TY - JOUR
T1 - p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1
AU - Quiñones, Mar
AU - Al-Massadi, Omar
AU - Folgueira, Cintia
AU - Bremser, Stephan
AU - Gallego, Rosalía
AU - Torres-Leal, Leonardo
AU - Haddad-Tóvolli, Roberta
AU - García-Caceres, Cristina
AU - Hernandez-Bautista, Rene
AU - Lam, Brian Y.H.
AU - Beiroa, Daniel
AU - Sanchez-Rebordelo, Estrella
AU - Senra, Ana
AU - Malagon, Jose A.
AU - Valerio, Patricia
AU - Fondevila, Marcos F.
AU - Fernø, Johan
AU - Malagon, Maria M.
AU - Contreras, Raian
AU - Pfluger, Paul
AU - Brüning, Jens C.
AU - Yeo, Giles
AU - Tschöp, Matthias
AU - Diéguez, Carlos
AU - López, Miguel
AU - Claret, Marc
AU - Kloppenburg, Peter
AU - Sabio, Guadalupe
AU - Nogueiras, Ruben
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052238323&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05711-6
DO - 10.1038/s41467-018-05711-6
M3 - Article
C2 - 30143607
AN - SCOPUS:85052238323
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3432
ER -