title: DNA Damage and the Activation of the p53 Pathway Mediate Alterations in Metabolic and Secretory Functions of Adipocytes.
abstract: Activation of the p53 pathway in adipose tissue contributes to insulin resistance associated with obesity. However, the mechanisms of p53 activation and the effect on adipocyte functions are still elusive. Here we found a higher level of DNA oxidation and a reduction in telomere length in adipose tissue of mice fed a high-fat diet and an increase in DNA damage and activation of the p53 pathway in adipocytes. Interestingly, hallmarks of chronic DNA damage are visible at the onset of obesity. Furthermore, injection of lean mice with doxorubicin, a DNA damage-inducing drug, increased the expression of chemokines in adipose tissue and promoted its infiltration by proinflammatory macrophages and neutrophils together with adipocyte insulin resistance. In vitro, DNA damage in adipocytes increased the expression of chemokines and triggered the production of chemotactic factors for macrophages and neutrophils. Insulin signaling and effect on glucose uptake and Glut4 translocation were decreased, and lipolysis was increased. These events were prevented by p53 inhibition, whereas its activation by nutlin-3 reproduced the DNA damage-induced adverse effects. This study reveals that DNA damage in obese adipocytes could trigger p53-dependent signals involved in alteration of adipocyte metabolism and secretory function leading to adipose tissue inflammation, adipocyte dysfunction, and insulin resistance.
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Vergoni
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Cornejo
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Gilleron
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Mansour
authors.initials: M
authors.lastname: Djedaini
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Ceppo
authors.affiliation: Université Côte d'Azur, C3M, Nice, France INSERM, UMR 1065, C3M, Team 2 Cell Death, Differentiation and Cancer, Nice, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Gwennaelle
authors.initials: G
authors.lastname: Bouget
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Ginet
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France INSERM, UMR 1062, Nutrition, Obesity and Risk of Thrombosis, Marseille, France.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gonzalez
authors.affiliation: CNRS, UMR 8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Maillet
authors.affiliation: CNRS, UMR 8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes, Lille, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dhennin
authors.affiliation: CNRS, UMR 8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes, Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Verbanck
authors.affiliation: Université Côte d'Azur, C3M, Nice, France INSERM, UMR 1065, C3M, Team 2 Cell Death, Differentiation and Cancer, Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.affiliation: CNRS, UMR 8199, Lille Pasteur Institute, Lille, France Lille University, Lille, France European Genomic Institute for Diabetes, Lille, France Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, U.K.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
authors.affiliation: INSERM, UMR 1065, C3M, Team 7 Molecular and Cellular Physiopathology of Obesity and Diabetes, Nice, France Université Côte d'Azur, C3M, Nice, France cormont@unice.fr.
authors.forename: Mireille
authors.initials: M
authors.lastname: Cormont
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002633:Chemotaxis / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000235:genetics* / Q000502:physiology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016615:Telomere / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53