Cdkn2a deficiency promotes adipose tissue browning
Autor: | 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. |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
Genome-wide association study
lcsh:Internal medicine Adipogenesis cdkn2a Induced Pluripotent Stem Cells Adipocytes Brown/cytology Adipocytes Brown/metabolism 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 Insulin sensitivity Obesity Type 2 diabetes stomatognathic diseases Adipocytes Brown Glucose Original Article lcsh:RC31-1245 neoplasms Cyclin-Dependent Kinase Inhibitor p16 |
Zdroj: | Molecular Metabolism, Vol 8, Iss, Pp 65-76 (2018) Molecular Metabolism Molecular metabolism, vol. 8, pp. 65-76 |
ISSN: | 2212-8778 |
Popis: | Objectives 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. Methods 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. Results 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. Conclusion 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. Highlights • Cdkn2a deficiency protects mice against high fat diet-induced obesity. • Cdkn2a modulates brown-like/beige fat gene networks involved in energy production and lipid metabolism. • Increased CDKN2A expression in human obese adipocytes. • Increased UCP1 levels in adipocytes differentiated from CDKN2A-silenced hiPS cells. |
Databáze: | OpenAIRE |
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