There is now compelling evidence that, in addition to signaling to the central nervous system (CNS), leptin also exerts its metabolic effects acting directly on peripheral tissues. It has been demonstrated by in vivo and in vitro studies, that leptin increases glucose and fatty acid metabolism in skeletal muscle. These direct leptin effects are supported by the presence of the long form of the leptin receptor, considered to be capable of performing intracellular signaling, in peripheral tissues, including skeletal muscle. The exposure of soleus muscle to supra-physiological leptin concentrations stimulate the activity of both the pyruvate-dehydrogenase (PDH) complex and 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 activating the mitochondrial uncoupling process. In addition, in soleus and extensor digitorum longus (EDL) muscles, leptin and insulin had opposite effects on lipid metabolism, with leptin favoring lipid oxidation and insulin favoring lipid storage as triglycerides (TG). The leptin effects on free fatty acid (FFA) oxidation were more pronounced in soleus than in EDL. The differences 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. When tissue TG content is severely depleted by hyperleptinemia in normal rats, there is a dramatic increase in insulin sensitivity. This lipopenic effect of leptin may protect from the development of insulin resistance and diabetes in animals. In humans, obesity is also associated with an increase in insulin resistance and the development of Type II diabetes, however, contrary to rats and mice, there is abundance of leptin, indicating a state of resistance to this hormone in humans. Future studies are necessary to investigate the reasons why lean subjects seem to respond properly to endogenous leptin while obese ones don't. The understanding of the putative direct leptin 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.