The Central Melanocortin System and Regulation of Energy Balance

中枢黑皮质素系统和能量平衡的调节

• 批准号: 7750580
• 负责人: Sharon L. Wardlaw
• 金额: $ 33.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750580
• 关键词: ART protein; Affect; Biological; Biological Assay; Body Weight; Brain; C-terminal; Diabetes Mellitus; Diet; Eating; Energy Metabolism; Enzymes; Fatty Liver; Fatty acid glycerol esters; Genetic Models; Hepatic; Hormonal; Human; Hypothalamic structure; In Vitro; Injection of therapeutic agent; Mus; Mutation; N-terminal; Names; Neurons; Nutrient; Obesity; Peptides; Peripheral; Play; Prevalence; Prevention; Principal Investigator; Pro-Opiomelanocortin; Process; Proprotein Convertase 1; Protocols documentation; Regulation; Research; Rodent Model; Role; Signal Transduction; System; Transgenic Mice; design; energy balance; feeding; glucose metabolism; improved; in vivo; melanocortin receptor; novel; nutrient metabolism; overexpression; oxidation; programs; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how the brain senses levels of peripheral energy stores and integrates these signals to maintain energy balance. Studies will focus on the central melanocortin system in rodent models and on the mechanisms by which it can sense and integrate a variety of nutrient, hormonal and neuronal signals to regulate food intake, energy expenditure and nutrient metabolism. This system consists of proopiomelanocortin (POMC) and the POMC-derived MSH peptides together with agouti related protein (AGRP) which is a potent antagonist of the MSH peptides at specific melanocortin receptors (MC3/4-R). a-MSH inhibits feeding and stimulates energy expenditure while AGRP exerts opposite effects. Aim 1 will use recently generated transgenic mice that overexpress a-MSH and g- MSH (Tg-MSH) to study the role of the melanocortin system in modulating responses to energy excess on a high fat diet and to characterize underlying mechanisms with a focus on energy expenditure, fuel oxidation, sympathetic activity and hepatic steatosis. Tg-MSH mice demonstrate reduced body weight, adiposity and hepatic fat accumulation (without changes in food intake) and improved glucose metabolism, particularly in the setting of diet-induced obesity. The role of AGRP will be similarly studied in Aim 2 using a genetic model of Agrp deletion and a novel, potent, small molecule AGRP antagonist. Aims 3 & 4 will focus on the regulation of POMC and AGRP peptide processing in the hypothalamus in vivo and in vitro with respect to energy balance. This is an important consideration because POMC is processed to a number of peptides with different and even opposing biological activities. The ability of these peptide products to interact and regulate energy balance will be studied in parallel using icv injection protocols. AGRP is also processed by PC1 to a biologically active C-terminal fragment but little is known about the regulation of processing or about the N-terminal peptides that are produced that may also affect energy balance. AGRP processing will be characterized using novel assays and the effects of these processed peptides on energy balance will then be studied. This proposal is highly relevant to human energy balance as mutations in POMC, POMC processing enzymes and in the MC4-R have all been associated with human obesity and there are many parallels with rodent models of melanocortin deficiency. PUBLIC HEALTH RELEVANCE: The increasing prevalence of obesity and diabetes makes it imperative to understand the mechanisms by which the brain regulates energy balance in order to design more effective prevention and treatment options. This proposal will use rodent models to study the brain melanocortin system which plays a key role in regulating energy balance. This system consists of proopiomelanocortin (POMC) and the POMC-derived MSH peptides together with agouti related protein (AGRP) which is a potent antagonist of the MSH peptides at specific melanocortin receptors (MC3/4-R). ?-MSH inhibits feeding and stimulates energy expenditure while AGRP exerts opposite effects. This proposal is highly relevant to human energy balance as mutations in POMC, POMC processing enzymes and in the MC4-R have all been associated with human obesity and there are many parallels with rodent models of melanocortin deficiency.

描述（由申请人提供）：本提案的长期目标是了解大脑如何感知外周能量储存水平并整合这些信号以维持能量平衡。研究将侧重于啮齿动物模型中的中央黑皮质素系统，以及它能够感知和整合各种营养、激素和神经元信号以调节食物摄入、能量消耗和营养代谢的机制。该系统由前阿黑皮素（POMC）和POMC衍生的MSH肽以及聚集蛋白相关蛋白（AGRP）组成，所述聚集蛋白相关蛋白是MSH肽在特异性黑皮质素受体（MC 3/4-R）处的有效拮抗剂。a-MSH抑制摄食并刺激能量消耗，而AGRP发挥相反的作用。目的1将使用最近产生的过表达a-MSH和g-MSH的转基因小鼠（Tg-MSH）来研究黑皮质素系统在调节对高脂肪饮食的能量过剩的反应中的作用，并表征关注能量消耗、燃料氧化、交感神经活性和肝脂肪变性的潜在机制。Tg-MSH小鼠表现出减轻的体重、肥胖和肝脏脂肪积累（没有食物摄入的变化）和改善的葡萄糖代谢，特别是在饮食诱导的肥胖的情况下。AGRP的作用将在Aim 2中使用Agrp缺失的遗传模型和新的有效的小分子AGRP拮抗剂进行类似的研究。目的3和4将集中在调节POMC和AGRP肽加工在下丘脑在体内和体外的能量平衡。这是一个重要的考虑因素，因为POMC被加工成许多具有不同甚至相反生物活性的肽。这些肽产物相互作用和调节能量平衡的能力将使用icv注射方案进行平行研究。AGRP也被PC 1加工成具有生物活性的C-末端片段，但对加工的调节或产生的也可能影响能量平衡的N-末端肽知之甚少。AGRP处理将使用新的分析方法进行表征，然后将研究这些处理过的肽对能量平衡的影响。该提议与人类能量平衡高度相关，因为POMC、POMC加工酶和MC 4-R中的突变都与人类肥胖相关，并且与黑皮质素缺乏的啮齿动物模型有许多相似之处。 公共卫生相关性：肥胖和糖尿病的日益流行使得了解大脑调节能量平衡的机制成为当务之急，以便设计更有效的预防和治疗方案。这项提议将使用啮齿动物模型来研究在调节能量平衡中起关键作用的大脑黑皮质素系统。该系统由前阿黑皮素（POMC）和POMC衍生的MSH肽以及聚集蛋白相关蛋白（AGRP）组成，所述聚集蛋白相关蛋白是MSH肽在特异性黑皮质素受体（MC 3/4-R）处的有效拮抗剂。?- MSH抑制摄食并刺激能量消耗，而AGRP发挥相反的作用。该提议与人类能量平衡高度相关，因为POMC、POMC加工酶和MC 4-R中的突变都与人类肥胖相关，并且与黑皮质素缺乏的啮齿动物模型有许多相似之处。