Leptin and Peripheral Glucose Metabolism

瘦素和周围葡萄糖代谢

• 批准号: 6844871
• 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/6844871
• 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持续增加，在美国，正常体重的人现在是人口的少数。当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。有明确的证据表明，外周给药瘦素（一种脂肪组织来源的激素），在实验动物和减肥饮食的肥胖人群中，都能显著降低体脂含量。我们将验证以下假设：外周输注生理剂量的瘦素通过多种机制减少体脂，而摄入高脂肪饮食或肥胖的发展，与饮食成分无关，会抑制部分或全部这些机制，从而诱导瘦素抵抗状态，促进肥胖的发展。这里我们将瘦素抵抗定义为瘦素无法降低体脂含量。具体目的一将确定瘦素如何降低低脂喂养小鼠的体脂含量，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，还是通过神经输入间接作用于组织，或通过调节其他代谢活性激素的释放。然后，我们将通过食用不会导致肥胖的高脂肪饮食或食用会导致肥胖的高糖饮食来测试哪一种机制被灭活了。具体目的二将研究瘦素是否通过改变脂肪细胞的数量来降低体脂含量。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，以及高脂喂养或肥胖小鼠的瘦素抵抗是否是由于瘦素对脂肪细胞发育或凋亡的抑制作用。初步研究表明，长形瘦素受体缺乏的db/db小鼠比所有膜结合瘦素受体缺乏的db/db小鼠更少肥胖，这可能是由于抑制了前脂肪细胞的增殖。因此，我们将利用这两株db/db小鼠来检验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，上述研究的成功完成将证明高脂肪饮食或肥胖如何使正常调节能量平衡的生理系统失活，为开发治疗或预防肥胖的新策略提供了新的机会。