The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction

p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high-fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more-severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small-molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism, and inflammation. [Display omitted] •A high-fat diet was fed to mice containing P72 and R72 variants of p53•Significantly increased fat accumulation was evident in R72 mice•Significant increases in two p53 target genes, Tnf and Npc1l1, occurred in R72 mice•Inhibitors of Tnf and Npc1l1 block the increased weight gain in R72 mice Kung et al. show that the R72 variant of p53 leads to increased obesity and glucose intolerance in mice fed a high-fat diet. They identify two p53 target genes, Tnf and Npc1l1, that are preferentially bound by R72 and that are responsible for this phenotype.