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

孤束核中黑皮质素 4 受体放大饱足感信号

• 批准号: 10014592
• 负责人: Samantha Fortin
• 金额: $ 7.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2021-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10014592
• 关键词: Afferent Neurons; Agonist; Anti-Obesity Agents; Appetite Depressants; Attenuated; Basic Science; Behavior; Behavior Therapy; Body Temperature; Body Weight; Body Weight decreased; Brain; Cell Nucleus; Chemosensitization; Cholecystokinin; Dependovirus; Development; Eating; Endocrine system; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; FOS gene; Feedback; Feeding behaviors; Fiber; Food Energy; Food Intake Regulation; Heart Rate; Immunohistochemistry; Intake; Lead; Measures; Mediating; Melanocortin 4 Receptor; Metabolic Pathway; Mus; Neurons; Nodose Ganglion; Obesity; Obesity Epidemic; Pancreas; Peripheral; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phenotype; Photometry; Population; Positioning Attribute; Presynaptic Receptors; Prevalence; Public Health; Receptor Activation; Receptor Signaling; Regulation; Research; Role; SHU 9119; Satiation; Signal Transduction; System; Testing; Transgenic Mice; Treatment Efficacy; United States; Vagus nerve structure; Weight; Weight maintenance regimen; Work; awake; cholecystokinin 8; energy balance; gastrointestinal; glucagon-like peptide 1; health economics; hindbrain; in vivo; knock-down; melanotan-II; neuroregulation; neurotransmission; novel; obesity treatment; postsynaptic; postsynaptic neurons; presynaptic; reduced food intake; relating to nervous system; response; success

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 energy balance control by reducing food intake and increasing energy expenditure 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 amplifies NTS neural signaling, food intake and body weight suppression and energy expenditure increases 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 and energy expenditure, we expect NTS delivered MTII to also enhance energy expenditure as well as 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 cre-recombinase delivered to either the nodose ganglion of the vagus nerve or to the NTS of MC4Rlox/lox mice to selectively knockdown MC4Rs expressed on vagal presynaptic afferents or postsynaptic NTS neurons, respectively. We will analyze feeding behavior and energy expenditure in each of these groups of mice to dissociate the endogenous contribution of pre- and postsynaptic NTS MC4Rs to food intake, energy expenditure 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 and energy expenditure-enhancing 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.

项目总结