The Central Melanocortin System and Regulation of Energy Balance

这项提议的长期目标是了解大脑如何感知外周能量水平。 存储和整合这些信号以维持能量平衡。研究将集中在中环 啮齿动物模型中的黑素皮质素系统及其感知和整合多种生物的机制 调节食物摄入量、能量消耗和营养的营养、激素和神经信号 新陈代谢。该系统由原阿片黑素皮质素(POMC)及其衍生的MSH多肽组成 与刺鼠相关蛋白(AGRP)一起使用，AGRP是MSH多肽的有效拮抗剂 黑素皮质素受体(MC3/4-R)。A-MSH抑制摄食并刺激能量消耗，而AGRP 会产生相反的效果。AIM 1将使用最近产生的过表达a-MSH和g-MSH的转基因小鼠 MSH(TG-MSH)研究黑素皮质素系统在调节对能量过剩的反应中的作用 高脂肪饮食和表征潜在的机制，重点是能量消耗，燃料氧化， 交感神经活动和肝脏脂肪变性。TG-MSH小鼠表现出体重减轻，肥胖症和 肝脏脂肪堆积(食物摄入量没有变化)和改善葡萄糖代谢，特别是在 饮食诱导性肥胖的设定。AGRP的作用将在目标2中类似地研究，使用一种基因 AgRP缺失模型和一种新型、有效的小分子AGRP拮抗剂。AIMS 3和4将专注于 体内和体外对下丘脑POMC和AGRP多肽加工的调节 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 具有不同甚至相反的生物活动。这些肽产品相互作用的能力和 将使用ICV注射方案并行研究调节能量平衡。AgRP也是由 PC1到生物活性的C-末端片段，但对加工或调节的调控知之甚少 关于N-端肽的产生也可能影响能量平衡。AgRP处理将 使用新的分析方法进行表征，以及这些经过处理的多肽对能量平衡的影响 然后被研究。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中的都与人类肥胖有关，有许多 与黑素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.