p53 Functions in Adipose Tissue Metabolism and Homeostasis

Abstract

As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue- and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53’s impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases.

P53/PANK1/miR‐107 signalling pathway spans the gap between metabolic reprogramming and insulin resistance induced by high‐fat diet

“…Zoltan Derdak demonstrated that pharmacologic inhibition of p53 with pifithrin‐α p‐nitro attenuates hepatic steatosis and liver injury in C57BL/6 mice fed HFD for 8 weeks . Moreover, systemic pifithrin‐α administration considerably diminished P53 levels and ameliorated Akt phosphorylation in all peripheral tissues including adipose tissues and alleviated IR . As Mdm2 protein functions as an E3 ubiquitin ligase that inhibits p53 transcriptional activation, the Mdm2 C305F mice are resistant to HFD‐induced obesity and obesity‐associated illnesses .…”

“…11 Moreover, systemic pifithrin-α administration considerably diminished P53 levels and ameliorated Akt phosphorylation in all peripheral tissues including adipose tissues and alleviated IR. 33 As Mdm2 protein functions as an E3 ubiquitin ligase that inhibits p53 transcriptional activation, the Mdm2 C305F mice are resistant to HFD-induced obesity and obesity-associated illnesses. 34 Our results showed that P53 protein levels were markedly elevated in the liver tissue induced by HFD for 12 weeks and PA incubation enhanced the expression of P53 in AML12 cells.…”

A Mouse Homolog of a Human TP53 Germline Mutation Reveals a Lipolytic Activity of p53

“…The masses of all three adipose tissue types were lower in p53 178C/C mice, with a more pronounced effect on iWAT, which showed smaller adipocytes compared with p53 wild-type or null mice ( Figure 2B). Given the various contrasting reports of BAT regulation by p53 (Krstic et al, 2018), we examined BAT mitochondria and the thermogenesis phenotype of p53 178C/C mice but did not observe significant differences, consistent with only a modest decrease in its mass .…”

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

“…Contrary to its role as a tumor suppressor, the sustained activation of p53 signaling has been linked to the development of insulin resistance and adiposity. Activation of p53 also contributes to the induction of inflammatory cytokines that can promote the initiation and progression of cancer …”

“…Activation of p53 also contributes to the induction of inflammatory cytokines that can promote the initiation and progression of cancer. [22][23][24] Another pathway that seems to associate obesity with cancer development is genetic instability. 25 Many studies have indicated that obesity-related modulations in DNA damage and/or repair pathways may be involved in obesity-induced genetic instability.…”