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

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.

Hepatocyte p53 ablation induces metabolic dysregulation that is corrected by food restriction and vertical sleeve gastrectomy in mice

“…7,8,35 Considering that the increase in body weight following hepatocyte-specific p53 ablation was independent of food intake and associated with a decrease in energy expenditure, the mechanism of action underlying this impairment likely relates to p53's role in mitochondrial energetics. 7,8,35 Considering that the increase in body weight following hepatocyte-specific p53 ablation was independent of food intake and associated with a decrease in energy expenditure, the mechanism of action underlying this impairment likely relates to p53's role in mitochondrial energetics.…”

“…Studies in whole-body p53 KO mouse models report conflicting findings on the effect of p53 KO on body weight and metabolic homeostasis, with some studies finding that p53 KO decreases body weight and improves glucose regulation in mice on HFD 38 and others finding the opposite. 7,8,10 The discrepancy in findings in whole-body p53 KO models, maybe due to, in part, the development of compensatory pathways. 7,8,10 The discrepancy in findings in whole-body p53 KO models, maybe due to, in part, the development of compensatory pathways.…”

“…39,40 However, when p53 KO is studied using tissue-specific approaches, p53 KO is found to promote weight gain and metabolic impairment. 7,8,10 The discrepancy in findings in whole-body p53 KO models, maybe due to, in part, the development of compensatory pathways. These conflicting findings point to the need to generate a more refined understanding of p53 in metabolic regulation through the study of tissue-specific manipulations.…”

“…3 Thus, disruption of p53 signaling is a key | 1847 HOLTER ET aL. [5][6][7][8] Furthermore, impairments in p53 signaling in humans are associated with metabolic disease. 4 However, the metabolic actions of p53 have been shown to be highly relevant in the maintenance of metabolic homeostasis in noncancerous states as well.…”

HYPOTHesizing about central comBAT against obesity

“…However, the PVH action on BAT activity seems 530 more related to a modulatory role, whereas a direct control 531 remains unclear. In this sense, it has been reported that direct stimulations of PVH do not induce effects on BAT activity 533 [174,175], whereas the inhibitory projections from the PVH to the rRPa could be implicated in the decrease of the sympa-535 thetic activity of the BAT [175,176]. tryptophan activate BAT thermogenesis [178,[191][192][193].…”