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This Article Full Text Full Text (PDF) All Versions of this Article: 292/2/E485    most recent 00080.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Todd, M. K. Articles by Turcotte, L. P. Search for Related Content PubMed PubMed Citation Articles by Todd, M. K. Articles by Turcotte, L. P.

Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance

¹Department of Kinesiology and ²Department of Biological Sciences, University of Southern California, Los Angeles, California; ³St. Vincent's Institute of Medical Research and the Department of Medicine, The University of Melbourne, Fitzroy, Australia; and ⁴Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 16 February 2006 ; accepted in final form 6 September 2006

In the present investigation, we studied the effects of thiazolidinedione (TZD) treatment on insulin-stimulated fatty acid (FA) and glucose kinetics in perfused muscle from high-fat (HF)-fed rats. We tested the hypothesis that TZDs prevent FA-induced insulin resistance by attenuating proinflammatory signaling independently of myocellular lipid levels. Male Wistar rats were assigned to one of three 3-wk dietary groups: control chow fed (CON), 65% HF diet (HFD), or TZD- (troglitazone or rosiglitazone) enriched HF diet (TZD + HFD). TZD treatment led to a significant increase in plasma membrane content of CD36 protein in muscle (red: P = 0.01, and white: P = 0.001) that correlated with increased FA uptake (45%, P = 0.002) and triacylglycerol (TG) synthesis (46%, P = 0.03) during the perfusion. Importantly, whereas HF feeding caused increased basal TG (P = 0.047), diacylglycerol (P = 0.002), and ceramide (P = 0.01) levels, TZD treatment only prevented the increase in muscle ceramide. In contrast, all of the muscle inflammatory markers altered by HF feeding (NIK protein content, P = 0.009; IKK activity, P = 0.006; IB- protein, P = 0.03; and JNK phosphorylation, P = 0.003) were completely normalized by TZD treatment. Consistent with this, HFD-induced decrements in insulin action were also prevented by TZD treatment. Thus our findings support the notion that TZD treatment causes increased FA uptake and TG accumulation in skeletal muscle under insulin-stimulated conditions. Despite this, TZDs suppress the inflammatory response to dietary lipid overload, and it is this mechanism that correlates strongly with insulin sensitivity.

insulin action; lipid oversupply; nuclear factor-B inflammatory pathway; lipotoxicity

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