α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors.

•Glucose stimulates α-MSH release from the pituitary.•Systemic α-MSH drives glucose disposal and thermogenesis in skeletal muscles.•α-MSH acts on MC5R expressed on skeletal muscles and activate cAMP-PKA pathway.•The combined treatment of nonselective or selective PDE 4 inhibitor and α-MSH ameliorates glucose intolerance in obese mice.