Multi-tissue, selective PPAR modulation of insulin sensitivity and metabolic pathways in obese rats

Department of Bioengineering, University of California, San Diego, CA, USA.
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 10/2010; 300(1):E164-74. DOI: 10.1152/ajpendo.00219.2010
Source: PubMed


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.

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    • "However, the mechanism by which increased supply of these substrates causes downregulation of the BCAA catabolic enzymes is unknown. Drugs that activate PPARγ (thiazolidindiones or TZDs) can restore expression of the catabolic genes to normal (68), already suggesting a role of suppressed PPAR signaling in this metabolic adaptation. The miR-29 family is implicated in diabetes based on studies of hepatic gluconeogenesis in diabetic rat models (69). "
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    • "In addition, metformin improves metabolic variables such as dyslipidemia and fibrinolysis [5]. Rosiglitazone, another anti-diabetic agent, is an artificial ligand of peroxisome proliferator-activated receptor gamma that improves insulin sensitivity [6]–[9] and mitochondrial function [10], [11] in peripheral tissues. Glimepiride, the latest second-generation sulfonylurea for treating T2DM, increases pancreatic β-cell function to stimulate insulin secretion resulting in a hypoglycemic action [12]. "
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    PLoS ONE 07/2013; 8(7):e69624. DOI:10.1371/journal.pone.0069624 · 3.23 Impact Factor
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    • "Sibutramine had previously been used as an appetite suppressant but has been withdrawn from the market due to an increased risk of psychiatric disorders and non-fatal myocardial infarction or stroke (Kang and Park 2012). The peroxisome proliferator-activated receptor-c (PPAR-c) agonistic thiazolidinediones (pioglitazone and rosiglitazone) may be an alternative option to improve insulin sensitivity (Hsiao et al. 2011; Pita et al. 2012). Moreover, fibrates, as PPARa agonists, decrease TG levels by 23–80 %, and LDL-C levels by up to 38–80 % (Millar et al. 2009; Srivastava 2011; Zaborska et al. 2000). "
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