Leptin and Peripheral Glucose Metabolism

瘦素和周围葡萄糖代谢

• 批准号: 6722682
• 负责人: Ruth B Harris
• 金额: $ 25.91万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722682
• 关键词: adipocytes; adipose tissue; apoptosis; bioenergetics; body composition; cell proliferation; dietary carbohydrates; dietary lipid; glucose metabolism; hormone receptor; hormone sensitivity /resistance; laboratory mouse; leptin; lipid metabolism; nutrition related tag; obesity; pathogenic diet; protein isoforms; sucrose

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.

描述（由申请人提供）：超重和肥胖的发生率继续增加，在美国，正常体重现在是人口的少数人。当前肥胖的流行似乎是由于环境因素灭活能量平衡的机制而引起的。有明确的证据表明，脂肪组织衍生的激素的瘦素外周给药可降低实验动物和肥胖人的体内脂肪含量，以减少体重减少饮食。我们将检验以下假设：瘦素生理剂量的外周输注通过多种机制降低体内脂肪，并消耗高脂饮食或肥胖的发展，独立于饮食组成，抑制某些或所有这些机制，以诱导瘦素抗性的状态，从而促进效率促进肥胖的进展。在这里，我们将瘦素的耐药性定义为瘦素降低体内脂肪含量的失败。特定的目标将确定瘦素如何减少低脂喂养小鼠的体内脂肪含量，测量脂质合成和分解的速率以及参与脂肪细胞脂质代谢的酶的水平。我们将测试瘦素是直接作用于脂肪细胞代谢上的，还是通过对组织的神经输入或通过修饰其他代谢活性激素的释放来间接作用。然后，我们将通过消耗不会诱导肥胖的高脂饮食或消耗诱导肥胖症的高核饮食来测试这些机制中的哪些机制。具体目标两个将通过改变存在的脂肪细胞数量来研究瘦素是否会减少体内脂肪含量。体内和体外研究将测试瘦素外周输注对脂肪细胞增殖，分化和凋亡的影响，以及高脂喂养或肥胖小鼠中瘦素的耐药性是否是由于瘦素作用对脂肪细胞发育或凋亡的抑制作用。初步研究表明，长长形式的瘦素受体缺乏的DB/DB小鼠比所有膜结合的瘦素受体缺乏的DB/DB小鼠肥胖，可能是由于抑制前脂肪细胞增殖所致。因此，我们将使用这两种DB/DB小鼠菌株来测试短形式瘦素受体在脂肪细胞发育和凋亡调节中的重要性。因此，成功完成拟议的研究将证明高脂饮食或肥胖是如何使通常调节能量平衡的生理系统之一，从而为制定肥胖的新策略提供了新的机会。