Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat.
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-Ca(2+)-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.
Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
Raffaele
R
Teperino
Sabine
S
Amann
Martina
M
Bayer
Sean L
SL
McGee
Andrea
A
Loipetzberger
Timothy
T
Connor
Carsten
C
Jaeger
Bernd
B
Kammerer
Lilli
L
Winter
Gerhard
G
Wiche
Kevin
K
Dalgaard
Madhan
M
Selvaraj
Michael
M
Gaster
Robert S
RS
Lee-Young
Mark A
MA
Febbraio
Claude
C
Knauf
Patrice D
PD
Cani
Fritz
F
Aberger
Josef M
JM
Penninger
J Andrew
JA
Pospisilik
Harald
H
Esterbauer
D000091162:AMP-Activated Protein Kinase Kinases; D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D006019:Glycolysis; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor
D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases