MK-3903 is a potent and selective AMPK activator (EC50 = 8 nM). MK-3903 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice. Chronic oral administration of MK-3903 robustly increased ACC phosphorylation in liver with more modest effects in skeletal muscle. Treatment of various mouse models with MK-3903 resulted in expected alterations in lipid metabolism and improvements in a measure of insulin sensitization.