The Central Melanocortin System and Regulation of Energy Balance

描述(申请人提供)：这项建议的长期目标是了解大脑如何感知外围能量储存的水平，并整合这些信号以维持能量平衡。研究将集中在啮齿动物模型中的中枢黑素皮质素系统，以及它可以感知和整合各种营养、激素和神经信号以调节食物摄入量、能量消耗和营养代谢的机制。该系统由原阿片黑素皮质素(POMC)及其衍生的MSH多肽和刺鼠相关蛋白(AGRP)组成，AGRP是MSH多肽对黑素皮质素受体(MC3/4-R)的有效拮抗剂。A-MSH抑制摄食，刺激能量消耗，AGRP则相反。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)来研究黑素皮质素系统在调节对高脂肪饮食能量过剩的反应中的作用，并以能量消耗、燃料氧化、交感活动和肝脏脂肪变性为重点来表征潜在的机制。TG-MSH小鼠表现出体重减轻、肥胖和肝脏脂肪堆积(不改变食物摄入量)和改善葡萄糖代谢，特别是在饮食诱导肥胖的背景下。在目标2中，将使用AgRP缺失的遗传模型和一种新的、有效的小分子AGRP拮抗剂来类似地研究AGRP的作用。AIMS 3和4将侧重于体内和体外对下丘脑POMC和AGRP肽加工的调节，以实现能量平衡。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学活性的多肽。这些多肽产品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PC1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-末端多肽知之甚少。AgRP处理过程将使用新的分析方法进行表征，然后将研究这些处理过的多肽对能量平衡的影响。这一建议与人类的能量平衡高度相关，因为POMC、POMC加工酶和MC4-R的突变都与人类肥胖有关，而且与啮齿动物的黑素皮质素缺乏模型有许多相似之处。 与公共健康相关：肥胖和糖尿病的流行日益增加，因此必须了解大脑调节能量平衡的机制，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大脑黑素皮质素系统，该系统在调节能量平衡方面起着关键作用。该系统由原阿片黑素皮质素(POMC)及其衍生的MSH多肽和刺鼠相关蛋白(AGRP)组成，AGRP是MSH多肽对黑素皮质素受体(MC3/4-R)的有效拮抗剂。？-MSH抑制摄食，刺激能量消耗，而AGRP则相反。这一建议与人类的能量平衡高度相关，因为POMC、POMC加工酶和MC4-R的突变都与人类肥胖有关，而且与啮齿动物的黑素皮质素缺乏模型有许多相似之处。

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.