AI Article Synopsis

  • - Diabetes, obesity, and cancer affect more than 15% of the global population, and all three are linked to issues with cellular signaling and metabolism.
  • - The study uncovers a specific signaling pathway known as the Smo-Ca(2+)-Ampk axis that can rapidly change cellular metabolism and is crucial for maintaining metabolic flexibility.
  • - Researchers found that certain compounds, like cyclopamine, can selectively modify hedgehog signaling, potentially offering new treatment options for managing obesity and diabetes through improved glucose uptake in tissues.

Article 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.

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Source
http://dx.doi.org/10.1016/j.cell.2012.09.021DOI Listing

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