Cdkn2a deficiency promotes adipose tissue browning
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 under...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-02-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877817309353 |
| _version_ | 1818267705668534272 |
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| author | Nabil Rabhi Sarah Anissa Hannou Xavier Gromada Elisabet Salas Xi Yao Frédérik Oger Charlène Carney Isabel C. Lopez-Mejia Emmanuelle Durand Iandry Rabearivelo Amélie Bonnefond Emilie Caron Lluis Fajas Christian Dani Philippe Froguel Jean-Sébastien Annicotte |
| author_facet | Nabil Rabhi Sarah Anissa Hannou Xavier Gromada Elisabet Salas Xi Yao Frédérik Oger Charlène Carney Isabel C. Lopez-Mejia Emmanuelle Durand Iandry Rabearivelo Amélie Bonnefond Emilie Caron Lluis Fajas Christian Dani Philippe Froguel Jean-Sébastien Annicotte |
| author_sort | Nabil Rabhi |
| collection | DOAJ |
| description | 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: Obesity, Type 2 diabetes, Insulin sensitivity, Energy expenditure, cdkn2a, Genome-wide association study, Adipose tissue browning |
| first_indexed | 2024-12-12T20:26:51Z |
| format | Article |
| id | doaj.art-b78363c754f44dd2856be9f0727becc3 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-12T20:26:51Z |
| publishDate | 2018-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-b78363c754f44dd2856be9f0727becc32022-12-22T00:13:08ZengElsevierMolecular Metabolism2212-87782018-02-0186576Cdkn2a deficiency promotes adipose tissue browningNabil Rabhi0Sarah Anissa Hannou1Xavier Gromada2Elisabet Salas3Xi Yao4Frédérik Oger5Charlène Carney6Isabel C. Lopez-Mejia7Emmanuelle Durand8Iandry Rabearivelo9Amélie Bonnefond10Emilie Caron11Lluis Fajas12Christian Dani13Philippe Froguel14Jean-Sébastien Annicotte15Lille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceUniversité Côte d'Azur, CNRS, INSERM, iBV, Faculté de Médecine, F-06107 Nice Cedex 2, FranceLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceCenter for Integrative Genomics, Université de Lausanne, CH-1015 Lausanne, SwitzerlandLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceLille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, FranceINSERM, UMR S-1172, Development and Plasticity of Postnatal Brain, F-59000 Lille, FranceCenter for Integrative Genomics, Université de Lausanne, CH-1015 Lausanne, SwitzerlandUniversité Côte d'Azur, CNRS, INSERM, iBV, Faculté de Médecine, F-06107 Nice Cedex 2, FranceLille 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; Corresponding authors. UMR 8199 (CNRS/Université de Lille 2/Institut Pasteur de Lille), Faculté de Médecine – Pôle recherche, 1 place de Verdun, 59045 Lille Cedex, France.Lille University, UMR 8199 – EGID, F-59000 Lille, France; CNRS, UMR 8199, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France; Corresponding authors. UMR 8199 (CNRS/Université de Lille 2/Institut Pasteur de Lille), Faculté de Médecine – Pôle recherche, 1 place de Verdun, 59045 Lille Cedex, France.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: Obesity, Type 2 diabetes, Insulin sensitivity, Energy expenditure, cdkn2a, Genome-wide association study, Adipose tissue browninghttp://www.sciencedirect.com/science/article/pii/S2212877817309353 |
| spellingShingle | Nabil Rabhi Sarah Anissa Hannou Xavier Gromada Elisabet Salas Xi Yao Frédérik Oger Charlène Carney Isabel C. Lopez-Mejia Emmanuelle Durand Iandry Rabearivelo Amélie Bonnefond Emilie Caron Lluis Fajas Christian Dani Philippe Froguel Jean-Sébastien Annicotte Cdkn2a deficiency promotes adipose tissue browning Molecular Metabolism |
| title | Cdkn2a deficiency promotes adipose tissue browning |
| title_full | Cdkn2a deficiency promotes adipose tissue browning |
| title_fullStr | Cdkn2a deficiency promotes adipose tissue browning |
| title_full_unstemmed | Cdkn2a deficiency promotes adipose tissue browning |
| title_short | Cdkn2a deficiency promotes adipose tissue browning |
| title_sort | cdkn2a deficiency promotes adipose tissue browning |
| url | http://www.sciencedirect.com/science/article/pii/S2212877817309353 |
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