The response of skeletal muscle to leptin

There is now compelling evidence that, in addition to signaling to the cent ral nervous system (CNS), leptin also exerts its metabolic effects acting d irectly on peripheral tissues. It has been demonstrated by in vivo and in v itro studies, that leptin increases glucose and fatty acid metabolism in sk eletal muscle. These direct leptin effects are supported by the presence of the long form of the leptin receptor, considered to be capable of performi ng intracellular signaling, in peripheral tissues, including skeletal muscl e. The exposure of soleus muscle to supraphysiological leptin concentration s stimulate the activity of both the pyruvate-dehydrogenase (PDH) complex a nd Krebs cycle. This could be due to a direct stimulation of PDH and krebs cycle by leptin or a consequence of an indirect effect of this hormone acti vating the mitochondrial uncoupling process. In addition, in soleus and ext ensor digitorum longus (EDL) muscles, leptin and insulin had opposite effec ts on lipid metabolism, with leptin favoring lipid oxidation and insulin fa voring lipid storage as triglycerides (TG). The leptin effects on free fatt y acid (FFA) oxidation were more pronounced in soleus than in EDL. The diff erences in response of soleus compared with that of EDL was probably due to differences in fiber type composition and metabolic characteristics. It has been demonstrated that leptin reduces the TG content of skeletal. Wh en tissue TG content is severely depleted by hyperleptinemia in normal rats , there is a dramatic increase in insulin sensitivity. This lipopenic effec t of leptin may protect from the development of insulin resistance and diab etes in animals. In humans, obesity is also associated with an increase in insulin resistance and the development of Type II diabetes, however, contra ry to rats and mice, there is abundance of leptin, indicating a state of re sistance to this hormone in humans. Future studies are necessary to investi gate the reasons why lean subjects seem to respond properly to endogenous l eptin while obese ones don't. The understanding of the putative direct lept in signaling pathway in skeletal muscle could be an important step towards the utilization of leptin or a leptin receptor agonist as therapeutic tools to treat obesity and its related metabolic disorders.