Molecular Studies of Leptin Action

描述(申请人提供)：这项申请提出的实验将有助于我们了解肥胖和2型糖尿病的原因，并可以提高我们治疗这些疾病的能力。为此，我们建议建立激素瘦素的确切作用部位和解释其新的代谢效应的分子机制。瘦素是一种由脂肪组织产生的激素，向包括大脑在内的许多其他组织发送营养信号。瘦素在维持全身脂肪总量恒定的反馈环路中起到传入信号的作用。Ob/ob小鼠或某些人类受试者的瘦素基因突变会导致严重肥胖。在大多数情况下，肥胖是对这种激素的影响相对不敏感的结果。在瘦素敏感的动物中，这种激素发挥了许多新的代谢作用。它可以降低细胞内的脂肪水平，改善胰岛素的作用。瘦素还能够纠正在患有脂肪营养不良(脂肪组织缺失)的人类受试者中出现的严重糖尿病。这种效果至少在一定程度上是瘦素降低肝脏和其他组织中脂肪含量的结果。在最近的工作中，我们已经证明，瘦素对细胞脂质含量和体重的影响是由于它能够抑制SCD1，一种将饱和脂肪酸转化为单不饱和脂肪酸的酶。在这一应用中，我们建议通过1)利用现代遗传学方法研究选择性去除各种组织中瘦素受体的作用，2)研究抑制SCD1降低体重和细胞脂含量的机制，3)评估其他基因产物在介导瘦素生物反应中的作用，4)研究瘦素调节SCD1和其他基因的机制。后一项工作将利用生物学和计算方法。总而言之，这些研究将增加我们对调节体重和新陈代谢的分子机制的了解，并可能导致新的治疗方法。

DESCRIPTION (provided by applicant): This application proposes that experiments that will contribute to our understanding of the causes of obesity and Type 2 diabetes and could improve our ability to treat these conditions. Toward that end we propose to establish the precise sites of action of the hormone leptin and the molecular mechanisms that account for its novel metabolic effects. Leptin is a hormone that is produced by adipose tissue and sends nutritional signals to a number of other tissues including brain. Leptin functions as an afferent signal in a feedback loop that maintains constancy of the total body fat mass. A mutation in the leptin gene in ob/ob mice or some human subjects leads to severe obesity. In most cases, obesity is the result of a relative insensitivity to the effects of this hormone. In leptin sensitive animals, this hormone exerts a number of novel metabolic effects. It reduces the cellular levels of lipid and improves insulin action. Leptin is also capable of correcting the severe diabetes that develops in human subjects with lipodystrophy (the absence of fat tissue). This effect is the result at least in part, of the ability of leptin to reduce lipid content in liver and other tissues. In recent work we have shown that leptin's effects on cellular lipid content and body weight is the result of its ability to repress SCD1, an enzyme that converts saturated fatty acids to mono-unsaturated fatty acids. In this application, we propose to follow up on these results by 1) using modern methods in genetics to study the effects of selective ablation of the receptor for leptin in a variety of tissues, 2) study the mechanism by which repression of SCD1 reduces body weight and cellular lipid content 3) assessing the role of other gene products in mediating the biologic response to leptin 4) studying the mechanism by which leptin regulates SCD1 and other genes. This latter effort will make use of biologic and computational approaches. In aggregate, these studies will add to our understanding of the molecular mechanisms regulating body weight and metabolism and potentially lead to new therapeutic approaches.