Leptin resistance: 1 mechanism underlying age-related ob

肥胖是西方社会最普遍的营养失调。超过十分之三的美国成年人体重超过理想体重至少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的稳定增加，进入早期衰老，类似于人类中发生的情况。大多数肥胖动物模型，无论是与遗传、饮食诱导还是年龄相关的肥胖相关，都显示出明显的瘦素抵抗，使得瘦素治疗在治疗肥胖中无效。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STAT 3信号减弱， 由于重组腺相关病毒（rAAV）瘦素基因递送引起的中枢瘦素在不同年龄的大鼠中诱导瘦素抗性。升高的中枢瘦素和降低的瘦素受体表达/数量似乎是所有瘦素抵抗模型所共有的。我们的中心假设集中在瘦素信号级联的两个方面：（1）与升高的中枢瘦素相关的瘦素信号传导减少，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-OH激酶（PI 3 K）途径的活性降低，构成年龄相关的或瘦素诱导的瘦素抵抗的一个组分;和（2） 随着年龄的增加，中枢瘦素的升高导致瘦素信号传导和瘦素抵抗的减少，而与肥胖无关。我们将检验我们的假设：（1）瘦素激活的IRS-PI 3 K信号通路是否随着年龄的增长和瘦素诱导的瘦素抵抗而受损;（2）瘦素信号的IRS-PI 3 K组分的抑制是否促进瘦素抵抗的发展;以及随着年龄的增长，中枢瘦素的升高是否是瘦素信号受损和瘦素抵抗的主要因素，而与肥胖无关。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充分利用瘦素在其他瘦素抵抗的啮齿动物或人类中的效力。这些发现可能会导致 肥胖症和与肥胖相关的糖尿病的新疗法。

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.