Editors' ChoiceMetabolism

Hedgehog Drives Glucose Metabolism

Sci. Signal.  23 Oct 2012:
Vol. 5, Issue 247, pp. ec275
DOI: 10.1126/scisignal.2003715

Hedgehog (Hh) regulates cellular differentiation through a transcriptional pathway referred to as the canonical pathway and also regulates other cellular behaviors through transcription-independent signaling referred to as the noncanonical pathway Teperino et al. examine the role of Hh in glucose metabolism in adipocytes and myocytes. Stimulation of the mouse white adipocyte cell line 3T3-L1 with exogenous sonic hedgehog (Shh) or a small-molecule activator (SAG) of the Hh effector smoothened (Smo) triggered a Warburg-like change in cellular metabolism. The Warburg effect is a metabolic shift observed in cancer cells such that they display a high rate of aerobic glycolysis through a pathway involving the conversion of glucose to lactate. Knockdown of Smo in 3T3-L1 cells or deletion of Smo in mouse embryonic fibroblasts (MEFs) abrogated these metabolic shifts. A phosphoproteomic screen of lysates of 3T3-L1 cells treated with SAG identified phosphorylated, and thus activated, adenosine monophosphate (AMP)–activated protein kinase (AMPK). Knockdown of AMPK or two protein kinases upstream of AMPK [Lkb11 or calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)] or administration of the calcium chelator EGTA, the calcium channel blocker nifedipine, or the G protein Gα subunit inhibitor pertussis toxin blocked the Warburg-like effects of Hh signaling in 3T3-L1 cells. These data suggest that Hh can stimulate a noncanonical signaling axis, resulting in AMPK activation. Contrary to expectation, treatment of 3T3-L1 cells with the canonical Hh antagonist cyclopamine induced the same Warburg-like effects triggered by the Smo agonist SAG, and these were abolished by knockdown of Smo or addition of an AMPK inhibitor, nifedipine, or pertussis toxin. Mice receiving cyclopamine had improved glucose tolerance compared with controls and had increased glucose uptake even when their insulin response was suppressed by somatostatin. A radiolabel-based study traced glucose uptake to brown adipose tissue and muscle fibers. Stimulation of myotubes or primary brown adipocytes with cyclopamine produced AMPK activation and Warburg-like effects as in 3T3-L1 cells. In contrast to canonical Hh signaling, which inhibits differentiation of white adipose tissue to limit glucose metabolism, noncanonical Hh signaling promotes increased energy expenditure and glucose metabolism in brown adipose tissue and muscle (see commentary by Lee and Kahn.).

R. Teperino, S. Amann, M. Bayer, S. L. McGee, A. Loipetzberger, T. Connor, C. Jaeger, B. Kammerer, L. Winter, G. Wiche, K. Dalgaard, M. Selvaraj, M. Gaster, R. S. Lee-Young, M. A. Febbraio, C. Knauf, P. D. Cani, F. Aberger, J. M. Penninger, J. A. Pospisilik, H. Esterbauer, Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 151, 414–426 (2012). [Online Journal]

K. Y. Lee, C. R. Kahn, Turning on brown fat and muscle metabolism: Hedging your bets. Cell 151, 248–250 (2012). [Online Journal]