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Cell Rep. 2016 Mar 15;14(10):2413-25. doi: 10.1016/j.celrep.2016.02.037. Epub 2016 Mar 3.

The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction.

Author information

1
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
2
Department of Genetics, The Perelman School at the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
3
Institute for Diabetes, Obesity, and Metabolism, The Perelman School at the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
4
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA; Biostatistics Unit, The Wistar Institute, Philadelphia, PA 19104, USA.
5
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: mmurphy@wistar.org.

Abstract

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:

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

PMID:
26947067
PMCID:
PMC4926645
DOI:
10.1016/j.celrep.2016.02.037
[Indexed for MEDLINE]
Free PMC Article

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