Hedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat

• Published in: Cell Vol. 151; no. 2; pp. 414 - 426
• Main Authors: Teperino, Raffaele, Amann, Sabine, Bayer, Martina, McGee, Sean L., Loipetzberger, Andrea, Connor, Timothy, Jaeger, Carsten, Kammerer, Bernd, Winter, Lilli, Wiche, Gerhard, Dalgaard, Kevin, Selvaraj, Madhan, Gaster, Michael, Lee-Young, Robert S., Febbraio, Mark A., Knauf, Claude, Cani, Patrice D., Aberger, Fritz, Penninger, Josef M., Pospisilik, J. Andrew, Esterbauer, Harald
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.10.2012
• Subjects: Adipocytes - metabolism; Adipose Tissue, Brown - metabolism; agonistic behavior; agonists; Animals; brown adipose tissue; Cell Line; Cells, Cultured; Cilia - metabolism; cyclopamine; diabetes; Diabetes Mellitus - metabolism; glucose; Glycolysis; Hedgehog Proteins - metabolism; Humans; metabolism; Mice; Muscle Cells - metabolism; muscles; Neoplasms - metabolism; obesity; Obesity - metabolism; Protein Kinases - metabolism; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; signals; Smoothened Receptor
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.09.021

Diabetes, obesity, and cancer affect upward of 15% of the world’s population. Interestingly, all three diseases 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-Ca2+-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of “selective partial agonists,” capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes. [Display omitted] ► Hedgehog signaling rapidly reprograms energy metabolism ► Smoothened activates a rapid primary cilium-dependent Smo-Ampk axis ► Cyclopamine and GDC-0449 uncouple canonical and noncanonical Smo signaling ► Smoothened drives insulin-independent glucose uptake in muscle and BAT in vivo A new hedgehog-induced regulatory circuit, mediated by a rapid noncanonical Smo-Ca2+-Ampk signaling arm, rewires cellular metabolism within minutes, prompting glucose uptake in muscle and brown fat in vivo.