p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1
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. ; This work has been supported by grants from Ministerio de Economia y Competitividad (C.D.: BFU2011-29102; M.L.: SAF2015-71026-R; and BFU2015-70454-REDT/Adipoplast; G.S.: SAF2016-79126-R; R.N.: BFU2015-70664R), Xunta de Galicia (M.L.: 2015-CP079 and 2016-PG068; R.N.: 2015-CP080 and 2016-PG057), Atresmedia Corporacion (M.L.), Astra Zeneca Fundation (R.N.), the European Foundation for the Study of Diabetes (G.S. and R.N.), DFG grant SFB 1218/TP B07 (P.K.); Helse Vest RHF (J.F.; the Western Norway Regional Health Authority); Comunidad de Madrid IMMUNOTHERCAN-CM (B2017/BMD3733) (G.S.), Fundacion BBVA (G.S.). Centro de Investigacion Biomedica en Red (CIBER) de Fisiopatologia de la Obesidad y Nutricion (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: ERC StG-2011-OBESITY53-281408 to R.N. M.Q. is a recipient of a Postdoctoral fellowship from Galician Government (Xunta de Galicia ED481B2014/039-0). R.H.-T. is a recipient of a postdoctoral fellowship FAPESP (Process: 2016/01868-2). O.A.-M. is funded by the ISCIII/SERGAS thought a research contract ``Sara Borrell´´ (CD14/00091). E.S.-R. is recipient of a Predoctoral fellowship from Ministerio de Economia y Competitividad (ref: BES-2013-062796). ; Sí
