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 insulinstimulated 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 ␣1 activity; increased expression of Akt1, peroxisome proliferator-activated receptor ␥ 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.

Yaspelkis BB 3rd, Lessard SJ, Reeder DW, Limon JJ, Saito M, Rivas DA, Kvasha I, Hawley JA. Exercise reverses high-fat dietinduced impairments on compartmentalization and activation of components of the insulin-signaling cascade in skeletal muscle. Am J Physiol Endocrinol Metab 293: E941-E949, 2007. First published July 10, 2007; doi:10.1152/ajpendo.00230.2007.-The aims of this investigation were 1) to determine whether endurance exercise training could reverse impairments in insulin-stimulated compartmentalization and/or activation of aPKC/ and Akt2 in skeletal muscle from high-fat-fed rodents and 2) to assess whether the PPAR␥ agonist rosiglitazone could reverse impairments in skeletal muscle insulin signaling typically observed after high-fat feeding. Sprague-Dawley rats were placed on chow (NORCON, n ϭ 16) or high-fat (n ϭ 64) diets for 4 wk. During a subsequent 4-wk experimental period, high-fat-fed rats were allocated (n ϭ 16/group) to either sedentary control (HFC), exercise training (HFX), rosiglitazone treatment (HFRSG), or a combination of both exercise training and rosiglitazone (HFRX). Following the 4-wk experimental period, animals underwent hindlimb perfusions. Insulin-stimulated plasma membrane-associated aPKC and -protein concentration, aPKC/ activity, GLUT4 protein concentration, cytosolic Akt2, and aPKC/ activities were reduced (P Ͻ 0.05) in HFC compared with NORCON. Cytosolic Akt2, aPKC, and aPKC protein concentrations were not affected in HFC compared with NORCON. Exercise training reversed the deleterious effects of the high-fat diet such that insulin-stimulated compartmentalization and activation of components of the insulin-signaling cascade in HFX were normalized to NORCON. High-fat diet-induced impairments to skeletal muscle glucose metabolism were not reversed by rosiglitazone administration, nor did rosiglitazone augment the effect of exercise. Our findings indicate that chronic exercise training, but not rosiglitazone, reverses high-fat diet induced impairments in compartmentalization and activation of components of the insulinsignaling cascade in skeletal muscle.

Our results indicate that high resistance training frequency extends the transient activation of inflammatory signaling cascades, concomitant with persistent suppression of key mediators of anabolic responses. We provide novel insights into the effects of the timing of exercise-induced overload and recovery on signal transduction pathways and transcriptional activity regulating skeletal muscle mass in vivo.

Collectively, these findings suggest that chronic aerobic exercise enhances components of both the classical and novel insulin signalling cascades in normal rodent skeletal muscle, which may contribute to an increased insulin-stimulated plasma membrane GLUT4 protein concentration.

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