Hedgehog partial agonism drives warburg-like metabolism in muscle and brown fat

Raffaele Teperino, Sabine Amann, Martina Bayer, Sean L McGee, Andrea Loipetzberger, Timothy Connor, Carsten Jaeger, Bernd Kammerer, Lilli Winter, Gerhard Wiche, Kevin Dalgaard, Madhan Selvaraj, Michael Gaster, Robert S. Lee-Young, Mark A. Febbraio, Claude Knauf, Patrice D. Cani, Fritz Aberger, Josef M Penninger, J. Andrew PospisilikHarald Esterbauer

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154 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)414-426
Number of pages13
JournalCell
Volume151
Issue number2
DOIs
Publication statusPublished - 12 Oct 2012
Externally publishedYes

Cite this

Teperino, R., Amann, S., Bayer, M., McGee, S. L., Loipetzberger, A., Connor, T., Jaeger, C., Kammerer, B., Winter, L., Wiche, G., Dalgaard, K., Selvaraj, M., Gaster, M., Lee-Young, R. S., Febbraio, M. A., Knauf, C., Cani, P. D., Aberger, F., Penninger, J. M., ... Esterbauer, H. (2012). Hedgehog partial agonism drives warburg-like metabolism in muscle and brown fat. Cell, 151(2), 414-426. https://doi.org/10.1016/j.cell.2012.09.021