Shimabukuro M, Koyama K, Chen G, Wang M Y, Trieu F, Lee Y, Newgard C B, Unger R H
Gifford Laboratories for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA.
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4637-41. doi: 10.1073/pnas.94.9.4637.
Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was approximately 20 times normal, and esterification capacity was increased 3- to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an "indirect pathway" of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes.
目前认为，瘦素主要（如果不是完全）通过调节食物摄入和产热的下丘脑受体来控制身体组成。在此，我们证明了瘦素具有直接的神经外作用，可将脂肪细胞和非脂肪细胞的脂肪含量降低至远低于配对喂养对照组的水平。在培养的胰岛中，瘦素通过阻止游离脂肪酸（FFA）形成甘油三酯（TG）以及增加FFA氧化来降低TG含量。在正常大鼠中，通过腺病毒基因转移诱导体内高瘦素血症，可降低肝脏、骨骼肌和胰腺中的TG含量，而不会增加血浆FFA或酮体，提示细胞内氧化。在患有瘦素受体突变的肥胖Zucker糖尿病脂肪大鼠的胰岛中，瘦素在体内和体外均无作用。TG含量约为正常水平的20倍，酯化能力增加了3至4倍。因此，在具有正常瘦素受体的大鼠中，而非在Zucker糖尿病脂肪大鼠中，非脂肪细胞和脂肪细胞将FFA酯化，将其储存为TG，随后通过瘦素控制的细胞内脂肪酸代谢的“间接途径”在细胞内将其氧化。通过维持胰岛素敏感性并防止胰岛脂毒性，瘦素的这种活性可能预防脂肪生成性糖尿病。
