Cdkn2a deficiency promotes adipose tissue browning.

Détails

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Etat: Serval
Version: Final published version
ID Serval
serval:BIB_2CA9563F93C5
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Cdkn2a deficiency promotes adipose tissue browning.
Périodique
Molecular metabolism
Auteur(s)
Rabhi N., Hannou S.A., Gromada X., Salas E., Yao X., Oger F., Carney C., Lopez-Mejia I.C., Durand E., Rabearivelo I., Bonnefond A., Caron E., Fajas L., Dani C., Froguel P., Annicotte J.S.
ISSN
2212-8778 (Electronic)
ISSN-L
2212-8778
Statut éditorial
Publié
Date de publication
02/2018
Peer-reviewed
Oui
Volume
8
Pages
65-76
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Genome-wide association studies have reported that DNA polymorphisms at the CDKN2A locus modulate fasting glucose in human and contribute to type 2 diabetes (T2D) risk. Yet the causal relationship between this gene and defective energy homeostasis remains elusive. Here we sought to understand the contribution of Cdkn2a to metabolic homeostasis.
We first analyzed glucose and energy homeostasis from Cdkn2a-deficient mice subjected to normal or high fat diets. Subsequently Cdkn2a-deficient primary adipose cells and human-induced pluripotent stem differentiated into adipocytes were further characterized for their capacity to promote browning of adipose tissue. Finally CDKN2A levels were studied in adipocytes from lean and obese patients.
We report that Cdkn2a deficiency protects mice against high fat diet-induced obesity, increases energy expenditure and modulates adaptive thermogenesis, in addition to improving insulin sensitivity. Disruption of Cdkn2a associates with increased expression of brown-like/beige fat markers in inguinal adipose tissue and enhances respiration in primary adipose cells. Kinase activity profiling and RNA-sequencing analysis of primary adipose cells further demonstrate that Cdkn2a modulates gene networks involved in energy production and lipid metabolism, through the activation of the Protein Kinase A (PKA), PKG, PPARGC1A and PRDM16 signaling pathways, key regulators of adipocyte beiging. Importantly, CDKN2A expression is increased in adipocytes from obese compared to lean subjects. Moreover silencing CDKN2A expression during human-induced pluripotent stem cells adipogenic differentiation promoted UCP1 expression.
Our results offer novel insight into brown/beige adipocyte functions, which has recently emerged as an attractive therapeutic strategy for obesity and T2D. Modulating Cdkn2a-regulated signaling cascades may be of interest for the treatment of metabolic disorders.
Mots-clé
Adipocytes, Brown/cytology, Adipocytes, Brown/metabolism, Adipogenesis, Animals, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16/genetics, Cyclin-Dependent Kinase Inhibitor p16/metabolism, Gene Regulatory Networks, Glucose/metabolism, Humans, Induced Pluripotent Stem Cells/cytology, Induced Pluripotent Stem Cells/metabolism, Mice, Obesity/metabolism, Thermogenesis, Adipose tissue browning, Energy expenditure, Genome-wide association study, Insulin sensitivity, Obesity, Type 2 diabetes, cdkn2a
Pubmed
Web of science
Open Access
Oui
Création de la notice
11/01/2018 21:16
Dernière modification de la notice
08/05/2019 16:25
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