Role of the MC3-R in Obesity and Metabolic Syndrome

描述(申请人提供)：肥胖是整个工业化国家的一个严重问题。特别是，中心性/内脏肥胖是代谢综合征的主要组成部分，代谢综合征是一组心血管疾病，包括胰岛素抵抗、高血压、血脂异常以及血栓前和炎症因子增加，与心血管疾病(CVD)的风险增加相关。脂肪毒性，即多余的脂肪在非脂肪组织中堆积，是与肥胖和代谢综合征相关的常见问题。这种脂质稳态的失衡与细胞功能障碍和细胞凋亡有关。许多肥胖的啮齿动物模型显示出脂毒性，包括饮食诱导肥胖(DIO)和瘦素缺乏的LEPOB/LEPOB小鼠。黑素皮质素系统在调节啮齿动物和人类的能量平衡方面起着关键作用。黑素皮质素受体MC3-R和MC4-R的基因缺失导致了两种截然不同的肥胖模型的产生。两者都显示体脂百分比和脂肪细胞肥大的总体增加，然而，在MC4-R缺失的小鼠中，体脂百分比的增加伴随着高胰岛素血症、高胆固醇血症、促炎变化和肝脏的脂肪毒性，或肝脏脂肪变性，而MC3-R缺失似乎保护了这些代谢综合征的共病。这表明黑素皮质素信号可能在调节糖稳态、脂稳态和炎症中起重要作用，并且MC3-R可能是治疗代谢综合征的一个良好的药理靶点。这项研究计划提出了一种多学科的方法来检查调节黑素皮质素信号对高胰岛素血症、高胆固醇血症、脂肪变性和炎症的影响。将开发MC3-R特异性激动剂和拮抗剂来探讨MC3-R在代谢综合征中的作用，并将利用组织特异性MC3-R基因敲除来探索MC3-R阻断导致的代谢综合征的明显保护作用所涉及的组织和机制。与公共健康相关的Melaoctin-3受体缺失导致一种新的肥胖综合征，缺乏在其他肥胖小鼠模型中看到的胰岛素抵抗、脂肪肝和促炎变化。本应用旨在确定MC3-R在这一现象中的作用部位和作用机制，以便更好地了解其病因，并最终发现更好的代谢综合征治疗方法。

DESCRIPTION (provided by applicant): Obesity is a significant problem throughout industrialized nations. In particular central/visceral obesity is a major constituent of the metabolic syndrome, a group of cormorbidities including insulin resistance, hypertension, dyslipidemia, and increased prothrombotic and proinflammatory factors, associated with an elevated risk of cardiovascular disease (CVD). Lipotoxicity, the accumulation of excess lipid in non- adipose tissue, is a common problem associated with obesity and the metabolic syndrome. This imbalance in lipid homeostasis is linked to cell dysfunction and apoptosis. A number of rodent models of obesity show lipotoxicity including diet-induced obese (DIO) and leptin deficient Lepob/Lepob mice. The melanocortin system plays a critical role in the regulation of energy homeostasis in rodents and humans. Genetic deletion of the melanocortin receptors MC3-R and MC4-R led to the generation of two distinct models of obesity. Both show an overall increase in percentage body fat, and adipocyte hypertrophy however, in the MC4-R null mouse this increase in percentage body fat is accompanied by hyperinsulinemia, hypercholesterolemia, proinflammatory changes, and lipotoxicity of the liver, or hepatic steatosis, while the MC3-R null appears to be protected from these comorbidities of metabolic syndrome. This suggests that melanocortin signaling may be important in the regulation of glucose homeostasis, lipid homeostasis, and inflammation, and that the MC3-R may represent a good pharmacological target for the treatment of aspects of metabolic syndrome. This research plan proposes a multi-disciplinary approach to examine the effect of modulating melanocortin signaling on hyperinsulinemia, hypercholoesterolemia, steatosis, and inflammation. MC3-R specific agonists and antagonists will be developed to probe the role of the MC3-R in metabolic syndrome, and tissue specific knockouts of the MC3-R will be used to probe the tissues and mechanisms involved in the apparent protection from metabolic syndrome that results from MC3-R blockade. PUBLIC HEALTH RELEVANCE Deletion of the melaocortin-3 receptor causes a novel obesity syndrome lacking the insulin resistance, fatty liver, and pro-inflammatory changes seen in other murine models of obesity. This application seeks to identify the sites and mechanisms of action of the MC3-R in this phenomenon, so as to better understand the etiology, and eventually discover better treatments for metabolic syndrome.