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

• Published in: Nature communications Vol. 9; no. 1; pp. 3432 - 16
• Main Authors: Quiñones, Mar, Al-Massadi, Omar, Folgueira, Cintia, Bremser, Stephan, Gallego, Rosalía, Torres-Leal, Leonardo, Haddad-Tóvolli, Roberta, García-Caceres, Cristina, Hernandez-Bautista, Rene, Lam, Brian Y. H., Beiroa, Daniel, Sanchez-Rebordelo, Estrella, Senra, Ana, Malagon, Jose A., Valerio, Patricia, Fondevila, Marcos F., Fernø, Johan, Malagon, Maria M., Contreras, Raian, Pfluger, Paul, Brüning, Jens C., Yeo, Giles, Tschöp, Matthias, Diéguez, Carlos, López, Miguel, Claret, Marc, Kloppenburg, Peter, Sabio, Guadalupe, Nogueiras, Ruben
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 38/77; 38/79; 38/88; 59/36; 64/60; 692/163/2743/2742; 692/163/2743/393; 82/80; Adaptation; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - metabolism; Agouti-Related Protein - metabolism; Animals; Body weight; Body weight loss; c-Jun protein; Diet; Diet - adverse effects; Energy balance; Food intake; Ghrelin; Humanities and Social Sciences; Hypothalamus; Hypothalamus - metabolism; JNK protein; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 8 - genetics; Mitogen-Activated Protein Kinase 8 - metabolism; multidisciplinary; Neurons; Neurons - metabolism; Obesity; Obesity - etiology; Obesity - metabolism; p53 Protein; Phenotypes; Pro-Opiomelanocortin - metabolism; Proopiomelanocortin; Rats, Sprague-Dawley; Rodents; Science; Science (multidisciplinary); Steroidogenic Factor 1 - metabolism; Thermogenesis; Transcription factors; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Weight control
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05711-6

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. Emerging studies suggest that p53 is an important regulator of energy metabolism, yet there is little known about the metabolic function of this tumor suppressor in the hypothalamus. Here, authors illustrate that p53, specifically in AgRP neurons, is required for adaptation to diet-induced obesity.