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.

7 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions.
    Nucleic Acids Research 11/2013; 42(3). DOI:10.1093/nar/gkt989 · 9.11 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene expression changes have been associated with type 2 diabetes mellitus (T2DM); however, the alterations are not fully understood. We investigated the effects of anti-diabetic drugs on gene expression in Zucker diabetic fatty (ZDF) rats using oligonucleotide microarray technology to identify gene expression changes occurring in T2DM. Global gene expression in the pancreas, adipose tissue, skeletal muscle, and liver was profiled from Zucker lean control (ZLC) and anti-diabetic drug treated ZDF rats compared with those in ZDF rats. We showed that anti-diabetic drugs regulate the expression of a large number of genes. We provided a more integrated view of the diabetic changes by examining the gene expression networks. The resulting sub-networks allowed us to identify several biological processes that were significantly enriched by the anti-diabetic drug treatment, including oxidative phosphorylation (OXPHOS), systemic lupus erythematous, and the chemokine signaling pathway. Among them, we found that white adipose tissue from ZDF rats showed decreased expression of a set of OXPHOS genes that were normalized by rosiglitazone treatment accompanied by rescued blood glucose levels. In conclusion, we suggest that alterations in OXPHOS gene expression in white adipose tissue may play a role in the pathogenesis and drug mediated recovery of T2DM through a comprehensive gene expression network study after multi-drug treatment of ZDF rats.
    PLoS ONE 07/2013; 8(7):e69624. DOI:10.1371/journal.pone.0069624 · 3.23 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: tert-Butylhydroquinone (tBHQ) is a commonly used antioxidant additive that is approved for human use by both the Food and Agriculture Organization and the World Health Organization (FAO/WHO). In this study, we examined the effect of tBHQ on body weight gain and found that food supplementation with 0.001 % (w/w) tBHQ inhibited 61.4 % (P < 0.01) of body weight gain in high-fat diet (HFD)-induced C57BL/6 mice, and the oral administration of tBHQ (1.5 mg/kg) reduced 47.5 % (P < 0.05) of body weight gain in normal diet fed db/db mice. The HFD increased lipid deposit in adipocytes, but these were reduced significantly by tBHQ treatment in C57BL/6 mice. tBHQ supplementation significantly lowered the plasma triglyceride and total cholesterol, with reduced size of accumulated fat mass. The rate limiting enzyme of beta-oxidation (ACOX1) was significantly over-expressed in the liver with tBHQ treatment. These results indicate that tBHQ suppresses body weight gain in mice, possibly at least related to the up-regulation of ACOX1 gene expression.
    Archives of Pharmacal Research 04/2013; 36(7). DOI:10.1007/s12272-013-0109-3 · 2.05 Impact Factor
Show more