The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue International Journal of Obesity Année : 2015

The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.

Résumé

Objectives The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals but its functional role in this tissue remains unknown. Methods Pharmacological manipulation of CRF-Receptors, CRF1 and CRF2, activity was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/Urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr null (Crhr-/-) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. Results Peptides of the CRF/Urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr-/- mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr-/- mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr-/- mice. Conclusions Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/Urocortin system. Targeting CRF-receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity.

Dates et versions

hal-01184131 , version 1 (12-08-2015)

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Citer

B. Lu, Y. Diz-Chaves, D. Markovic, A. Contarino, Luc Penicaud, et al.. The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.. International Journal of Obesity, 2015, 39 (3), pp.408-17. ⟨10.1038/ijo.2014.164⟩. ⟨hal-01184131⟩
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