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

Diabetes, obesity, and cancer affect upward of 15% of the world&rsquo;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 &ldquo;selective partial agonists,&rdquo; 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.<br /

Programmed intermittent epidural bolus versus continuous epidural infusion for postoperative analgesia after major abdominal and gynecological cancer surgery: a randomized, triple-blinded clinical trial

Abstract Background Continuous epidural infusion (CEI) is the standard application setting for epidural infusion. A new mode, the programmed intermittent epidural bolus (PIEB) technique, showed reduced local anesthetic (LA) consumption and improved analgesia in obstetric analgesia. Goal of this trial was to evaluate the effects of PIEB versus CEI [combined with patient-controlled bolus (PCEA)] on LA consumption and pain scorings in major abdominal cancer surgery. Methods Following ethical approval, patients scheduled for major abdominal cancer surgery under general anesthesia in combination with epidural analgesia were randomized to receive either a PIEB mode of 6 mL/h or a CEI mode set at 6 mL/h of ropivacaine 0.2%, both combined with a PCEA mode set at a 4 mL bolus. LA consumptions and pain scorings were documented until the second postoperative evening. Results Eighty-four datasets were analyzed (CEI: n = 40, PIEB: n = 44). Regarding the primary endpoint, cumulative LA PCEA bolus volumes until day 2 differed significantly between the groups [PIEB 10 mL (2–28 mL) versus CEI, 28 mL (12–64 mL), median (25th–75th percentiles), p = 0.002]. Overall, LA consumption volumes were significantly lower in the PIEB group versus in the CEI group [PIEB: 329 mL (291–341 mL) vs. CEI: 350 mL (327–381 mL), p = 0.003]. Pain scores were comparable at each time point. Conclusions This trial demonstrates reduced needs for PCEA bolus in the PIEB group. There were no clinically relevant benefits regarding morphine consumption, pain scorings, or other secondary outcome parameters. Trial registration This study has been registered retrospectively in the ClinicalTrials.gov registry (NCT03378804), date of registration: December, 20th 2017