Jiang Guoqiang, Dallas-Yang Qing, Li Zhihua, Szalkowski Deborah, Liu Franklin, Shen Xiaolan, Wu Margaret, Zhou Gaochao, Doebber Thomas, Berger Joel, Moller David E, Zhang Bei B
Department of Molecular Endocrinology-Diabetes, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Diabetes. 2002 Aug;51(8):2412-9. doi: 10.2337/diabetes.51.8.2412.
Thiazolidinediones (TZDs), agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma), improve insulin sensitivity in vivo, and the mechanism remains largely unknown. In this study, we showed that, in Zucker obese (fa/fa) rats, acute (1-day) treatment with both rosiglitazone (a TZD) and a non-TZD PPARgamma agonist (nTZD) reduced plasma free fatty acid and insulin levels and, concomitantly, potentiated insulin-stimulated Akt phosphorylation at threonine 308 (Akt-pT308) in adipose and muscle tissues. A similar effect on Akt was observed in liver after a 7-day treatment. The increase in Akt-pT308 was correlated with an increase in Akt phosphorylation at serine 473 (Akt-pS473), tyrosine phosphorylation of insulin receptor beta subunit and insulin receptor substrate-1, and serine phosphorylation of glycogen synthase kinase-3alpha/beta. The agonists appeared to potentiate Akt1 phosphorylation in muscle and liver and both Akt1 and Akt2 in adipose. Finally, potentiation of insulin signaling was also observed in isolated adipose tissue ex vivo and differentiated 3T3 L1 adipocytes in vitro, but not in rat primary hepatocytes in vitro. These results suggest that 1) PPARgamma agonists acutely potentiate insulin signaling in adipose and muscle tissues and such regulation may be physiologically relevant to insulin sensitization in vivo; 2) the agonists directly target adipose tissues; and 3) the metabolic and signaling effects of the agonists are mediated by structurally distinct PPARgamma agonists.
噻唑烷二酮类药物（TZDs）是过氧化物酶体增殖物激活受体γ（PPARγ）的激动剂，可在体内改善胰岛素敏感性，但其机制仍 largely 未知。在本研究中，我们表明，在 Zucker 肥胖（fa/fa）大鼠中，用罗格列酮（一种 TZD）和非 TZD 的 PPARγ激动剂（nTZD）进行急性（1 天）治疗可降低血浆游离脂肪酸和胰岛素水平，并同时增强脂肪和肌肉组织中胰岛素刺激的苏氨酸 308 位点的 Akt 磷酸化（Akt-pT308）。7 天治疗后在肝脏中观察到对 Akt 有类似作用。Akt-pT308 的增加与丝氨酸 473 位点的 Akt 磷酸化（Akt-pS473）、胰岛素受体β亚基的酪氨酸磷酸化以及胰岛素受体底物-1 的酪氨酸磷酸化以及糖原合酶激酶-3α/β的丝氨酸磷酸化增加相关。这些激动剂似乎增强了肌肉和肝脏中 Akt1 的磷酸化以及脂肪中 Akt1 和 Akt2 的磷酸化。最后，在离体分离的脂肪组织和体外分化的 3T3 L1 脂肪细胞中也观察到胰岛素信号的增强，但在体外大鼠原代肝细胞中未观察到。这些结果表明：1）PPARγ激动剂可急性增强脂肪和肌肉组织中的胰岛素信号，且这种调节可能在体内胰岛素致敏中具有生理相关性；2）这些激动剂直接作用于脂肪组织；3）激动剂的代谢和信号作用由结构不同的 PPARγ激动剂介导。
