The Central Melanocortin System and Regulation of Energy Balance

这项计划的长期目标是了解大脑如何感知周围能量的水平 储存并整合这些信号以维持能量平衡。研究将集中在中央 黑皮质素系统在啮齿动物模型和机制，它可以感觉和整合各种 调节食物摄入、能量消耗和营养物质的营养、激素和神经元信号 新陈代谢.该系统由前阿黑皮素（POMC）和POMC衍生的MSH肽组成 与作为MSH肽的有效拮抗剂的聚集蛋白相关蛋白（AGRP）一起， 黑皮质素受体（MC 3/4-R）。a-MSH抑制摄食并刺激能量消耗，而AGRP 产生相反的效果。目的1将使用最近产生的过表达a-MSH和g- MSH（Tg-MSH）研究黑皮质素系统在调节能量过剩反应中的作用， 高脂肪饮食，并以能量消耗，燃料氧化， 交感神经活性和肝脂肪变性。Tg-MSH小鼠表现出降低的体重、肥胖和 肝脏脂肪蓄积（食物摄入量无变化）和葡萄糖代谢改善，特别是 饮食引起的肥胖症。AGRP的作用将在目标2中使用遗传学方法进行类似的研究。 Agrp缺失模型和一种新的、有效的小分子AGRP拮抗剂。目标3和4将侧重于 调节POMC和AGRP肽加工在下丘脑在体内和体外关于 能量平衡这是一个重要的考虑因素，因为POMC被加工成许多肽 有着不同甚至相反的生物活性这些肽产物相互作用的能力， 调节能量平衡将使用ICV注入协议并行研究。AGRP也由 PC 1与生物活性的C-末端片段连接，但对加工或 产生的N-末端肽也可能影响能量平衡。AGRP处理将 使用新的测定来表征，并且这些加工的肽对能量平衡的影响将 然后被研究。这一建议与人类能量平衡高度相关，因为POMC突变，POMC 加工酶和MC 4-R都与人类肥胖有关， 与黑皮质素缺乏的啮齿动物模型相似。

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.