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Mol Metab. 2018 Feb;8:65-76. doi: 10.1016/j.molmet.2017.11.012. Epub 2017 Dec 1.

Cdkn2a deficiency promotes adipose tissue browning.

Author information

1
Lille University, UMR 8199 - EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France.
2
Université Côte d'Azur, CNRS, INSERM, iBV, Faculté de Médecine, F-06107 Nice Cedex 2, France.
3
Center for Integrative Genomics, Université de Lausanne, CH-1015 Lausanne, Switzerland.
4
INSERM, UMR S-1172, Development and Plasticity of Postnatal Brain, F-59000 Lille, France.
5
Lille University, UMR 8199 - EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France; Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Electronic address: p.froguel@imperial.ac.uk.
6
Lille University, UMR 8199 - EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France. Electronic address: jean-sebastien.annicotte@inserm.fr.

Abstract

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.

KEYWORDS:

Adipose tissue browning; Energy expenditure; Genome-wide association study; Insulin sensitivity; Obesity; Type 2 diabetes; cdkn2a

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