Fos) (8). These findings imply a role for the melanocortin system in the effect of CNP on food intake and, together with evidence that both CNP and NPR-B are concentrated in the ARC (7), raise the possibility that CNP-containing ARC neurons synapse onto and activate adjacent POMC neurons (Fig. 1B). Alternatively, CNP neurons could conceivably activate POMC cells via an indirect mechanism involving an intermediary neuronal subpopulation. These untested possibilities are of interest because, although the anorectic effects of both leptin (11) and serotonin (12) involve activation of POMC cells, neither leptin receptors (which signal via Janus kinase–signal transducer and activator of transcription and phosphatidylinositol-3-kinase pathways) nor serotonin receptors [in this case, the Gas-coupled 5HT2C receptor (13), which activates adenylate cyclase-cAMP] are known to activate the intracellular guanylyl cyclase–cGMP pathway used by NPR-B. These observations point to a novel, cGMP-based mechanism underlying activation of a key neuronal subset for energy homeostasis, a concept with implications for obesity drug development. The recent approval by the Food and Drug Administration of two obesity drugs—Lorcaserin, a 5HT2C receptor agonist (Arena Pharmaceuticals), and Qsymia, a combination of the anticonvulsant topiramate and the amphetamine derivative phentermine (VIVUS, Inc.)—was a significant advance in obesity treatment, but the era of effective medical therapy for obesity is still in its infancy. The melanocortin system has long been a target for obesity drug development, in part because of its potential to bypass obesity-associated leptin resistance. However, Mc4r agonists have been abandoned because of hypertension and other adverse effects. An alternative strategy for engaging the melanocortin system in obesity treatment involves the selective activation of discrete subsets of POMC neurons. Sohn et al. (13) have found that the ARC POMC cell population is not homogenous; rather, functionally and anatomically distinct subsets exist, each being responsive to distinct neuropeptide, neurotransmitter, and/or hormonal inputs. Thus, although leptin and serotonin each reduce food intake in a melanocortin-dependent manner (11,12), POMC neuron subsets activated by leptin and serotonin are distinct from one another (13). Could yet another POMC-cell subset exist that is activated preferentially by CNP? If so, perhaps it is possible to pharmacologically target distinct POMC neuron subsets in a stepwise manner that induces weight loss while averting the untoward effects of broad-based Mc4r activation. Hypothalamic actions of CNP (8) add to a small, but growing, body of evidence connecting hypothalamic guanylyl cyclase-cGMP signaling to the control of food intake. Like CNP, uroguanylin (a peptide liberated within From the Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington. Corresponding author: Michael W. Schwartz, email@example.com. DOI: 10.2337/db12-1841 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 1500.