Role of the MC3-R in Obesity and Metabolic Syndrome

MC3-R 在肥胖和代谢综合征中的作用

• 批准号: 8066681
• 负责人: Roger D. Cone
• 金额: $ 33.52万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066681
• 关键词: Adipocytes; Adipose tissue; Affinity; Agonist; Alleles; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Autoreceptors; Blood Vessels; Body fat; Cardiovascular Diseases; Cells; Central obesity; Comorbidity; Data; Defect; Developed Countries; Development; Diabetes Mellitus; Diet; Dyslipidemias; Etiology; Exhibits; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Generations; Genetic; Genome; Goals; Growth; Health; Homeostasis; Human; Hyperinsulinism; Hypertension; Hypertrophy; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Knock-out; Knockout Mice; Lactams; Lead; Learning; Leptin; Leptin deficiency; Link; Lipids; Lipolysis; Liver; Measures; Mediating; Metabolic syndrome; Modeling; Molecular; Mus; Neurons; Obesity; Phenotype; Physiological; Play; Regulation; Research; Research Personnel; Resistance; Rodent; Rodent Model; Role; SHU 9119; Series; Serum; Signal Transduction; Site; Specificity; Structure; Symptoms; Syndrome; System; TNF gene; Testing; Tissues; Transgenic Mice; Work; adipokines; adiponectin; animal tissue; base; blood glucose regulation; cardiovascular disorder risk; cytokine; hypercholesterolemia; melanocortin receptor; mouse model; novel; peptide structure; receptor

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.

描述（由申请人提供）：肥胖是整个工业化国家的一个重大问题。特别是中枢/内脏肥胖是代谢综合征的主要组成部分，包括胰岛素抵抗，高血压，血脂异常以及促促血栓性和促炎性因素，与心血管疾病（CVD）升高有关的促胰岛素和促促血栓性和促炎因素。脂毒性是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。脂质稳态中这种失衡与细胞功能障碍和凋亡有关。肥胖的许多啮齿动物模型都表现出脂肪毒性，包括饮食诱导的肥胖（DIO）和瘦素缺乏的麻lepob/Lepob小鼠。黑素皮质素系统在啮齿动物和人类的能量稳态调节中起着至关重要的作用。黑色素性受体MC3-R和MC4-R的遗传缺失导致了两个不同的肥胖模型。两者均显示体内脂肪百分比和脂肪细胞肥大的总体增加，但是，在MC4-R NULL小鼠中，体内脂肪百分比的增加伴随着高胰岛素血症，高胆固醇血症，促炎性变化，促炎的变化以及肝脏的脂肪毒性，肝脏或肝Steatosis，而MC3-R-R-R-ROLICAL却在这些null中受到了这些调解的效果。这表明黑色素性信号传导对于调节葡萄糖稳态，脂质稳态和炎症可能很重要，并且MC3-R可能代表了治疗代谢综合征方面的良好药理靶标。该研究计划提出了一种多学科的方法，以检查调节黑色皮质素信号传导对高胰岛素血症，高胆固醇血症，脂肪增生和炎症的影响。将开发MC3-R特异性激动剂和拮抗剂，以探测MC3-R在代谢综合征中的作用，而MC3-R的组织特异性敲除将用于探测来自MC3-R阻滞引起的明显保护侵害代谢综合征的组织和机制。 Melaocortin-3受体的公共卫生相关性缺失会导致一种新型的肥胖综合征，缺乏胰岛素抵抗，脂肪肝和促炎性变化，在其他肥胖的鼠模型中都可以看到。该应用程序旨在确定MC3-R在这种现象中的作用位点和机制，以更好地理解病因，并最终发现更好的代谢综合征治疗方法。