Interactions of Leptin and the Melanocortin System

摘要 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)。了解瘦素如何与葡萄糖不同地调节能量平衡 动态平衡是开发抗肥胖和抗糖尿病疗法的关键。基于早期观察 关于产前基因操作导致LEPR表达POMC神经元的广泛存在的模型 然而，现在有证据表明，这些途径更多地参与了瘦素的代谢活动。 比最初预期的要复杂。当前的应用程序通过直接扩展我们早期的开发模型 检测瘦素在成年黑素皮质素神经元调节糖代谢和反应中的作用 应对动态挑战，包括禁食和寒冷暴露。我们手头还有一个模型，在这个模型中肝脏 胰岛素抵抗可以以一种暂时的方式诱导，使我们能够研究瘦素- 黑素皮质素途径在其发育中的作用。这些研究将拓宽我们对功能的理解 瘦素-黑素皮质素系统调节内分泌、自主神经和行为功能的机制， 特别是在脂肪组织和肝脏水平上。

Abstract 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). Understanding how leptin differentially regulates energy balance versus glucose homeostasis is key for the development of anti-obesity and anti-diabetes therapies. Early observations based on prenatal genetic manipulations led to the widely-held model that LEPR-expressing POMC neurons mediated the metabolic actions of leptin, however, evidence now suggests that these pathways are more complex than originally anticipated. The current application extends our early developmental models by directly testing the role of leptin action in adult melanocortin neurons in regulating glucose metabolism and responding to dynamic challenges, including fasting and cold exposure. We also have in hand a model in which liver insulin resistance can be induced in a temporal manner, allowing us to investigate the role of the leptin- melanocortin pathway in its development. These studies will broaden our understanding of the functional mechanism by which the leptin-melanocortin system regulates endocrine, autonomic, and behavioral functions, particularly at the level of adipose tissues and liver.