Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats
Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats
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DOI：
10.1152/ajpendo.00219.2010
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发表时间：
2011-01-01
影响因子：
5.1
通讯作者：
Sears, Dorothy D.
中科院分区：
文献类型：
--
作者：
Hsiao, Gene;Chapman, Justin;Sears, Dorothy D.
肖钢，查普曼J，奥弗雷西奥JM，威尔克斯J，雷斯尼克JL，塔帕尔D，苏布拉马尼亚S，西尔斯DD。多组织选择性PPAR伽马调节肥胖大鼠的胰岛素敏感性和代谢途径。AM J生理学内分泌代谢酶300：E164-E174,2011年。2010年10月20日首次出版；DOI：10.1152/ajpendo.00219.2010。-过氧化物体增殖物激活受体-伽马(PPAR Gamma)配体，包括胰岛素敏化的噻唑烷二酮类药物，转录调节数百个基因。PPARγ配体特异性细胞调控机制与胰岛素增敏之间的关系知之甚少。我们研究了四种PPAR伽玛配体(吡格列酮、罗格列酮、曲格列酮和AG-035029)未治疗或治疗的瘦削和胰岛素抵抗肥胖Zucker大鼠的胰岛素敏感性和多组织基因表达谱。我们分析了大鼠脂肪组织、骨骼肌和肝脏的转录谱，并确定配体处理的胰岛素增敏效力是否与配体处理诱导的功能通路的改变有关。配体治疗在不同程度上改善了肥胖大鼠的胰岛素敏感性。脂肪组织图谱显示配体治疗选择性调节炎症和支链氨基酸(BCAA)代谢途径，这与配体治疗特异性胰岛素增敏效力相关。骨骼肌谱显示肥胖大鼠脂肪细胞和慢抽动纤维标记物的表达增加，配基治疗后进一步增加，但治疗引起的改变的程度与胰岛素增敏无关。尽管PPAR伽马配体治疗异质性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，但这些变化与配体胰岛素增敏效力无关。PPARγ配体治疗的特异性胰岛素增敏效力与脂肪组织炎症和支链氨基酸代谢途径的调节相关，表明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、骨骼肌和肝脏中也检测到了PPAR伽马配体治疗引起的其他功能通路的变化，但与胰岛素敏化程度无关。
Hsiao G, Chapman J, Ofrecio JM, Wilkes J, Resnik JL, Thapar D, Subramaniam S, Sears DD. Multi-tissue, selective PPAR gamma modulation of insulin sensitivity and metabolic pathways in obese rats. Am J Physiol Endocrinol Metab 300: E164-E174, 2011. First published October 20, 2010; doi:10.1152/ajpendo.00219.2010.-Peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPAR gamma 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 PPAR gamma 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 PPAR gamma 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. PPAR gamma 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 PPAR gamma 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.