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Tissue-specific effects of Rosiglitazone and Exercise in the treatment of lipid-induced insulin resistance.

¹School of Medical Sciences, RMIT University,Australia
²Dept. of Kinesiology, California State University, Northridge, USA
³Dept. of Human Health and Nutritional Sciences, University of Guelph, Canada
⁴St. Vincent's Institute, University of Melbourne, Australia
⁵CSIRO Molecular & Health Technologies, Parkville, Australia
⁶Baker Heart Research Institute, Prahran, Australia

Correspondence: john.hawley{at}rmit.edu.au

OBJECTIVE:Both pharmacological intervention (i.e. thiazolidinediones [TZD]), 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.

RESEARCH DESIGN AND METHODS:We determined the effects of 4 wk Rosiglitazone (RSG) treatment and exercise training (EX), as well as their combined actions (EX RSG) on lipid and glucose metabolism in high-fat fed rats.

RESULTS:High-fat feeding (HF) 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 signalling pathway. EX, but not RSG 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 EX were associated with increased AMPK1 activity, increased expression of Akt1, PGC-1 and GLUT4 and a decrease in AS160 expression. In contrast, RSG treatment exacerbated lipid accumulation and decreased insulin-stimulated glucose transport in skeletal muscle. However, RSG, but not EX, increased adipose tissue GLUT4 and ACC expression. Both EX and RSG decreased liver triacylglycerol content.

CONCLUSION:Although both interventions can improve whole-body insulin sensitivity, our results show 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.

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