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

A G Dulloo,D Mainieri,G Solinas,J P Montani,J Seydoux,M Gubler,S R Smith,S Summermatter

doi:10.1210/en.2005-1033

A G Dulloo, D Mainieri + Show 6 more

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https://doi.org/10.1210/en.2005-1033

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Journal: EndocrinologyJN	Publication Date: Oct 6, 2005
Citations: 42	License type: cc-by

Affiliation: University of Fribourg, Roche (Switzerland)

Abstract

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.

Highlights

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
To test whether the observed direct effect of CRH on muscle thermogenesis was due to binding of CRH to CRH-R2␤ receptors, we investigated whether the CRH-induced increase in soleus muscle MO2 could be prevented by the presence of antisauvagine-30, a selective CRH-R2 antagonist, and whether it could be mimicked by urocortin 2, a selective
We have previously proposed that substrate cycling between de novo lipogenesis and lipid oxidation, a futile cycle known to be involved in brown adipose tissue thermogenesis [24], operate as a thermogenic effector in skeletal muscle [15] on the basis of previously reported calorimetric studies indicating that inhibition of key control points along pathways in this substrate cycle resulted in the blunting of the direct effect of leptin in stimulating thermogenesis in skeletal muscle [14]

Summary

Introduction

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. We decided to test the hypothesis that CRH, like leptin, may directly stimulate thermogenesis in skeletal http://doc.rero.ch muscle on the basis of the following: 1) a splice variant of the CRH receptor encoded by the crhr-2 gene (CRH-R2␤) is expressed in skeletal muscle [19, 20], and 2) peripheral infusion of CRH stimulates thermogenesis and fat oxidation in humans without signs of increased adipose tissue lipolysis or activation of the sympatho-adrenal system [21] To this end, we have evaluated the direct effect of CRH on skeletal muscle thermogenesis by assessing changes in the respiration rate of intact murine skeletal muscle (ex vivo) by a method that involves repeated oxygen uptake determinations for several hours in indirect microcalorimeter chambers. We investigated the role of PI3K and AMPK signaling in the peripheral thermogenic effect of CRH in skeletal muscle

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