Leptin regulates energy homoeostasis through central and peripheral mechanisms. Initial steps in leptin action include signalling through a cytokine-like receptor which activates the JAK/STAT pathway. We investigated whether the metabolic effects of leptin in muscle could be mediated by the AMP-activated protein kinase (AMP kinase). Through studies involving leptin injection intrahypothalamically or intravenously, as well as incubation of soleus muscle or cultured muscle cells with leptin, we determined that leptin stimulates fatty acid oxidation in skeletal muscle by activating AMP kinase. Leptin exerts this effect directly at the level of muscle and also through the hypothalamic sympathetic nervous system, specifically engaging α-adrenergic receptors in muscle. This represents a novel and important pathway mediating leptin's metabolic actions.

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