Mechanisms for regulation of the sympathetic nervous system by melanocortin-4 receptors

Abstract

Melanocortin-4 receptors (MC4Rs) expressed by the central nervous system are essential regulators of energy homeostasis, and Mc4r mutation is the most common cause of human monogenic obesity. Notably, obese patients with Mc4r mutations are protected against obesity-induced hypertension and MC4R agonists elevate blood pressure (BP). Although increased sympathetic tone by MC4Rs was suggested to underlie this phenotype, the detailed mechanisms remain to be identified. Here, we investigated how MC4Rs regulate the sympathetic preganglionic neurons, and found that MC4Rs excite these neurons via the protein kinase A-dependent activation of the transient receptor potential vanilloid 1 (TRPV1) channel. Importantly, we demonstrate that the inhibition of TRPV1 prevents MC4R-induced elevation of BP, but does not affect MC4R-induced anorexia. We further show that TRPV1 is responsible for MC4R-dependent excitation of the sympathetic preganglionic neurons when high-fat diet activates the central melanocortin pathway. Together, our results provide insight how MC4Rs regulate sympathetic function.