Hedgehog signalling has been implicated in many physiological and pathological processes, including adipocyte differentiation, cancer, diabetes and obesity. Despite its involvement in these metabolic processes, a mechanism connecting Hedgehog signalling to metabolic reprogramming has been elusive. Pospisilik, Esterbauer and colleagues now reveal that Hedgehog activates Smoothened (Smo)–AMPK signalling to promote a Warburg-like transition to glycolytic metabolism (Cell 151, 414–426; 2012).

Treatment of 3T3-L1 adipocytes with Smoothened agonist or Sonic Hedgehog ligand induced a metabolic shift towards aerobic glycolysis. Smoothened agonist treatment promoted phosphorylation of AMPK, and knocking down AMPK blocked Hedgehog-induced metabolic reprogramming. Hedgehog signalling depends on its localization to the primary cilium, and mouse epithelial fibroblasts (MEFs) that lacked these structures showed impaired AMPK activation and glucose uptake.

Surprisingly, the Hedgehog antagonist cyclopamine was found to activate this non-canonical Smo–AMPK pathway independently of canonical Hedgehog signalling. The authors found that cyclopamine treatment improved glucose tolerance in mice, promoted glucose uptake by muscle and brown adipose tissue, and also increased core body temperature. These findings suggest that Hedgehog partial agonism might have therapeutic benefit in metabolic diseases. Indeed, the authors found that an FDA-approved Hedgehog inhibitor, GDC-0449, promoted AMPK phosphorylation and glucose uptake. It will be important to determine whether this compound, or other Hedgehog inhibitors undergoing development, are useful reagents in treating cancer, obesity or diabetes.