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

Teperino, Raffaele, Amann, Sabine, Bayer, Martina, McGee, Sean, Loipetzberger, Andrea, Connor, Timothy, Jaeger, Carsten, Kammerer, Bernd, Winter, Lilli, Wiche, Gerhard, Dalgaard, Kevin, Selvaraj, Madhan, Gaster, Michael, Lee-Young, Robert, Febbraio, Mark, Knauf, Claude and Cani, Patrice 2012, Hedgehog partial agonism drives warburg-lie metabolism in muscle and brown fat, Cell, vol. 151, no. 2, pp. 414-426.

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Title Hedgehog partial agonism drives warburg-lie metabolism in muscle and brown fat
Author(s) Teperino, Raffaele
Amann, Sabine
Bayer, Martina
McGee, Sean
Loipetzberger, Andrea
Connor, Timothy
Jaeger, Carsten
Kammerer, Bernd
Winter, Lilli
Wiche, Gerhard
Dalgaard, Kevin
Selvaraj, Madhan
Gaster, Michael
Lee-Young, Robert
Febbraio, Mark
Knauf, Claude
Cani, Patrice
Journal name Cell
Volume number 151
Issue number 2
Start page 414
End page 426
Total pages 13
Publisher Cell Press
Place of publication Cambridge, Mass.
Publication date 2012-10-12
ISSN 0092-8674
1097-4172
Keyword(s) adenylate kinase
calcium
insulin
smoothened protein
sonic hedgehog protein
Summary 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.
Language eng
Field of Research 111699 Medical Physiology not elsewhere classified
Socio Economic Objective 920104 Diabetes
HERDC Research category C1 Refereed article in a scholarly journal
Restricted until 2016-10-12
Copyright notice ©2012, Elsevier
Persistent URL http://hdl.handle.net/10536/DRO/DU:30050130

Document type: Journal Article
Collection: School of Medicine
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