title: The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.
abstract: OBJECTIVE
  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 the activity of CRF receptors, CRF1 and CRF2, 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 Crhr1-null (Crhr1(-/-)) 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. Crhr1(-/-) 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. Crhr1(-/-) 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 Crhr1(-/-) 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.
authors.affiliation: Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: B
authors.initials: B
authors.lastname: Lu
authors.affiliation: Laboratory of Endocrinology, Center for Biomedical Research, Campus As Lagoas-Marcosende, University of Vigo, Vigo, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Diz-Chaves
authors.affiliation: Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: D
authors.initials: D
authors.lastname: Markovic
authors.affiliation: Université de Bordeaux 2, INCIA, CNRS UMR 5287, Bordeaux, France.
authors.forename: A
authors.initials: A
authors.lastname: Contarino
authors.affiliation: Centre des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS, UMR 1324 INRA, Université de Bourgogne, Dijon, France.
authors.forename: L
authors.initials: L
authors.lastname: Penicaud
authors.affiliation: Endocrinology Unit and Centro di Ricerca Biomedica Applicata, Department of Clinical Medicine, S.Orsola-Malpighi Hospital, Alma Mater University of Bologna, Bologna, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fanelli
authors.affiliation: 1] INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux, France [2] Université de Bordeaux, Bordeaux, France.
authors.forename: S
authors.initials: S
authors.lastname: Clark
authors.affiliation: Department of Internal Medicine I, University of Luebeck, Luebeck, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Lehnert
authors.affiliation: 1] INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux, France [2] Université de Bordeaux, Bordeaux, France.
authors.forename: D
authors.initials: D
authors.lastname: Cota
authors.affiliation: Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: D K
authors.initials: DK
authors.lastname: Grammatopoulos
authors.affiliation: 1] INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, Bordeaux, France [2] Université de Bordeaux and Dpt of Endocrinology, USN Haut Leveque, CHU of Bordeaux, Pessac, France.
authors.forename: A
authors.initials: A
authors.lastname: Tabarin
mesh_terms: D041721:3T3-L1 Cells; D052437:Adipocytes, Brown / Q000378:metabolism*; D052438:Adipocytes, White / Q000378:metabolism*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D051379:Mice; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D010860:Pigments, Biological / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D015398:Signal Transduction; D054832:Urocortins / Q000378:metabolism*
chemical_list: D010860:Pigments, Biological; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone