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.
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Che-Pei
authors.initials: CP
authors.lastname: Kung
authors.affiliation: Department of Genetics, The Perelman School at the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Julia I-Ju
authors.initials: JI
authors.lastname: Leu
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Subhasree
authors.initials: S
authors.lastname: Basu
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Sakina
authors.initials: S
authors.lastname: Khaku
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, The Perelman School at the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Anokye-Danso
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA; Biostatistics Unit, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Genetics, The Perelman School at the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Donna L
authors.initials: DL
authors.lastname: George
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, The Perelman School at the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: mmurphy@wistar.org.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D059305:Diet, High-Fat; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C572524:DRAM-1 protein, mouse; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Ccl2; NAFLD; Npc1l1; Pck1; Tnf; diabetes; inflammation; islet hypertrophy; lipid metabolism; obesity; p53