A carboxypeptidase in the regulation of hypothalamic circuitry

描述(申请人提供)：肥胖和相关的代谢功能障碍，如2型糖尿病，已成为发达国家发病率和死亡率的主要原因。肥胖和2型糖尿病的发展可能由中枢神经系统机制触发或消除。下丘脑黑素皮质素系统在能量平衡调节中起着重要作用。下丘脑中的主要厌食肽是α-黑素细胞刺激素(1-MSH)，它是前阿片黑素皮质素(POMC)基因的产物。当释放时，1-MSH被迅速降解，这一过程可能在黑素皮质素信号转导中发挥重要作用。我们已经确定了一种在下丘脑表达的羧基酶，即脯氨酸羧肽酶(PRCP)，它可以启动细胞外1-MSH的降解和失活。我们发现PRCP在神经元群体中表达，这些神经元群体向轴突终末释放1-MSH的区域发送传出信号。我们证实1-MSH1-13是PRCP的底物，PRCP降解的1-MSH(1-MSH1-12)不具有神经活性。在野生型和肥胖型动物中，外周或中枢应用小分子蛋白酶抑制剂抑制PRCP活性会减少摄食量。此外，全身或外侧下丘脑区域特定区域的PRCP基因的消融导致了对饮食诱导的肥胖的抵抗。综上所述，这些观察结果支持了这一假设的中心假设，即PRCP是黑素皮质素细胞下游的黑素皮质素信号的重要调节因子。我们认为PRCP活性升高会促进代谢功能障碍，包括肥胖和2型糖尿病。为了进一步了解PRCP在代谢调节中的作用，我们提出了以下具体目标：具体目标1)我们将研究PRCP和黑素皮质素在瘦小鼠和肥胖小鼠中的水平。具体目的2)研究瘦素和Ghrelin在PRCP中的作用。具体目的3)研究PRCP在肥胖和2型糖尿病发病中的作用。上述具体目标的实现将揭示能量代谢调节中的一个新的中央调节要素。这些研究的成功完成将为包括肥胖症和2型糖尿病在内的代谢紊乱提供新的药物靶点。 与公共健康相关：这项提案旨在研究下丘脑羧基酶在控制食物摄入量和能量消耗的大脑回路调节中的作用。这些研究的成功完成将为包括肥胖症和2型糖尿病在内的代谢紊乱提供新的药物靶点。

DESCRIPTION (provided by applicant): Obesity and related metabolic dysfunctions, such as type 2 diabetes, have emerged as a leading cause of morbidity and mortality in developed societies. The development of obesity and type 2 diabetes may be triggered or abrogated by central nervous system mechanisms. The hypothalamic melanocortin system plays an important role in the regulation of energy balance. The major anorexigenic peptide in the hypothalamus is alpha-melanocyte-stimulating hormone (1-MSH), the product of the pro-opiomelanocortin (POMC) gene. When released, 1-MSH is rapidly degraded, a process that is likely to play an important role in melanocortin signaling. We have identified a carboxylase enzyme, prolyl carboxypeptidase (PRCP), which is expressed in the hypothalamus and initiates degradation and inactivation of extracellular 1-MSH. We found that PRCP is expressed in neuronal populations that send efferents to areas where 1-MSH is released from axon terminals. We confirmed that 1-MSH1-13 is a substrate of PRCP, and PRCP-degraded 1-MSH (1-MSH1-12) is not neuroactive. Inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in wild type as well as obese animals. In addition, whole body or lateral hypothalamic area-specific ablation of the PRCP gene resulted in resistance to diet-induced obesity. Taken together, these observations gave impetus to the central hypothesis of this proposal that PRCP is an important regulator of melanocortin signaling downstream of the melanocortin cells. We suggest that elevated PRCP activity promotes metabolic dysfunctions, including obesity and type 2 diabetes. To further our understanding of the role of PRCP in metabolic regulation, we propose the following specific aims: Specific Aim 1) we will study PRCP and melanocortin peptides levels in lean and obese mice. Specific Aim 2) we will study leptin and ghrelin effects on PRCP. Specific Aim 3) We will study PRCP in the development of obesity and type 2 diabetes. The execution of the above specific aims will shed light on a novel central regulatory element in the regulation of energy metabolism. Successful completion of these studies will deliver new drug targets for metabolic disorders, including obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: This proposal aims to investigate the role of a hypothalamic carboxylase in the regulation of brain circuits that control food intake and energy expenditure. Successful completion of these studies will deliver new drug targets for metabolic disorders, including obesity and type 2 diabetes.