Interactions of Leptin and the Melanocortin System

项目总结 肥胖率和糖尿病患病率的上升突显了了解大脑回路和细胞的必要性 调节能量平衡和葡萄糖动态平衡的机制。其中最突出的是中枢瘦素- 黑素皮质素系统，包括前阿片黑素皮质素(POMC)神经元，其亚群表达 瘦素受体(LEPR)。虽然在理解下丘脑的作用方面已经取得了巨大的进步 在新陈代谢中产生α-MSH的POMC神经元，对的三种亚型是如何表达的知之甚少。 下丘脑和脑下垂体表达POMC的细胞产生MSH，对代谢挑战做出反应。 目前的应用扩展了我们之前的发现，即表达LEPR的POMC神经元是 协调肝脏葡萄糖的产生和应对代谢挑战。我们将确定角色 对于-msh产生的多肽在POMC神经元代谢调节中的动态挑战。这 该项目还具有重大意义，因为它将是第一个将老鼠遗传学的力量与先进的 质谱学方法定量测定和定位-MSH多肽 下丘脑和脑下垂体组织。我们还将-MSH多肽水平与能量和 葡萄糖动态平衡，以及作为代谢适应基础的多肽--鹿角胺。这些研究将拓宽 我们对瘦素-黑素皮质素系统调节内分泌作用机制的理解 以及自主神经功能，特别是在肝脏和脂肪组织水平上。

PROJECT SUMMARY The increasing rates of obesity and diabetes highlight the need to understand the brain circuits and cellular mechanisms regulating energy balance and glucose homeostasis. Prominent among these is the central leptin- melanocortin system, which includes the pro-opiomelanocortin (POMC) neurons, subsets of which express leptin receptors (LEPRs). While enormous strides have been made to understand the role of hypothalamic POMC neurons that produce α-MSH in metabolism, relatively little is known about how the three isoforms of - MSH produced in hypothalamus and pituitary gland POMC-expressing cells respond to metabolic challenges. The current application extends our previous discovery that LEPR-expressing POMC neurons are required for coordinating hepatic glucose production and responding to metabolic challenges. We will determine the roles for -MSH peptides produced from POMC neurons in the regulation of metabolism in dynamic challenges. This project is also significant because it will be the first to combine the power of mouse genetics with advanced mass spectrometry to quantitatively measure and map specific POMC-derived -MSH peptides in hypothalamic and pituitary tissues. We will also correlate -MSH peptide levels with parameters of energy and glucose homeostasis, and deermine which peptides underlie metabolic adaptation. These studies will broaden our understanding of the functional mechanism by which the leptin-melanocortin system regulates endocrine and autonomic functions, particularly at the level of liver and adipose tissues.