The anti-oxidant alpha-lipoic acid (LA) has been shown to improve insulin action in high fat-fed animal models, yet little is known about its underlying mechanisms of action. We hypothesize that LA acts by inducing heat shock proteins which then inhibit stress kinases known to interfere with insulin signaling intermediates. Male Wistar rats were fed a high fat diet (HF diet, 60% calories from fat) for six weeks, while controls received a chow diet (10% calories from fat). Half of the rats in each group received daily LA injections (30 mg/kg body wt). In rats fed a HF diet, LA increased expression of heat shock protein 72 (HSP72) and activation of HSP25 in soleus muscle, but had no effect on heat shock proteins in muscle from chow-fed rats. LA treatment reduced phosphorylation of c-Jun N-terminal kinase (JNK) and Inhibitor of Kappa B Kinase beta (IKK) activity (IB protein levels) in rats fed a HF diet and effectively restored insulin responsiveness, as seen by insulin-stimulated pAkt/Akt and 2-deoxyglucose uptake in soleus muscle. LA also induced activation of p38 MAPK and AMPK, proteins previously implicated in insulin-independent glucose uptake. In addition, acute LA treatment induced heat shock proteins in vitro in L6 muscle cells and prevented the activation of JNK and IKK with stimulants such as anisomycin and TNF-, respectively. In conclusion, our results suggest chronic LA treatment results in stress kinase inhibition and improved insulin signaling through a heat shock protein-mediated mechanism.