Regulation of Hypothalamic Proopiomelanocortin by Leptin

描述(申请人提供)：瘦素调节的机制 能量动态平衡还没有完全被理解。人类肥胖是最常见的 以高瘦素血症和瘦素抵抗为特征 解释过了。大量观察表明，下丘脑 前阿片黑素皮质素(POMC)是瘦素作用的重要介质。 大脑。下丘脑POMC阳性神经元表达瘦素受体 下丘脑POMC mRNA水平受瘦素正向调节。这个 瘦素调节下丘脑POMC的细胞内信号机制 基因表达是未知的，将在这篇文章中详细研究 求婚。POMC是一种前体，它包含许多较小的多肽， 包括α-黑素细胞刺激素(α-MSH)，它是由 通过前激素转换酶(PC1和PC2)进行蛋白分解。 下丘脑来源的α-MSH是中枢神经系统配体的主要来源 黑素皮质素受体在中枢神经系统中起着至关重要的抑制作用 饲喂和储能的调节。我们有新的数据表明 瘦素还能刺激下丘脑PC1和PC2的表达。这表明 瘦素在转录和转录水平对下丘脑POMC的调节 翻译后水平。我们将通过以下方式调查协调监管 下丘脑POMC基因的瘦素-转录、生物合成和加工， 并将表征翻译后修饰和分泌 阿尔法-MSH。由于POMC神经元表达黑素皮质素受体，并且是 NPY/AgRP神经元，我们还将研究POMC表达的调节和 通过这些神经肽进行加工。除了转染法和活体法 研究后，我们将作为一个关键的模型系统，利用一个独特的和定义良好的 胎儿下丘脑神经元的原代培养。生理学上的相关性 黑素皮质素调节体重的途径也被证实 这一途径的突变会导致人类和啮齿动物的肥胖。这个 拟议的研究将有助于更好地了解瘦素的作用 关于下丘脑POMC生物学的研究，因此很可能揭示 体重调节机制与肥胖的发生发展。

DESCRIPTION (provided by applicant): The mechanisms by which leptin regulates energy homeostasis are not fully understood. Human obesity is most often characterized by hyperleptinemia and by leptin resistance that yet has to be explained. A number of observations demonstrate that hypothalamic proopiomelanocortin (POMC) is an important mediator of leptin action in the brain. POMC-expressing neurons in the hypothalamus express the leptin receptor and hypothalamic POMC mRNA levels are positively regulated by leptin. The intracellular signaling mechanisms by which leptin regulate hypothalamic pomc gene expression are unknown and will be investigated in detail in this proposal. POMC is a precursor that encompasses a number of smaller peptides, including alpha-melanocyte-stimulating-hormone (alpha-MSH), which is generated via proteolytic processing by prohormone convertases (PC1 and PC2). Hypothalamic-derived alpha-MSH is a primary source of ligand for central melanocortin receptors and plays a crucial inhibitory role in central regulation of feeding and energy storage. We have new data demonstrating that leptin also stimulates expression of hypothalamic PC1 and PC2. This suggests that leptin can regulate hypothalamic POMC at both the transcriptional and posttranslational levels. We will investigate the coordinated regulation by leptin of hypothalamic POMC gene-transcription, biosynthesis and processing, and will characterize the post-translational modification and secretion of alpha-MSH. Since POMC neurons express melanocortin receptors and are targets of NPY/AgRP neurons, we will also investigate modulation of POMC expression and processing by these neuropeptides. In addition to transfection and in vivo studies, we will as a key model system utilize a unique and well-defined primary fetal culture of hypothalamic neurons. The physiological relevance of the melanocortin pathway in regulation of body weight is also testified by the mutations in this pathway causing obesity in humans and in rodents. The proposed studies will lead to a better understanding of the effects of leptin on hypothalamic POMC biology and are therefore likely to shed light on mechanisms of body-weight regulation and the development of obesity.