Role of the MC3-R in Obesity and Metabolic Syndrome

描述（由申请人提供）：肥胖是整个工业化国家的一个重要问题。特别是中心性/内脏性肥胖是代谢综合征的主要组成部分，代谢综合征是一组合并症，包括胰岛素抵抗、高血压、血脂异常、血栓形成前因子和促炎因子增加，与心血管疾病（CVD）的风险升高有关。脂肪毒性是指非脂肪组织中过量脂质的积累，是与肥胖和代谢综合征相关的常见问题。脂质平衡失衡与细胞功能障碍和细胞凋亡有关。许多肥胖啮齿类动物模型显示脂肪毒性，包括饮食性肥胖（DIO）和瘦素缺陷Lepob/Lepob小鼠。黑素皮质素系统在调节啮齿动物和人类的能量稳态中起着关键作用。黑素皮质素受体MC3-R和MC4-R的基因缺失导致了两种不同的肥胖模式的产生。然而，在MC4-R缺失的小鼠中，这种体脂百分比的增加伴随着高胰岛素血症、高胆固醇血症、促炎改变和肝脏脂毒性或肝脂肪变性，而MC3-R缺失的小鼠似乎没有这些代谢综合征的合并症。这表明黑素皮质素信号传导可能在调节葡萄糖稳态、脂质稳态和炎症中起重要作用，MC3-R可能是治疗代谢综合征的一个很好的药理靶点。本研究计划提出一种多学科的方法来研究调节黑素皮质素信号在高胰岛素血症、高胆固醇血症、脂肪变性和炎症中的作用。MC3-R特异性激动剂和拮抗剂将被开发，以探索MC3-R在代谢综合征中的作用，而MC3-R的组织特异性敲除将被用于探索参与MC3-R阻断导致的代谢综合征的明显保护的组织和机制。褪黑皮质素-3受体的缺失导致一种新型肥胖综合征，缺乏胰岛素抵抗、脂肪肝和在其他肥胖小鼠模型中看到的促炎变化。本应用旨在确定MC3-R在这一现象中的作用位点和作用机制，从而更好地了解代谢综合征的病因，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.