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 PflugerJens C. Brüning, Giles Yeo, Matthias Tschöp, Carlos Diéguez, Miguel López, Marc Claret, Peter Kloppenburg, Guadalupe Sabio, Ruben Nogueiras

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

46 Zitate (Scopus)

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.

OriginalspracheEnglisch
Aufsatznummer3432
FachzeitschriftNature Communications
Jahrgang9
Ausgabenummer1
DOIs
PublikationsstatusVeröffentlicht - 1 Dez. 2018
Extern publiziertJa

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