An Intestinal Prouroguanylin-Hypothalamic GUCY2C Axis Mediates Nutrient-Induced Satiety

We live amidst a global obesity pandemic with far-reaching health and economic consequences, underscored by the absence of FDA-approved therapies that produce safe, durable weight loss. Guanylyl cyclase C (GUCY2C), an intestinal transmembrane receptor, is a member of a family of homologous signaling proteins synthesizing cyclic GMP as their proximal effector. GUCY2C is the receptor for the endogenous paracrine hormones, guanylin and uroguanylin, which regulate epithelial cell dynamics contributing to the spatiotemporal organization of the crypt-villus axis. Unexpectedly, GUCY2C has emerged as an important intermediary in signaling programs controlling appetite and body weight. C57/Bl6 mice in which GUCY2C signaling was eliminated exhibited excess body weight, which was amplified by a high-fat/high-calorie diet. This excess body weight was associated with an increase in visceral and subcutaneous adipose mass and several obesity-related co-morbidities, including cardiac hypertrophy, hepatic steatosis, hyperinsulinemia, and glucose intolerance. Interestingly, elimination of GUCY2C signaling produced obesity in the absence of differences in intestinal lipid absorption efficiency, circadian activity cycles, and energy expenditure. However, GUCY2C-deficient mice were hyperphagic, and their excess weight gain was eliminated by restricting their daily food consumption to wildtype levels. Moreover, GUCY2C-deficient mice exhibited deficient nutrient-induced satiety responses, and their hyperphagia was exacerbated by fasting, suggesting a defect in mechanisms regulating central satiety. Beyond nutrient digestion and absorption, the intestine plays an important role in energy homeostasis by regulating appetite circuits within the hypothalamus, mediated by the intestinal secretion of anorexigenic hormones following food intake. While the pro-hormones of guanylin and uroguanylin are secreted by the intestine into the circulation in both mice and humans, extraintestinal GUCY2C expression has not been conclusively demonstrated, making their endocrine functions ambiguous. Interestingly, there is an established role for neuronal guanylyl cyclase, cGMP, and downstream cGMP-dependent protein kinase (PKG) signaling in reducing food intake in invertebrates. Here, GUCY2C expression in the hypothalamus, the primary regulator of mammalian appetite and satiety, was confirmed by qRT-PCR, immunoblotting, immunohistochemistry, and functional assays of GUCY2C-ligand induced cGMP accumulation. Stimulation of extraintestinal GUCY2C by IV administration of the exogenous ligand, heat-stable enterotoxin (ST), or the endogenous ligand, prouroguanylin, produced an acute (2 h) satiety response, an effect which was not replicated in GUCY2C-deficient mice. Furthermore, prouroguanylin levels rose rapidly following food intake in both mice and humans, and antibody-mediated depletion of circulating prouroguanylin increased food consumption. These observations demonstrate a novel gut-neural signaling pathway in the regulation of appetite and body weight, providing an evolutionary link between primordial and mammalian appetite regulation and highlighting a therapeutic paradigm in which pharmacologic activation of GUCY2C may enhance satiety responses, thereby restricting appetite and defending against obesity