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

Author(s):Show less -

Quinones, Mar ^{[1, 2]} ; Al-Massadi, Omar ^{[1, 2]} ; Folgueira, Cintia ^{[1, 2]} ; Bremser, Stephan ^{[3, 4]} ; Gallego, Rosalia ^[5] ; Torres-Leal, Leonardo ^[2] ; Haddad-Tovolli, Roberta ^{[6, 7]} ; Garcia-Caceres, Cristina ^[8] ; Hernandez-Bautista, Rene ^[2] ; Lam, Brian Y. H. ^[9] ; Beiroa, Daniel ^{[1, 2]} ; Sanchez-Rebordelo, Estrella ^{[1, 2]} ; Senra, Ana ^[2] ; Malagon, Jose A. ^[2] ; Valerio, Patricia ^[2] ; Fondevila, Marcos F. ^[2] ; Ferno, Johan ^{[10, 11]} ; Malagon, Maria M. ^{[1, 12]} ; Contreras, Raian ^[8] ; Pfluger, Paul ^[8] ; Bruening, Jens C. ^{[13, 14, 15]} ; Yeo, Giles ^[9] ; Tschoep, Matthias ^[8] ; Dieguez, Carlos ^{[1, 2]} ; Lopez, Miguel ^{[1, 2]} ; Claret, Marc ^{[6, 7]} ; Kloppenburg, Peter ^{[3, 4]} ; Sabio, Guadalupe ^[16] ; Nogueiras, Ruben ^{[1, 2]}

Affiliation:Show less -

^[1] CIBER Fisiopatol Obesidad & Nutr CIBERobn, Santiago De Compostela 15706 - Spain

^[2] Univ Santiago de Compostela, Inst Invest Sanitaria, CIMUS, Dept Physiol, Santiago De Compostela 15782 - Spain

^[3] Univ Cologne, Inst Zool, Bioctr, D-50923 Cologne - Germany

^[4] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50923 Cologne - Germany

^[5] Univ Santiago de Compostela, Sch Med, Dept Morphol Sci, Inst Invest Sanitaria, Santiago De Compostela 15782 - Spain

^[6] IDIBAPS, Neuronal Control Metab NeuCoMe Lab, Barcelona 08036 - Spain

^[7] CIBER Diabet & Enfermedades Metabol Asociadas CIB, Barcelona 08036 - Spain

^[8] Helmholtz Zentrum Munchen, Inst Diabet & Obes, Helmholtz Diabet Ctr, D-85764 Neuherberg - Germany

^[9] Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Addenbrookes Hosp, MRC Metab Dis Unit, Metab Res Labs, Cambridge CB2 0QQ - England

^[10] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, N-5007 Bergen - Norway

^[11] Haukeland Hosp, Hormone Lab, N-5021 Bergen - Norway

^[12] Univ Cordoba, Dept Cell Biol Physiol & Immunol, Inst Maimonides Invest Biomed Cordoba IMIBIC, Hosp Univ Reina Sofia, E-14004 Cordoba - Spain

^[13] Univ Cologne, Inst Genet & Ctr Mol Med CMMC, Dept Mouse Genet & Metab, Zulpicher Str 47b, D-50674 Cologne - Germany

^[14] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Zulpicher Str 47b, D-50674 Cologne - Germany

^[15] Max Planck Inst Neurol Res, Gleueler Str 50, D-50931 Cologne - Germany

^[16] Fdn Ctr Nacl Invest Cardiovasc Carlos III, Madrid 28029 - Spain

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 9, AUG 24 2018.
• Web of Science Citations: 10

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. (AU)

• FAPESP's process: 16/01868-2 - Translatome analysis of mouse POMC neurons and epigenetic analysis of the median eminence BBB in diet-induced obese offspring
• Grantee: Roberta Haddad Tóvolli
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor