The hypothalamus controls glucose and lipid metabolism in peripheral tissues. Recent studies have revealed that the ventromedial hypothalamus (VMH) and arcuate nucleus (ARC) of the hypothalamus play an important role in the regulation of glucose and lipid metabolism in skeletal muscle and the liver. The fat-derived hormone leptin was thus shown to stimulate glucose uptake and fatty acid oxidation in red-type skeletal muscle by activating VMH neurons - likely mediated in part by augmentation of synaptic plasticity between leptin receptor and proopiomelanocortin (POMC)-expressing neurons in the ARC and melanocortin receptor (MCR)-expressing VMH neurons - and consequent activation of sympathetic nerves innervating the muscle tissue. The VMH - sympathetic nerve axis was also found to be activated by orexin-positive neurons in mediation of hedonic feeding-induced glucose uptake in red-type skeletal muscle. The effects of orexin and leptin on glucose metabolism in skeletal muscle are interconnected with those of insulin, with the action of VMH also being necessary for the beneficial effects of exercise on metabolism. Leptin ameliorates diabetic phenotypes in animals with uncontrolled insulin-deficient diabetes as well as in patients with or animal models of lipodystrophy through the central nervous system (CNS). Finally, a single injection of fibroblast growth factor 1 (FGF1) into the lateral ventricle was shown to induce sustained remission of hyperglycemia in several animal models of type 2 diabetes, at least in part by increasing glucose uptake in skeletal muscle. The CNS thus plays an important role in the control of glucose and lipid metabolism, with the VMH as well as POMC neurons being implicated as key regulators of such metabolism in skeletal muscle.