| dc.description.abstract | Impaired insulin action, termed insulin resistance, is characteristic of type 2 diabetes, obesity and aging. Given the rising epidemic of diabetes, efforts to understand the mechanisms of insulin resistance and discover effective therapeutic interventions are urgent. Considerable evidence now implicates oxidative stress in the patho-physiology of insulin resistance, a condition prevalent in the elderly and obese. Oxidative stress is known to activate several signaling cascades. This includes pathways that activate the stress kinases c-Jun N-terminal kinase (JNK) and the inhibitor of kappa B kinase beta (IKK beta), which interact with and inhibit the insulin signaling cascade. The heat shock proteins HSP72 and HSP25 have been recently identified as natural inhibitors of JNK and IKK beta, respectively, and therefore represent novel therapeutic targets against insulin resistance. Overexpression of HSPs has been shown to protect against obesity-induced insulin resistance as well as age-related muscle damage. Skeletal muscle, the largest glucose disposing tissue, also contains large amounts of inducible HSPs. We hypothesized that heat shock protein overexpression in skeletal muscle could protect against insulin resistance in obesity and aging. We tested this hypothesis using aged male Fischer 344 rats (24-month-old) as the aging model of insulin resistance and male Wistar rats given a high fat diet (60% calories from fat) as the model of diet induced-insulin resistance. We examined the role of HSPs in insulin resistance by inducing HSP expression with both in vitro and in vivo heat treatments and anti-oxidant administration. Our results showed that reduced HSP expression in the aging muscles is associated with a higher degree of stress kinase activation and insulin resistance in fast-twitch muscles compared to slow-twitch muscles. Increasing HSP72 expression in the muscles of young and old animals via heat treatment inhibited JNK activation. Heat-mediated JNK inhibition was specific to HSP72 induction, as determined by HSP72-inhibition studies, and was mediated by a direct interaction between HSP72 and JNK. In contrast to the muscle, brain sections from aging rats showed a robust increase in HSP25 expression, suggesting a tissue-specific regulation of HSPs in aging. In the high fat diet model, alpha-lipoic acid (LA), a potent antioxidant, was administered to relieve oxidative stress associated with high fat feeding. LA treatment improved insulin signaling and glucose transport, reduced stress kinase activation and increased HSP expression. As another method of HSP-induction, heat treatment, given in parallel with a high fat diet, improved glucose tolerance, reduced hyperinsulinemia, and reduced epididymal fat storage. In skeletal muscles, heat treatment induced HSP72 expression, improved insulin sensitivity, and reduced stress kinase activities. Heat treatment also enhanced mitochondrial function in fast-twitch muscles, normalizing the compensatory changes in mitochondrial protein expression seen with high fat feeding. Studies in L6 myotubes showed that heat treatment improved oxygen consumption and fatty acid oxidation. Mechanistically, our results indicate that heat shock proteins can 1). improve insulin sensitivity, 2). directly inhibit stress kinase activities, and 3). protect and enhance mitochondrial function. Our studies provide strong evidence that HSP induction in skeletal muscle could be a potential therapeutic treatment for age-related and obesity-induced insulin resistance. | |
