Hedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat

Abstract

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.

Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics

“…Previous reports have suggested a role for HH-regulated Ca 2+ signaling during development (34) and in metabolic regulation (35). We show that HH signaling controls Ca 2+ dynamics to regulate ciliary cyclases and downstream signaling through cAMP to PKA and Gli proteins (Fig.…”

AMP-activated Protein Kinase Stimulates Warburg-like Glycolysis and Activation of Satellite Cells during Muscle Regeneration

“…Smoothened Agonist Promotes Satellite Proliferation through Activating AMPK-It has been recently reported that noncanonical Sonic Hedgehog (Shh) signaling promotes a Warburglike glycolysis in differentiated C2C12 myotubes (22). Therefore, we questioned whether this pathway is also present in undifferentiated myoblasts and satellite cells and whether AMPK␣1 has a mediatory role in eliciting Warburg-like glycolysis.…”

“…We first tested the effect of Smoothened (Smo) agonist (SAG), an activator of Shh pathway, on AMPK activity in C2C12 myoblasts and WT satellite cells. C2C12 myoblasts and WT satellite cells were treated with 200 nM SAG for only 10 min to avoid the activation of canonical Shh signaling (22,29). In both C2C12 cells and WT satellite cells, 10 min of SAG treatment activated AMPK (Fig.…”

“…Selective Activation of noncanonical Shh Promotes Satellite Cell Activation and Proliferation-To further test whether the observed effects of SAG on satellite cells was through noncanonical Shh signaling, WT primary myoblasts were treated with cyclopamine, a noncanonical Shh specific activator, which is also known to inhibit canonical Shh (22). 10 min of cyclopamine treatment successfully activated AMPK (Fig.…”

Inversion of Sonic hedgehog action on its canonical pathway by electrical activity

“…Inhibition of Gli activity may be necessary for engaging Shh in distinct signaling pathways and functions of the maturing and adult tissues. Noncanonical Shh signaling (47,48) is implicated in regulation of muscle and brown-fat metabolism (49) and, in the spinal cord, participates in neurotransmitter specification and axon guidance (28,50). Interestingly, in the adult ventrolateral nucleus of the tractus solitarius, Shh acutely modulates neuronal excitability (51).…”