Leptin and Peripheral Glucose Metabolism

描述(申请人提供)：超重和肥胖的发生率持续增加，在美国，正常体重的人现在是人口的少数。目前肥胖的流行似乎是由于环境因素使调节能量平衡的机制失活所致。有明确的证据表明，外周服用瘦素，一种脂肪组织衍生激素，在实验动物和减肥饮食中的肥胖者中都能特别减少体内脂肪含量。我们将测试这样一种假设，即外周输注生理剂量的瘦素可以通过各种机制减少体内脂肪，并且高脂肪饮食的摄入或肥胖的发展独立于饮食组成，抑制部分或全部这些机制，以诱导瘦素抵抗状态促进肥胖的进展。在这里，我们将瘦素抵抗定义为瘦素未能减少体内脂肪含量。具体目标一将确定瘦素如何降低低脂喂养小鼠的体脂含量，测量脂肪合成和分解的速度，以及参与脂肪细胞脂肪代谢的酶的水平。我们将测试瘦素是直接作用于脂肪细胞的新陈代谢，还是通过对组织的神经输入或通过改变其他代谢活性激素的释放来间接作用。然后，我们将测试这些机制中的哪一种是通过食用不会导致肥胖的高脂肪饮食或通过食用确实会导致肥胖的高蔗糖饮食来灭活的。具体目标二将研究瘦素是否通过改变脂肪细胞的数量来减少体内脂肪含量。体内和体外研究将测试外周输注瘦素对脂肪细胞增殖、分化和凋亡的影响，以及高脂饮食或肥胖小鼠的瘦素抵抗是否是由于瘦素抑制脂肪细胞的发育或凋亡。初步研究表明，缺乏长型瘦素受体的db/db小鼠比缺乏所有膜结合的瘦素受体的db/db小鼠的肥胖程度要轻，这可能是由于抑制了前脂肪细胞的增殖。因此，我们将使用这两个品系的db/db小鼠来测试短型瘦素受体在调节脂肪细胞发育和凋亡中的重要性。因此，拟议研究的成功完成将证明高脂饮食或肥胖如何使正常调节能量平衡的生理系统之一失活，为开发治疗或预防肥胖症的新策略提供新的机会。

DESCRIPTION (provided by applicant): Incidence of overweight and obesity continues to increase and, in the US, normal weight individuals are now a minority of the population. The current epidemic of obesity appears to result from environmental factors inactivating mechanisms that regulate energy balance. There is unequivocal evidence that peripheral administration of leptin, an adipose tissue-derived hormone, specifically reduces body fat content in both experimental animals and obese humans on a weight reducing diet. We will test the hypothesis that peripheral infusions of physiological doses of leptin reduce body fat through a variety of mechanisms and that consumption of a high-fat diet or development of obesity, independent of diet composition, inhibits some, or all of these mechanisms to induce a state of leptin resistance facilitating the progression of obesity. Here we define leptin resistance as a failure of leptin to reduce body fat content. Specific Aim One will determine how leptin reduces body fat content in low-fat fed mice, measuring rates of lipid synthesis and breakdown, and the levels of enzymes involved in adipocyte lipid metabolism. We will test whether leptin acts directly on adipocyte metabolism, or indirectly through neural input to the tissue or by modifying the release of other metabolically active hormones. We will then test which of these mechanisms is inactivated either by consumption of a high-fat diet that does not induce obesity or by consumption of a high-sucrose diet that does induce obesity. Specific Aim Two will investigate whether leptin reduces body fat content by changing the number of adipocytes present. In vivo and in vitro studies will test the effect of peripheral infusions of leptin on adipocyte proliferation, differentiation and apoptosis and whether leptin resistance in high-fat fed or obese mice is due to an inhibition of leptin action on adipocyte development or apoptosis. Preliminary studies show that db/db mice that are deficient in the long-form leptin receptor are less obese than db/db mice that are deficient in all membrane-bound leptin receptors, possibly due to inhibition of preadipocyte proliferation. Therefore, we will use these two strains of db/db mice to test the importance of short-form leptin receptors in the regulation of adipocyte development and apoptosis. Thus, successful completion of the proposed studies will demonstrate how high-fat diets or obesity inactivate one of the physiological systems that normally regulate energy balance, providing new opportunities for development of new strategies for the treatment, or prevention, of obesity.