The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.
Int J Obes. 2014-09-05; 39(3): 408-417
DOI: 10.1038/ijo.2014.164
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1. Int J Obes (Lond). 2015 Mar;39(3):408-17. doi: 10.1038/ijo.2014.164. Epub 2014
Sep 5.
The corticotrophin-releasing factor/urocortin system regulates white fat browning
in mice through paracrine mechanisms.
Lu B(1), Diz-Chaves Y(2), Markovic D(1), Contarino A(3), Penicaud L(4), Fanelli
F(5), Clark S(6), Lehnert H(7), Cota D(6), Grammatopoulos DK(1), Tabarin A(8).
Author information:
(1)Division of Metabolic and Vascular Health, Warwick Medical School, University
of Warwick, Coventry, UK.
(2)Laboratory of Endocrinology, Center for Biomedical Research, Campus As
Lagoas-Marcosende, University of Vigo, Vigo, Spain.
(3)Université de Bordeaux 2, INCIA, CNRS UMR 5287, Bordeaux, France.
(4)Centre des Sciences du Goût et de l’Alimentation, UMR 6265 CNRS, UMR 1324
INRA, Université de Bourgogne, Dijon, France.
(5)Endocrinology Unit and Centro di Ricerca Biomedica Applicata, Department of
Clinical Medicine, S.Orsola-Malpighi Hospital, Alma Mater University of Bologna,
Bologna, Italy.
(6)1] INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale,
U862, Bordeaux, France [2] Université de Bordeaux, Bordeaux, France.
(7)Department of Internal Medicine I, University of Luebeck, Luebeck, Germany.
(8)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.
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 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.
DOI: 10.1038/ijo.2014.164
PMID: 25189177 [Indexed for MEDLINE]