Regulation of Hypothalamic Proopiomelanocortin by Leptin

描述（由申请人提供）：瘦素调节的机制 能量平衡还没有被完全理解。人类肥胖最常见的原因 以高瘦素血症和瘦素抵抗为特征， 解释道许多观察表明，下丘脑 前阿黑皮素（POMC）是瘦素在脑组织中作用的重要介质。 个脑袋下丘脑中POMC表达神经元表达瘦素受体 下丘脑POMC mRNA水平受瘦素正调控。的 瘦素调节下丘脑pomc细胞内信号转导机制 基因表达是未知的，将在本研究中详细研究。 提议POMC是一种包含许多较小肽的前体， 包括α-黑素细胞刺激激素（α-MSH）， 通过激素原转化酶（PC 1和PC 2）的蛋白水解加工。 下丘脑衍生的α-MSH是中枢神经系统配体的主要来源。 黑皮质素受体，并在中枢神经系统中起着至关重要的抑制作用。 调节进料和能量储存。我们有新的数据表明， 瘦素还刺激下丘脑PC 1和PC 2的表达。这表明 Leptin在转录水平和转录水平均能调节下丘脑POMC， 翻译后水平我们将通过以下方式研究协调监管 瘦素是下丘脑POMC基因的转录、生物合成和加工， 并将表征的翻译后修饰和分泌 α-MSH由于POMC神经元表达黑皮质素受体，并且是 我们还将研究POMC表达的调节， 由这些神经肽处理。除了转染和体内 研究，我们将作为一个关键的模型系统，利用一个独特的和明确的 下丘脑神经元的原代胎儿培养。的生理相关性 黑皮质素途径在体重调节中的作用也得到了证实， 这一途径的突变导致人类和啮齿动物肥胖。的 拟议的研究将导致更好地了解瘦素的作用， 下丘脑POMC生物学，因此可能揭示 体重调节机制和肥胖症的发展。

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.