p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1.

Autor: Quiñones M; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain., Al-Massadi O; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain., Folgueira C; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain., Bremser S; Biocenter, Institute for Zoology, University of Cologne, 50923, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923, Cologne, Germany., Gallego R; Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain., Torres-Leal L; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain., Haddad-Tóvolli R; Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036, Barcelona, Spain., García-Caceres C; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764, Neuherberg, Germany., Hernandez-Bautista R; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain., Lam BYH; MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK., Beiroa D; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain., Sanchez-Rebordelo E; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain., Senra A; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain., Malagon JA; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain., Valerio P; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain., Fondevila MF; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain., Fernø J; KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, 5007, Bergen, Norway.; Hormone Laboratory, Haukeland University Hospital, 5021, Bergen, Norway., Malagon MM; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain.; Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigacion Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia/University of Cordoba, 14004, Córdoba, Spain., Contreras R; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764, Neuherberg, Germany., Pfluger P; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764, Neuherberg, Germany., Brüning JC; Department of Mouse Genetics and Metabolism, Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Zülpicher Strasse 47b, 50674, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47b, 50674, Cologne, Germany.; Max Planck Institute for Neurological Research, Gleueler Strasse 50, 50931, Cologne, Germany., Yeo G; MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK., Tschöp M; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764, Neuherberg, Germany., Diéguez C; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain., López M; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain., Claret M; Neuronal Control of Metabolism (NeuCoMe) Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036, Barcelona, Spain., Kloppenburg P; Biocenter, Institute for Zoology, University of Cologne, 50923, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50923, Cologne, Germany., Sabio G; Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029, Madrid, Spain., Nogueiras R; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain. ruben.nogueiras@usc.es.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain. ruben.nogueiras@usc.es.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2018 Aug 24; Vol. 9 (1), pp. 3432. Date of Electronic Publication: 2018 Aug 24.
DOI: 10.1038/s41467-018-05711-6
Abstrakt: p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity.
Databáze: MEDLINE
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