Zhang B, Graziano M P, Doebber T W, Leibowitz M D, White-Carrington S, Szalkowski D M, Hey P J, Wu M, Cullinan C A, Bailey P, Lollmann B, Frederich R, Flier J S, Strader C D, Smith R G
Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
J Biol Chem. 1996 Apr 19;271(16):9455-9. doi: 10.1074/jbc.271.16.9455.
Obese (ob) is a recently identified gene involved in the regulation of energy balance in the mouse. We report here that AD-5075, a potent thiazolidinedione which lowered plasma glucose and triglyceride in Zucker diabetic fatty (ZDF) rats and db/db mice, decreased the expression of the ob gene in these animal models of obesity and non-insulin-dependent diabetes mellitus. The level of adipose ob mRNA in ZDF rats was 3-fold greater than that detected in the Zucker lean littermates. Chronic treatment with AD-5075 elicited a 67 and 70% reduction of ob mRNA in ZDF and control lean rats, respectively. Furthermore, the amount of adipose ob mRNA in db/db mice was 7 times higher than that detected in lean littermates. Treatment of db/db mice with AD-5075 resulted in a 78% reduction of the level of ob mRNA with parallel changes in circulating level of the ob gene product, leptin. The reduction of the ob mRNA in the Zucker lean rats was accompanied by significantly greater food intake and weight gain. However, in ZDF rats and db/db mice, there was profound increase in body weight without hyperphagia. The results demonstrate that the expression of the ob gene is up-regulated in these two rodent models of diabetes compared to their lean counterparts and that such overexpression is attenuated by treatment with an agent that improves insulin sensitivity and glucose homeostasis in vivo.
肥胖（ob）基因是最近在小鼠中发现的参与能量平衡调节的基因。我们在此报告，AD - 5075是一种强效噻唑烷二酮类药物，可降低Zucker糖尿病脂肪（ZDF）大鼠和db/db小鼠的血糖和甘油三酯水平，在这些肥胖和非胰岛素依赖型糖尿病动物模型中，它能降低ob基因的表达。ZDF大鼠脂肪组织中ob mRNA水平比其瘦的同窝对照大鼠高3倍。用AD - 5075长期治疗后，ZDF大鼠和对照瘦大鼠的ob mRNA水平分别降低了67%和70%。此外，db/db小鼠脂肪组织中ob mRNA的量比其瘦的同窝对照小鼠高7倍。用AD - 5075治疗db/db小鼠后，ob mRNA水平降低了78%，同时ob基因产物瘦素的循环水平也发生了相应变化。Zucker瘦大鼠中ob mRNA的减少伴随着食物摄入量和体重的显著增加。然而，在ZDF大鼠和db/db小鼠中，体重显著增加但没有食欲亢进。结果表明，与它们的瘦同窝对照相比，这两种啮齿类糖尿病模型中ob基因的表达上调，并且用一种能在体内改善胰岛素敏感性和葡萄糖稳态的药物治疗可减弱这种过表达。
