TY - JOUR
T1 - Hedgehog partial agonism drives warburg-like metabolism in muscle and brown fat
AU - Teperino, Raffaele
AU - Amann, Sabine
AU - Bayer, Martina
AU - McGee, Sean L
AU - Loipetzberger, Andrea
AU - Connor, Timothy
AU - Jaeger, Carsten
AU - Kammerer, Bernd
AU - Winter, Lilli
AU - Wiche, Gerhard
AU - Dalgaard, Kevin
AU - Selvaraj, Madhan
AU - Gaster, Michael
AU - Lee-Young, Robert S.
AU - Febbraio, Mark A.
AU - Knauf, Claude
AU - Cani, Patrice D.
AU - Aberger, Fritz
AU - Penninger, Josef M
AU - Pospisilik, J. Andrew
AU - Esterbauer, Harald
PY - 2012/10/12
Y1 - 2012/10/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867536639&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.09.021
DO - 10.1016/j.cell.2012.09.021
M3 - Article
AN - SCOPUS:84867536639
SN - 0092-8674
VL - 151
SP - 414
EP - 426
JO - Cell
JF - Cell
IS - 2
ER -