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Submitted on August 12, 2005
Accepted on September 16, 2005
Department of Medicine, Division of Physiology, University of Fribourg, Switzerland; Department of Vascular and Metabolic Diseases, Hoffman-La Roche, Switzerland; Department of Neuroscience, Centre Médical Universitaire, Geneva, Switzerland; Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
* To whom correspondence should be addressed. E-mail: abdul.dulloo{at}unifr.ch.
The mechanisms by which CRH (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 which is more pronounced in oxidative than in glycolytic muscles, and which can be inhibited by a selective CRH-R2 antagonist or blunted by a non-selective 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 (PI3K) or AMP-activated protein kinase (AMPK). 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 PI3K and AMPK 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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