Department of Bioengineering, University of California, San Diego, CA, USA.
Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E164-74. doi: 10.1152/ajpendo.00219.2010. Epub 2010 Oct 19.
Peroxisome proliferator-activated receptor-γ (PPARγ) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARγ ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin-sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPARγ ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPARγ ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPARγ ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization.
过氧化物酶体增殖物激活受体-γ（PPARγ）配体，包括胰岛素增敏噻唑烷二酮类药物，可转录调控数百个基因。关于 PPARγ 配体对细胞机制的特异性调节与胰岛素敏感性之间的关系，我们知之甚少。我们描述了瘦型和胰岛素抵抗型肥胖 Zucker 大鼠的胰岛素敏感性和多组织基因表达谱，这些大鼠未经处理或用 4 种 PPARγ 配体（吡格列酮、罗格列酮、曲格列酮和 AG-035029）之一进行处理。我们分析了大鼠脂肪组织、骨骼肌和肝脏的转录谱，并确定配体治疗的胰岛素增敏效力是否与配体治疗诱导的功能途径改变有关。配体治疗在不同程度上改善了肥胖大鼠的胰岛素敏感性。脂肪组织谱显示，配体治疗选择性地调节炎症和支链氨基酸（BCAA）代谢途径，这与配体治疗特异性的胰岛素增敏效力相关。骨骼肌谱显示，肥胖大鼠表现出脂肪细胞和慢肌纤维标志物的表达升高，这些标志物在配体治疗后进一步增加，但治疗引起的变化幅度与胰岛素敏感性无关。尽管 PPARγ 配体治疗不均一地改善了肥胖大鼠肝脏中胆固醇和脂肪酸生物合成途径的失调表达，但这些改变与配体的胰岛素增敏效力无关。PPARγ 配体治疗特异性的胰岛素增敏效力与脂肪组织炎症和 BCAA 代谢途径的调节相关，提示这些途径与全身胰岛素敏感性之间存在功能关系。在脂肪组织、骨骼肌和肝脏谱中还检测到其他 PPARγ 配体治疗诱导的功能途径变化，但与胰岛素敏感性的程度无关。
