The Central Melanocortin System and Regulation of Energy Balance

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。研究将集中在啮齿动物模型中的黑素皮质素中枢系统，以及它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proopiomanocortin （POMC）和POMC衍生的MSH肽以及AGRP （AGRP）组成，AGRP是MSH肽在特定黑素皮质素受体（MC3/4-R）上的有效拮抗剂。a-MSH抑制摄食和刺激能量消耗，而AGRP具有相反的作用。目的1将使用最近产生的过表达a-MSH和g-MSH （Tg-MSH）的转基因小鼠，研究黑素皮质素系统在调节高脂肪饮食对能量过剩的反应中的作用，并以能量消耗、燃料氧化、交感神经活动和肝脏脂肪变性为重点，表征其潜在机制。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），并改善葡萄糖代谢，特别是在饮食引起的肥胖的情况下。AGRP的作用将在Aim 2中进行类似的研究，使用AGRP缺失的遗传模型和一种新型的、有效的小分子AGRP拮抗剂。目的3和4将重点关注体内和体外下丘脑POMC和AGRP肽加工对能量平衡的调节。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注射方案并行研究。AGRP也被PC1加工成具有生物活性的c端片段，但对加工的调控或所产生的可能影响能量平衡的n端肽知之甚少。AGRP加工将使用新的分析方法进行表征，然后研究这些加工的肽对能量平衡的影响。这一建议与人类能量平衡高度相关，因为POMC、POMC加工酶和MC4-R的突变都与人类肥胖有关，并且与黑素皮质素缺乏的啮齿动物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.