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1 Kinesiology, University of Southern California, Los Angeles, California, United States
2 Medicine, St. Vincent's Institute of Medical Research and the University of Melbourne, Fitzroy, Victoria, Australia
3 Medicine, University of California, San Diego, La Jolla, California, United States
4 Kinesiology, University of Southern California, Los Angeles, California, United States; Biological Sciences, University of Southern California, Los Angeles, California, United States
* To whom correspondence should be addressed. E-mail: ahevener{at}ucsd.edu.
In the current 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 pro-inflammatory signaling independently of changes in myocellular lipid levels. Male Wistar rats were assigned to one of three 3-week 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. While 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; 
I
B-
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. 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 which correlates strongly with insulin sensitivity.
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