Molecular Mechanisms Mediating Resistance to Leptin Signaling During Fat Gain

脂肪增加期间调节瘦素信号传导抵抗的分子机制

• 批准号: 7693763
• 负责人: Virend K Somers
• 金额: $ 18.89万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693763
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Arts; Biochemical; Biochemistry; Blood Vessels; Body Weight Changes; Body Weight decreased; Body fat; Cardiovascular Diseases; Caveolae; Child; Development; Diet; Eating; Endothelium; Energy Metabolism; Equilibrium; Failure; Fatty acid glycerol esters; Feedback; Histology; Human; In Vitro; Lead; Leptin; Leptin resistance; Lipids; Mediating; Membrane Microdomains; Modeling; Molecular; Molecular Biology; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peripheral; Phase; Play; Prevalence; Proteins; Protocols documentation; Resistance; Risk; Risk Factors; Role; Satiation; Series; Serum; Signal Transduction; Staging; Testing; Therapeutic Intervention; United States; Vasodilation; Weight Gain; attenuation; caveolin 1; frontier; human NOS3 protein; human subject; interest; leptin receptor; novel; prevent; protein expression; public health relevance; response; therapeutic development

DESCRIPTION (provided by applicant): Obesity is associated with increased risk for the development of type 2 diabetes mellitus and cardiovascular disorders. New frontiers in therapeutic intervention against obesity lie in the recognition of novel mechanisms involved during the initial stages of weight gain in humans. There has been increasing interest in the role leptin, a peripheral circulating satiety factor, which plays a key role in balancing energy expenditure and preventing fat gain. However, leptin is found at higher levels in obese humans than in non-obese humans. The failure of elevated leptin to elicit weight loss in common forms of human obesity suggests the attenuation of leptin action (leptin resistance). To this end, we propose a novel hypothesis that resistance to leptin signaling is a result of molecular and structural changes in caveolar membrane microdomains. To test our hypothesis we propose a series of studies directed at investigating the molecular mechanisms involved in disruption of leptin signaling during weight gain, using abdominal adipose tissue obtained from healthy human subjects who gain body fat in response to an overfeeding protocol. We also propose to investigate the reversibility of these changes during fat loss. In our preliminary studies we have observed first, increases in circulating leptin levels during weight gain accompanied by decreased endothelium mediated vasodilation and increased adipocyte fat accumulation. Second, increases in caveolin-1 and endothelial nitric oxide synthase (eNOS) expression during weight gain and reversal of these changes during weight loss. Third, increases in leptin-dependent caveolin-1 expression in vitro. Fourth, the ability of caveolin-1 to inhibit leptin signaling in-vitro. These observations point to a probable role of caveolin-1 and caveolar microdomains in disruption of leptin signaling as a feedback mechanism in response to high leptin levels. In this proposal we will combine histological and molecular biologic approaches to study the morphological and compositional changes in caveolar membrane microdomains associated with weight gain and weight loss (AIM#1), and the role of caveolin-1 during weight gain and weight loss in adipocytes and adipose tissue microvasculature (AIM#2). We hypothesize that during weight gain, increased circulating leptin leads to increased caveolin-1 expression in adipose tissue, which in turn leads to increased caveolin-1 and Ob-R interaction in the caveolar microdomains. This increased interaction may result in disruption of downstream Ob-R signaling which would then lead to leptin resistance. Attenuation of leptin signaling will result in increased lipid accumulation and decreased eNOS activity. The uniqueness and translational strength of this proposal lies in studying at the molecular level dynamic weight changes in human subjects, and in our ability to differentially study them in adipocytes and adipose tissue microvessels along with in-vitro studies. The long term significance of the proposal will be in understanding the mechanisms involved in attenuation of leptin signaling during weight gain in human subjects and its reversibility during weight loss. This understanding would be pivotal in development of therapeutics related to leptin resistance and obesity. PUBLIC HEALTH RELEVANCE: The proposed studies will have clear and important implications regarding the molecular mechanisms involved in attenuation of leptin signaling during weight gain and its reversibility during weight loss. In addition the results of our proposed studies may be critical in development of therapeutics relating to leptin resistance and obesity.

描述（由申请人提供）：肥胖与罹患 2 型糖尿病和心血管疾病的风险增加相关。肥胖治疗干预的新前沿在于认识到人类体重增加初始阶段涉及的新机制。人们对瘦素的作用越来越感兴趣，瘦素是一种外周循环饱腹感因子，在平衡能量消耗和防止脂肪增加方面发挥着关键作用。然而，肥胖人群中瘦素的含量高于非肥胖人群。在常见的人类肥胖形式中，升高的瘦素未能引起体重减轻，这表明瘦素作用减弱（瘦素抵抗）。为此，我们提出了一个新的假设，即对瘦素信号传导的抵抗是小凹膜微区分子和结构变化的结果。为了检验我们的假设，我们提出了一系列研究，旨在调查体重增加期间瘦素信号中断所涉及的分子机制，使用从因过度喂养方案而增加身体脂肪的健康人类受试者中获得的腹部脂肪组织。我们还建议研究减脂过程中这些变化的可逆性。在我们的初步研究中，我们首先观察到，体重增加期间循环瘦素水平增加，伴随着内皮介导的血管舒张减少和脂肪细胞脂肪积累增加。其次，体重增加期间 Caveolin-1 和内皮一氧化氮合酶 (eNOS) 表达增加，而体重减轻期间这些变化则逆转。第三，体外瘦素依赖性caveolin-1表达增加。第四，caveolin-1 体外抑制瘦素信号传导的能力。这些观察结果表明，caveolin-1 和 Caveolar 微结构域可能在瘦素信号传导破坏中发挥作用，作为响应高瘦素水平的反馈机制。在本提案中，我们将结合组织学和分子生物学方法来研究与体重增加和体重减轻相关的小凹膜微区的形态和成分变化（AIM#1），以及caveolin-1在脂肪细胞和脂肪组织微血管系统体重增加和体重减轻过程中的作用（AIM#2）。我们假设，在体重增加期间，循环瘦素增加导致脂肪组织中的 Caveolin-1 表达增加，进而导致小凹微区中的 Caveolin-1 和 Ob-R 相互作用增加。这种相互作用的增加可能会导致下游 Ob-R 信号传导的破坏，从而导致瘦素抵抗。瘦素信号减弱将导致脂质积累增加和 eNOS 活性降低。该提案的独特性和转化优势在于在分子水平上研究人类受试者的动态体重变化，以及我们在脂肪细胞和脂肪组织微血管中以及体外研究中对其进行差异化研究的能力。该提案的长期意义在于了解人类受试者体重增加期间瘦素信号减弱所涉及的机制及其在减肥期间的可逆性。这种理解对于开发与瘦素抵抗和肥胖相关的疗法至关重要。 公共健康相关性：拟议的研究将对体重增加期间瘦素信号减弱及其在体重减轻期间可逆性的分子机制产生明确而重要的影响。此外，我们提出的研究结果可能对于瘦素抵抗和肥胖相关疗法的开发至关重要。