Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance
Open Access
- 1 July 2007
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 56 (7), 1856-1864
- https://doi.org/10.2337/db06-1065
Abstract
Both pharmacological intervention (i.e., thiazolidinediones [TZDs]) and lifestyle modification (i.e., exercise training) are clinically effective treatments for improving whole-body insulin sensitivity. However, the mechanism(s) by which these therapies reverse lipid-induced insulin resistance in skeletal muscle is unclear. We determined the effects of 4 weeks of rosiglitazone treatment and exercise training and their combined actions (rosiglitazone treatment and exercise training) on lipid and glucose metabolism in high-fat–fed rats. High-fat feeding resulted in decreased muscle insulin sensitivity, which was associated with increased rates of palmitate uptake and the accumulation of the fatty acid metabolites ceramide and diacylglycerol. Impairments in lipid metabolism were accompanied by defects in the Akt/AS160 signaling pathway. Exercise training, but not rosiglitazone treatment, reversed these impairments, resulting in improved insulin-stimulated glucose transport and increased rates of fatty acid oxidation in skeletal muscle. The improvements to glucose and lipid metabolism observed with exercise training were associated with increased AMP-activated protein kinase α1 activity; increased expression of Akt1, peroxisome proliferator–activated receptor γ coactivator 1, and GLUT4; and a decrease in AS160 expression. In contrast, rosiglitazone treatment exacerbated lipid accumulation and decreased insulin-stimulated glucose transport in skeletal muscle. However, rosiglitazone, but not exercise training, increased adipose tissue GLUT4 and acetyl CoA carboxylase expression. Both exercise training and rosiglitazone decreased liver triacylglycerol content. Although both interventions can improve whole-body insulin sensitivity, our results show that they produce divergent effects on protein expression and triglyceride storage in different tissues. Accordingly, exercise training and rosiglitazone may act as complementary therapies for the treatment of insulin resistance.Keywords
This publication has 51 references indexed in Scilit:
- 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat AdipocytesJournal of Biological Chemistry, 2006
- siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscleCell Metabolism, 2006
- AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3Biochemical Pharmacology, 2006
- Regulation of AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation by palmitate in skeletal muscle cellsJournal of Lipid Research, 2006
- Evidence for prescribing exercise as therapy in chronic diseaseScandinavian Journal of Medicine & Science in Sports, 2006
- Chronic rosiglitazone treatment restores AMPKα2 activity in insulin-resistant rat skeletal muscleAmerican Journal of Physiology-Endocrinology and Metabolism, 2006
- Characterization of the Role of the Rab GTPase-activating Protein AS160 in Insulin-regulated GLUT4 TraffickingJournal of Biological Chemistry, 2005
- Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker ratsJournal of Lipid Research, 2005
- Effects of Rexinoids on Glucose Transport and Insulin-mediated Signaling in Skeletal Muscles of Diabetic (db/db) MiceJournal of Biological Chemistry, 2004
- Effects of Troglitazone and Voluntary Running on Insulin Resistance Induced High Fat Diet in the RatHormone and Metabolic Research, 2001