Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three dis-eases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca 2+ -Ampk axis that triggers rapid Warburg-like metabolic re-programming within minutes of activation and is required for proper metabolic selectivity and flexi-bility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of ''selec-tive partial agonists,'' capable of concomitant inhibi-tion of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-inde-pendent glucose uptake in muscle and brown adipose tissue. These data identify multiple nonca-nonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new thera-peutic avenue for obesity and diabetes.