@article{ed6dea7a3b4c4f80823da73e3589d7f1,
title = "The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction",
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, Diabetes, Inflammation, Islet hypertrophy, Lipid metabolism, NAFLD, Npc1l1, Obesity, P53, Pck1, Tnf",
author = "Kung, {Che Pei} and Leu, {Julia I.Ju} and Subhasree Basu and Sakina Khaku and Frederick Anokye-Danso and Qin Liu and George, {Donna L.} and Ahima, {Rexford S.} and Murphy, {Maureen E.}",
note = "Funding Information: We would like to thank Frederick Keeney and James Hayden for their assistance with imaging analysis, Dmitri Gourevitch for help with mouse tissue sectioning and H&E staining, and Marie Webster for help with senescence-associated β-galactosidase staining. We would like to thank Alex Kist and Abbey Goldenberg for blinded counting of IHC images as well as Matt Jennis and Jeremy Scott for their help with in vivo experiments. This project was supported by NIH grant CA102184 (to M.E.M.), P01 CA114046-07 (to D.L.G.), the Penn Diabetes Research Center Mouse Phenotyping Core grant P30DK19525, and the Penn Molecular Pathology & Imaging Core grant P30DK050306. Support for Core Facilities utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute. Funding Information: We would like to thank Frederick Keeney and James Hayden for their assistance with imaging analysis, Dmitri Gourevitch for help with mouse tissue sectioning and H&E staining, and Marie Webster for help with senescence-associated {\ss}-galactosidase staining. We would like to thank Alex Kist and Abbey Goldenberg for blinded counting of IHC images as well as Matt Jennis and Jeremy Scott for their help with in vivo experiments. This project was supported by NIH grant CA102184 (to M.E.M.), P01 CA114046-07 (to D.L.G.), the Penn Diabetes Research Center Mouse Phenotyping Core grant P30DK19525, and the Penn Molecular Pathology & Imaging Core grant P30DK050306. Support for Core Facilities utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute. Publisher Copyright: {\textcopyright} 2016 The Authors.",
year = "2016",
month = mar,
day = "15",
doi = "10.1016/j.celrep.2016.02.037",
language = "English (US)",
volume = "14",
pages = "2413--2425",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}