Παρασκευή, 4 Μαρτίου 2016

The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction

Publication date: Available online 3 March 2016
Source:Cell Reports
Author(s): Che-Pei Kung, Julia I-Ju Leu, Subhasree Basu, Sakina Khaku, Frederick Anokye-Danso, Qin Liu, Donna L. George, Rexford S. Ahima, Maureen E. Murphy
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.

Graphical abstract

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Teaser

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.


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