IMPAIRED LEPTIN RESPONSIVENESS WITH AGE

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比理想体重至少高出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大鼠是一个合理的人类衰老肥胖模型。这些大鼠的身体脂肪稳步增加，进入早期衰老，这与人类的情况相似。瘦素是ob基因的产物，是一种传入信号分子，由白色脂肪组织合成，与大脑中的食欲和饱腹感中心相互作用，帮助调节体重。人类肥胖，包括迟发性肥胖，通常与循环瘦素水平升高有关，这表明这种肥胖不是由瘦素水平不足引起的，这些肥胖的人对瘦素有抵抗性。我们的数据表明，像肥胖的人一样，年老的老鼠对瘦素有抵抗力。本研究将探讨F- 344/BN大鼠瘦素抵抗的细胞和分子机制，以及通过降低血清瘦素逆转瘦素抵抗的潜力。具体来说，这项资助旨在解决四个问题：1)老年大鼠对中央给药瘦素的反应是否受损？2)老龄大鼠下丘脑瘦素受体密度和/或瘦素受体信号转导是否受损？3)瘦素基因表达的调节是否随着年龄的增长而受损？4)减少饲粮或在饮食中补充维生素A是否能降低老年大鼠的血清瘦素并部分逆转瘦素抵抗？瘦素基因表达、摄食行为和肥胖通过正负反馈循环相互关联。如果这些反馈循环随着年龄的增长而维持，那么血浆瘦素水平、瘦素基因表达和肥胖水平应该保持不变。我们预测肥胖会随着年龄的增长而增加，部分原因是对瘦素的反应会随着年龄的增长而下降。我们的数据表明，瘦素减少食物摄入，增加氧气消耗，降低下丘脑NPY基因表达，而在老年大鼠中，这些反应减弱或不存在。此外，随着肥胖和年龄的增长，血清瘦素水平升高可能是有害的，可能会导致肥胖引起的糖尿病。我们的数据表明，饮食中补充维生素A降低了年轻瘦鼠的血清瘦素。补充维生素A逆转与年龄相关的血清瘦素增加和恢复瘦素反应的潜力在本建议中得到了解决。

Obesity is the most prevalent nutritional disorder in Western societies. More than three in ten adult Americans weigh at least 20 percent 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 obesity model for human aging. These rats demonstrate a steady increase in body fat into early senescence similar to what occurs in humans. Leptin, the product of the ob gene, is an afferent signal molecule, synthesized by white adipose tissue, that interacts with the appetite and satiety centers in the brain to help regulate body weight. Obesity in humans, including late-onset obesity is usually associated with increased levels of circulating leptin, suggesting that this obesity is not caused by inadequate levels of leptin and that these obese humans are leptin resistant. Our data suggest that aged rats like obese humans are leptin resistant. This proposal will examine the cellular and molecular mechanisms of leptin resistance in the F- 344/BN rat model and the potential of reversing the leptin resistance by lowering serum leptin. Specifically, this grant seeks to address four questions: 1) Is there impaired responsiveness to centrally administered leptin in aged rats? 2) Is leptin receptor density and/or leptin receptor signal transduction impaired in the hypothalamus of aged rats? 3) Is the regulation of leptin gene expression impaired with age? 4) Can reduced feeding or dietary vitamin A supplementation decrease serum leptin and partially reverse the leptin resistance in aged rats? Leptin gene expression, feeding behavior and adiposity are interrelated through positive and negative feedback loops. If these feedback loops are maintained with age, then plasma leptin levels, the gene expression of leptin, and adiposity levels should remain constant. We predict that adiposity increases with age, in part, because the responsiveness to leptin declines with age. Our data indicate that leptin decreases food intake, increases oxygen consumption, and decreases NPY gene expression in the hypothalamus, whereas in older rats, these responses are blunted or absent. Moreover, the elevated serum leptin levels with obesity and with age may be harmful and may be contributing to the diabetes caused by obesity. Our data indicate that dietary vitamin A supplementation lowers serum leptin in young lean rats. The potential for vitamin A supplementation to reverse the age-related increase in serum leptin and restore leptin responsiveness is addressed in this proposal.