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

Mar Quiñones, Omar Al-Massadi, Cintia Folgueira, Stephan Bremser, Rosalía Gallego, Leonardo Torres-Leal, Roberta Haddad-Tóvolli, Cristina García-Caceres, Rene Hernandez-Bautista, Brian Y. H. Lam, Daniel Beiroa, Estrella Sanchez-Rebordelo, Ana Senra, Jose A. Malagon, Patricia Valerio, Marcos F. Fondevila, Johan Fernø, Maria M. Malagon, Raian Contreras, Paul Pfluger, Jens C. Brüning, Giles Yeo, Matthias Tschöp, Carlos Diéguez, Miguel López, Marc Claret, Peter Kloppenburg, Guadalupe Sabio and Ruben Nogueiras ()
Additional contact information
Mar Quiñones: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Omar Al-Massadi: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Cintia Folgueira: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Stephan Bremser: University of Cologne
Rosalía Gallego: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Leonardo Torres-Leal: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Roberta Haddad-Tóvolli: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Cristina García-Caceres: Helmholtz Zentrum München
Rene Hernandez-Bautista: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Brian Y. H. Lam: Addenbrooke’s Hospital
Daniel Beiroa: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Estrella Sanchez-Rebordelo: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Ana Senra: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Jose A. Malagon: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Patricia Valerio: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Marcos F. Fondevila: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Johan Fernø: University of Bergen
Maria M. Malagon: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)
Raian Contreras: Helmholtz Zentrum München
Paul Pfluger: Helmholtz Zentrum München
Jens C. Brüning: University of Cologne
Giles Yeo: Addenbrooke’s Hospital
Matthias Tschöp: Helmholtz Zentrum München
Carlos Diéguez: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Miguel López: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Marc Claret: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Peter Kloppenburg: University of Cologne
Guadalupe Sabio: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III
Ruben Nogueiras: University of Santiago de Compostela-Instituto de Investigación Sanitaria

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05711-6

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