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Leptin and adiponectin are the major adipokines secreted by fat cells. Leptin effects energy homeostasis by decreasing food intake and by acting on lipogenesis and fatty acid oxidation. Elucidation of the mechanisms of action of adiponectin (Acrp30), a hormone considered to be a major insulin-sensitizing hormone, and leptin has been improved by the delineation of their impact on muscle and liver cells via regulation of AMP kinase function. A recent study has defined a human skeletal muscle pathway by which adiponectin increases mitochondrial number and function. In addition, adiponectin signaling pathways have recently been clarified by the discovery of a protein that interacts with adiponectin receptors.