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Corticotropin-Releasing Hormone Directly Stimulates Thermogenesis in Skeletal Muscle Possibly through Substrate Cycling between de Novo Lipogenesis and Lipid Oxidation

Department of Medicine (G.S., S.S., D.M., J.P.M., A.G.D.), Division of Physiology, University of Fribourg, Fribourg CH-1700, Switzerland; Department of Vascular and Metabolic Diseases (M.G.), Hoffman-La Roche, CH-4070 Basel, Switzerland; Department of Neuroscience (J.S.), Centre Médical Universitaire, CH-1211 Geneva, Switzerland; and Pennington Biomedical Research Center (S.R.S.), Baton Rouge, Louisiana 70808

Address all correspondence and requests for reprints to: Dr. A. G. Dulloo, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland. E-mail: abdul.dulloo{at}unifr.ch.

The mechanisms by which CRH and related peptides (i.e. the CRH/urocortin system) exert their control over thermogenesis and weight regulation have until now focused only upon their effects on brain centers controlling sympathetic outflow. Using a method that involves repeated oxygen uptake determinations in intact mouse skeletal muscle, we report here that CRH can act directly on skeletal muscle to stimulate thermogenesis, an effect that is more pronounced in oxidative than in glycolytic muscles and that can be inhibited by a selective CRH-R2 antagonist or blunted by a nonselective CRH receptor antagonist. This thermogenic effect of CRH can also be blocked by interference along pathways of de novo lipogenesis and lipid oxidation, as well as by inhibitors of phosphatidylinositol 3-kinase or AMP-activated protein kinase. Taken together, these studies demonstrate that CRH can directly stimulate thermogenesis in skeletal muscle, and in addition raise the possibility that this thermogenic effect, which requires both phosphatidylinositol 3-kinase and AMP-activated protein kinase signaling, might occur via substrate cycling between de novo lipogenesis and lipid oxidation. The effect of CRH in directly stimulating thermogenesis in skeletal muscle underscores a potentially important peripheral role for the CRH/urocortin system in the control of thermogenesis in this tissue, in its protection against excessive intramyocellular lipid storage, and hence against skeletal muscle lipotoxicity and insulin resistance.

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