Leptin resistance: 1 mechanism underlying age-related ob

瘦素抵抗：年龄相关性肥胖的潜在机制之一

• 批准号: 6948924
• 负责人: PHILIP J SCARPACE
• 金额: $ 33.72万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948924
• 关键词: JAK kinase; age difference; biological signal transduction; dietary restriction; enzyme activity; gene environment interaction; gene expression; gene therapy; genetically modified animals; hormone receptor; hormone regulation /control mechanism; hormone sensitivity /resistance; hypothalamus; insulin receptor; laboratory rat; leptin; nutrition related tag; obesity; phosphatidylinositol 3 kinase; phosphorylation; polymerase chain reaction; receptor expression; transcription factor

Obesity is the most prevalent nutritional disorder in Western societies. More than three in ten adult Americans weigh at least 20% in excess of their ideal body weight. Increased body weight is an important public health problem because it is associated with type II diabetes, hypertension and hyperlipidemia. Moreover, adults tend to gain weight, as they get older. Our data suggests that the F-344/BN rat is a reasonable model for age-related obesity in humans. These rats demonstrate a steady increase in body fat into early senescence similar to what occurs in humans. Most obese animal models, whether associated with genetic, diet-induced or age-related obesity, display pronounced leptin resistance, rendering leptin treatment futile in treating obesity. We discovered that aged rats display central leptin resistance characterized by reduced hypothalamic leptin receptors and diminished STAT3 signaling, and that elevated central leptin due to recombinant adeno-associated virus (rAAV) leptin gene delivery induces a leptin resistance in rats of various ages. Elevated central leptin and reduced leptin receptor expression/numbers appear to be common to all models of leptin resistance. Our central hypothesis focuses on two aspects of the leptin signal cascade: (1) diminished leptin signaling associated with elevated central leptin, in particular reduced activity of the leptin-activated insulin receptor substrate (IRS)-mediated phosphatidylinositol-3-OH kinase (PI3K) pathway constitutes one component of age-related or leptin-induced leptin resistance; and (2) elevated central leptin with age contributes to diminished leptin signaling and leptin resistance independent of obesity. We will test our hypotheses by examining (1) whether the leptin activated IRS-PI3K signaling pathway is impaired with age and with leptin-induced leptin resistance; (2) whether inhibition of the IRS-PI3K component of leptin signaling facilitates the development of leptin resistance; and if elevated central leptin with age is the primary factor in impaired leptin signaling and leptin resistance independent of obesity. Understanding the nature of the leptin resistance is paramount to combating obesity, for only then can we fully exploit the potency of leptin in otherwise leptin-resistant rodents or humans. Such discoveries may lead to new treatments for obesity and the diabetes associated with obesity.

肥胖是西方社会最普遍的营养失调。超过三成的美国成年人体重至少超过理想体重的20%。体重增加是一个重要的公共卫生问题，因为它与II型糖尿病、高血压和高脂血症有关。此外，随着年龄的增长，成年人的体重往往会增加。我们的数据表明，F-344/BN大鼠是人类年龄相关性肥胖的合理模型。这些大鼠表现出体内脂肪稳步增加，进入早期衰老，类似于人类的情况。大多数肥胖动物模型，无论是与遗传、饮食诱导或年龄相关的肥胖有关，都表现出明显的瘦素抵抗，使瘦素治疗在治疗肥胖症方面无效。我们发现，老年大鼠表现出中枢性瘦素抵抗，其特征是下丘脑瘦素受体减少和STAT3信号减弱，而后者升高 重组腺相关病毒(RAAV)介导的中枢性瘦素可诱导不同年龄大鼠的瘦素抵抗。中枢瘦素升高和瘦素受体表达/数量减少似乎在所有瘦素抵抗模型中都是常见的。我们的中心假设集中在瘦素信号级联的两个方面：(1)与中枢瘦素升高相关的瘦素信号减弱，特别是瘦素激活的胰岛素受体底物(IRS)介导的磷脂酰肌醇-3-羟基激酶(PI3K)途径活性降低，构成年龄相关或瘦素诱导的瘦素抵抗的一个组成部分；以及(2) 随着年龄的增长，中枢瘦素水平升高导致瘦素信号减弱，瘦素抵抗独立于肥胖。我们将通过检测(1)瘦素激活的IRS-PI3K信号通路是否随着年龄和瘦素诱导的瘦素抵抗而受损；(2)抑制瘦素信号的IRS-PI3K成分是否促进瘦素抵抗的发展；以及中枢瘦素是否随着年龄的增加而升高是瘦素信号受损和瘦素抵抗独立于肥胖的主要因素。了解瘦素抵抗的本质对于对抗肥胖至关重要，因为只有这样，我们才能在其他瘦素抵抗的啮齿动物或人类身上充分发挥瘦素的效力。这样的发现可能会导致 为肥胖和与肥胖相关的糖尿病提供新的治疗方法。