Amplification of satiation signaling by melanocortin-4 receptors in the nucleus tractus solitarius

项目总结

Project Summary The astounding prevalence of obesity presents major public health and economic consequences. The development of more effective therapeutics for weight loss is paramount and requires basic science research to characterize the neural control of feeding behavior. Melanocortin signaling, through melanocortin 4 receptors (MC4Rs) in the nucleus tractus solitarius (NTS) contributes to food intake control by reducing meal size via amplification of within-meal gastrointestinally (GI)-derived satiation signals. However, the mechanism of MC4R signaling within the NTS is not clear and the translational significance of the interaction between NTS melanocortin signaling and other hormonal systems at the level of the NTS has not been adequately explored. The proposed research aims to test the hypothesis that endogenous pre- and postsynaptic NTS MC4R activity modulates NTS neural signaling and food intake and body weight suppression evoked by the GI- derived satiation signals cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). Specific Aim I will use in vivo fiber photometry to examine bidirectional modulation of CCK- and GLP-1-evoked NTS neural activity by hindbrain delivery of the MC4R agonist MTII or antagonist Shu9119. We hypothesize that neural activity evoked by either of these satiation signals will be amplified by exogenous MTII and attenuated by Shu9119. As we hypothesize that potentiation of NTS neural activity will result in amplified satiation signaling, we expect NTS delivered MTII to also enhance the food intake and body weight suppressive effects of peripherally administered CCK or GLP-1. Specific Aim II will utilize an adeno-associated virus (AAV)-encoding a validated shRNA construct for the MC4R, delivered to either the nodose ganglion of the vagus nerve or to the NTS, to selectively knockdown MC4Rs expressed on vagal presynaptic afferents or postsynaptic NTS neurons, respectively. We will analyze day-to-day meal patterns in each of these groups of rats to dissociate the endogenous contribution of pre- and postsynaptic NTS MC4Rs to food intake and body weight control. We will go on to use this strategy to examine the role of pre- and postsynaptic MC4Rs in mediating the intake-suppressive effects of exogenous NTS MTII delivery and in potentiating the anorectic actions of CCK and GLP-1. Finally, we will begin to characterize the phenotype of MTII-activated neurons within the NTS. By determining the functional relevance and mechanism of MC4R signaling within the NTS, these studies will contribute to identification of a novel NTS MC4R-activated circuit that may be manipulated through pharmacological approaches to reduce food intake and body weight.