Expression of p53 in human adipose tissue correlates positively with FAS and BMI

Abstract

Activation of Fas (CD95) in adipocytes inhibits browning and may contribute to body weight gain in mice. Moreover, Fas expression in white adipose tissue (WAT) correlates positively with body mass index (BMI) in humans. However, molecular pathways involved in the inhibitory effect of Fas on energy metabolism remain incompletely understood. Herein, we report that protein levels of the tumor suppressor p53 were reduced in primary white adipocytes of adipocyte-specific Fas-knockout mice. Moreover, Fas ligand (FasL) treatment increased p53 concentrations in cultured adipocytes and decreased mitochondrial oxygen consumption in control but not in p53-depleted cells, indicating that Fas activation reduces energy expenditure in a p53-dependent manner. In line, in differentiated human mesenchymal stem cells and WAT derived from different anatomical depots, FAS expression was positively associated with p53. Furthermore, p53 expression in human subcutaneous and visceral WAT correlated positively with BMI, whereas its expression in visceral WAT was inversely associated with insulin sensitivity (as assessed by hyperinsulinemic-euglycemic clamp). Taken together, our data suggest that Fas regulates p53 expression in adipocytes, and may thereby affect body weight gain and insulin sensitivity.

Fig. 1. Fas regulates p53 protein levels in adipocytes.

a Left panel: Western blot and quantification of Fas and p53 protein levels in white adipocytes harvested from HFD-fed Fas^F/F and Fas^Δadipo mice. n = 6–7 mice per group. **p < 0.01. Right panel: Western blot and quantification of p53 protein levels in subcutaneous white adipocytes treated with or without 0.4 ng/ml FasL for 24 h. n = 5 cell culture wells of 3 independent experiments. *p < 0.05. b Representative Western blot and oxygen consumption rate (OCR; n = 37–41 cell culture wells of 2 independent experiments) in control (Co) and p53-depleted (p53 KO) subcutaneous adipocytes treated with or without 0.4 ng/ml FasL for 72 h. Co vs. Co + FasL, p < 0.001; p53 KO vs. p53 KO + FasL, p = 0.43; Co vs. p53 KO, p < 0.001. c Basal and proton leak-linked respiration calculated from OCR data. *p < 0.05, **p < 0.01, ***p < 0.001. d Scatter plot and correlation coefficient (r) of FAS and p53 mRNA expression in differentiated human mesenchymal stem cells derived from paired femoral (n = 18) and abdominal (n = 16) subcutaneous adipose tissue samples. Statistical tests used: Mann–Whitney (left panel) and Student’s t test (right panel) for (a); two-way ANOVA for (b, c); Spearman correlation for (d).

Fig. 2. p53 expression in human WAT correlates positively with FAS and BMI.

a Scatter plot and correlation coefficient (r) of subcutaneous (sc; n = 254) or visceral (v; n = 250) WAT FAS mRNA and p53 mRNA expression. b Scatter plot and correlation coefficient (r) of p53 expression in scWAT (n = 281) or vWAT (n = 284) and BMI. c Scatter plot and correlation coefficient (r) of p53 expression in scWAT (n = 129) or vWAT (n = 128) and glucose infusion rate during hyperinsulinemic-euglycemic clamps. d Scatter plot and correlation coefficient (r) of scWAT (n = 255) or vWAT (n = 265) UCP1 and p53 mRNA expression. Statistical tests used: Spearman correlation.