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

基本信息

  • 批准号:
    7795183
  • 负责人:
  • 金额:
    $ 34.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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要问题。特别是中心性/内脏肥胖是代谢综合征的主要组成部分,代谢综合征是一组与心血管疾病(CVD)风险升高相关的并发症,包括胰岛素抵抗、高血压、血脂异常以及血栓前和促炎症因子增加。脂毒性,即过量脂质在非脂肪组织中的积聚,是与肥胖和代谢综合征相关的常见问题。脂质体内平衡的这种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脂毒性,包括饮食诱导的肥胖(DIO)和瘦素缺陷的Lepob/Lepob小鼠。黑皮质素系统在啮齿动物和人类的能量稳态调节中起着关键作用。黑皮质素受体MC 3-R和MC 4-R的基因缺失导致了两种不同的肥胖模型的产生。两者都显示出体脂百分比和脂肪细胞肥大的总体增加,然而,在MC 4-R缺失小鼠中,体脂百分比的这种增加伴随着高胰岛素血症、高胆固醇血症、促炎性变化和肝脏的脂毒性或肝脂肪变性,而MC 3-R缺失小鼠似乎受到保护而免受代谢综合征的这些共病。这表明黑皮质素信号传导在葡萄糖稳态、脂质稳态和炎症的调节中可能是重要的,并且MC 3-R可能代表用于治疗代谢综合征方面的良好药理学靶标。这项研究计划提出了一个多学科的方法来检查调节黑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MC 3-R特异性激动剂和拮抗剂以探测MC 3-R在代谢综合征中的作用,并且将使用MC 3-R的组织特异性敲除来探测参与由MC 3-R阻断引起的代谢综合征的表观保护的组织和机制。 黑皮质素-3受体的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观察到的胰岛素抵抗、脂肪肝和促炎性变化。本申请旨在确定MC 3-R在这种现象中的作用部位和机制,以便更好地了解病因,并最终发现代谢综合征的更好治疗方法。

项目成果

期刊论文数量(0)
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Roger D. Cone其他文献

Le système de la mélanocortine centrale et son rôle dans l'homéostase énergétique
中枢黑皮质素系统及其在体内平衡中的作用
  • DOI:
  • 发表时间:
    1999
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Roger D. Cone
  • 通讯作者:
    Roger D. Cone
A cellular basis for the munchies
“贪吃”的细胞基础
  • DOI:
    10.1038/nature14206
  • 发表时间:
    2015-02-18
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Sachin Patel;Roger D. Cone
  • 通讯作者:
    Roger D. Cone
Aqueous remote loading of setmelanotide in poly(lactic-emco/em-glycolic acid) microspheres for long-term obesity treatment
水性远程加载赛美拉肽在聚乳酸-乙醇酸共聚物微球中用于长期肥胖治疗
  • DOI:
    10.1016/j.jconrel.2023.09.015
  • 发表时间:
    2023-12-01
  • 期刊:
  • 影响因子:
    11.500
  • 作者:
    Shuying Wang;Griffin Downing;Karl F. Olsen;Tomi K. Sawyer;Roger D. Cone;Steven P. Schwendeman
  • 通讯作者:
    Steven P. Schwendeman

Roger D. Cone的其他文献

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{{ truncateString('Roger D. Cone', 18)}}的其他基金

Role of HDAC6 in the Regulation of Energy Homeostasis and Leptin Sensitivity
HDAC6 在能量稳态和瘦素敏感性调节中的作用
  • 批准号:
    10352472
  • 财政年份:
    2021
  • 资助金额:
    $ 34.41万
  • 项目类别:
Role of HDAC6 in the Regulation of Energy Homeostasis and Leptin Sensitivity
HDAC6 在能量稳态和瘦素敏感性调节中的作用
  • 批准号:
    10209006
  • 财政年份:
    2021
  • 资助金额:
    $ 34.41万
  • 项目类别:
Role of HDAC6 in the Regulation of Energy Homeostasis and Leptin Sensitivity
HDAC6 在能量稳态和瘦素敏感性调节中的作用
  • 批准号:
    10580593
  • 财政年份:
    2021
  • 资助金额:
    $ 34.41万
  • 项目类别:
Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor
Melanocortin-3 受体的性别二态性表达和功能
  • 批准号:
    10468942
  • 财政年份:
    2020
  • 资助金额:
    $ 34.41万
  • 项目类别:
Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor
Melanocortin-3 受体的性别二态性表达和功能
  • 批准号:
    10262943
  • 财政年份:
    2020
  • 资助金额:
    $ 34.41万
  • 项目类别:
Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor
Melanocortin-3 受体的性别二态性表达和功能
  • 批准号:
    10093675
  • 财政年份:
    2020
  • 资助金额:
    $ 34.41万
  • 项目类别:
ALLOSTERIC MODULATORS OF MC4R SIGNALING
MC4R 信号传导的变构调节剂
  • 批准号:
    9463221
  • 财政年份:
    2017
  • 资助金额:
    $ 34.41万
  • 项目类别:
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:
    8288270
  • 财政年份:
    2008
  • 资助金额:
    $ 34.41万
  • 项目类别:
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:
    7585249
  • 财政年份:
    2008
  • 资助金额:
    $ 34.41万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 34.41万
  • 项目类别:

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