Cell Reports
Volume 14, Issue 10, 15 March 2016, Pages 2413-2425
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Article
The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction

https://doi.org/10.1016/j.celrep.2016.02.037Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

p53
obesity
diabetes
islet hypertrophy
NAFLD
lipid metabolism
inflammation
Pck1
Ccl2
Tnf
Npc1l1

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).