1. Hedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat
- Author
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Fritz Aberger, Josef M. Penninger, J. Andrew Pospisilik, Kevin Dalgaard, Carsten Jaeger, Sabine Amann, Madhan Selvaraj, Mark A. Febbraio, Lilli Winter, Robert S. Lee-Young, Claude Knauf, Michael Gaster, Raffaele Teperino, Gerhard Wiche, Patrice D. Cani, Harald Esterbauer, Timothy Connor, Bernd Kammerer, Martina Bayer, Andrea Loipetzberger, and Sean L. McGee
- Subjects
medicine.medical_specialty ,Cyclopamine ,Population ,Adipose tissue ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Receptors, G-Protein-Coupled ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,AMP-Activated Protein Kinase Kinases ,Adipose Tissue, Brown ,Neoplasms ,Internal medicine ,Adipocytes ,Diabetes Mellitus ,medicine ,Sonic Hedgehog Protein ,Animals ,Humans ,Hedgehog Proteins ,Cilia ,Obesity ,education ,Hedgehog ,Cells, Cultured ,030304 developmental biology ,Muscle Cells ,0303 health sciences ,education.field_of_study ,Biochemistry, Genetics and Molecular Biology(all) ,Smoothened Receptor ,Hedgehog signaling pathway ,3. Good health ,Cell biology ,Endocrinology ,chemistry ,030220 oncology & carcinogenesis ,Signal transduction ,Glycolysis ,Protein Kinases ,Signal Transduction - Abstract
SummaryDiabetes, 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.
- Published
- 2012
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