Way J M, Harrington W W, Brown K K, Gottschalk W K, Sundseth S S, Mansfield T A, Ramachandran R K, Willson T M, Kliewer S A
Department of Molecular Endocrinology, Glaxo Wellcome Inc., Research and Development, Research Triangle Park, North Carolina 27709, USA.
Endocrinology. 2001 Mar;142(3):1269-77. doi: 10.1210/endo.142.3.8037.
Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR gamma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR gamma activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR gamma-mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR gamma agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，包括噻唑烷二酮类药物，是胰岛素增敏剂，可降低2型糖尿病患者的血糖和血脂水平。为了更全面地了解其治疗作用的分子机制，我们已对强效的、基于酪氨酸的PPARγ配体GW1929对Zucker糖尿病脂肪大鼠的血糖和血脂参数以及基因表达的影响进行了表征。在时间进程研究中，GW1929治疗在降低血糖和甘油三酯水平之前降低了循环FFA水平。我们使用了一种全面且无偏倚的信使核糖核酸谱分析技术，以鉴定在附睾白色脂肪组织、肩胛间棕色脂肪组织、肝脏和比目鱼肌骨骼肌中直接或间接受PPARγ调节的基因。PPARγ激活刺激了白色脂肪组织和棕色脂肪组织中大量参与脂肪生成和脂肪酸代谢的基因的表达。在肌肉中，PPARγ激动剂治疗降低了抑制氧化葡萄糖代谢的丙酮酸脱氢酶激酶4的表达，并且还降低了参与脂肪酸转运和氧化的基因的表达。这些变化提示了PPARγ介导的肌肉中葡萄糖利用增加的分子基础。在肝脏中，PPARγ激活协同降低了参与糖异生的基因的表达。我们从这些研究中得出结论，PPARγ激动剂的抗糖尿病作用可能是1）它们对FFA水平的影响，以及2）它们对多个胰岛素敏感组织中基因表达的协同作用的结果。
