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

Nat Commun. 2018 Aug 24;9(1):3432. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Agouti-Related Protein / metabolism
  • Animals
  • Diet / adverse effects*
  • Hypothalamus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Neurons / metabolism
  • Obesity / etiology*
  • Obesity / metabolism*
  • Pro-Opiomelanocortin / metabolism
  • Rats, Sprague-Dawley
  • Steroidogenic Factor 1 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Agouti-Related Protein
  • Steroidogenic Factor 1
  • Tumor Suppressor Protein p53
  • steroidogenic factor 1, mouse
  • Pro-Opiomelanocortin
  • Mitogen-Activated Protein Kinase 8