Koyama K, Shimabukuro M, Chen G, Wang M Y, Lee Y, Kalra P S, Dube M G, Kalra S P, Newgard C B, Unger R H
Gifford Laboratories for Diabetes Research, Departments of Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
J Clin Invest. 1998 Aug 15;102(4):728-33. doi: 10.1172/JCI3353.
Leptin regulates appetite and body weight via hypothalamic targets, but it can act directly on cultured pancreatic islets to regulate their fat metabolism. To obtain in vivo evidence that leptin may act peripherally as well as centrally, we compared the effect of adenovirally induced hyperleptinemia on food intake, body weight, and islet fat content in ventromedial hypothalamic-lesioned (VMHL) rats, sham-lesioned (SL) controls, and Zucker Diabetic Fatty (ZDF) rats in which the leptin receptor is mutated. Infusion with recombinant adenovirus containing the rat leptin cDNA increased plasma leptin by approximately 20 ng/ml in VMHL and ZDF rats but had no effect on their food intake, body weight, or fat tissue weight. Caloric matching of hyperphagic VMHL rats to SL controls did not reduce their resistance to hyperleptinemia. Whereas prediabetic ZDF rats had a fourfold elevation in islet fat, in VMHL rats islet fat was normal and none of them became diabetic. Isolated islets from ZDF rats were completely resistant to the lipopenic action of leptin, while VMHL islets exhibited 50% of the normal response; caloric matching of VMHL rats to SL controls increased leptin responsiveness of their islets to 92% of controls. We conclude that leptin regulation of adipocyte fat requires an intact VMH but that islet fat content is regulated independently of the VMH.
瘦素通过下丘脑靶点调节食欲和体重，但它也可直接作用于培养的胰岛来调节其脂肪代谢。为了获得瘦素可能在中枢和外周均发挥作用的体内证据，我们比较了腺病毒诱导的高瘦素血症对腹内侧下丘脑损伤（VMHL）大鼠、假手术（SL）对照大鼠以及瘦素受体发生突变的Zucker糖尿病肥胖（ZDF）大鼠的食物摄入量、体重和胰岛脂肪含量的影响。向VMHL和ZDF大鼠输注含大鼠瘦素cDNA的重组腺病毒可使血浆瘦素增加约20 ng/ml，但对它们的食物摄入量、体重或脂肪组织重量没有影响。将食欲亢进的VMHL大鼠与SL对照大鼠进行热量匹配并不能降低它们对高瘦素血症的抵抗性。尽管糖尿病前期的ZDF大鼠胰岛脂肪增加了四倍，但VMHL大鼠的胰岛脂肪正常，且它们均未患糖尿病。从ZDF大鼠分离的胰岛对瘦素的脂肪减少作用完全抵抗，而VMHL大鼠的胰岛表现出正常反应的50%；将VMHL大鼠与SL对照大鼠进行热量匹配可使它们的胰岛对瘦素的反应性提高到对照的92%。我们得出结论，瘦素对脂肪细胞脂肪的调节需要完整的腹内侧核，但胰岛脂肪含量的调节独立于腹内侧核。
