title: Protection against High-Fat-Diet-Induced Obesity in MDM2C305FMice Due to Reduced p53 Activity and Enhanced Energy Expenditure.
abstract: The RPL11-MDM2 interaction constitutes a p53 signaling pathway activated by deregulated ribosomal biosynthesis in response to stress. Mice bearing an MDM2C305Fmutation that disrupts RPL11-MDM2 binding were analyzed on a high-fat diet (HFD). The Mdm2C305F/C305Fmice, although phenotypically indistinguishable from wild-type (WT) mice when fed normal chow, demonstrated decreased fat accumulation along with improved insulin sensitivity and glucose tolerance after prolonged HFD feeding. We found that HFD increases expression of c-MYC and RPL11 in both WT and Mdm2C305F/C305Fmice; however, p53 was induced in WT but not in Mdm2C305F/C305Fmice. Reduced p53 activity in HFD-fed Mdm2C305F/C305Fmice resulted in higher levels of p53 downregulated targets GLUT4 and SIRT1, leading to increased biosynthesis of NAD+, and increased energy expenditure. Our study reveals a role for the RPL11-MDM2-p53 pathway in fat storage during nutrient excess and suggests that targeting this pathway may be a potential treatment for obesity.
authors.affiliation: Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA.
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA.
authors.forename: Tae-Hyung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Franklin
authors.affiliation: Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China. Electronic address: ypzhang@med.unc.edu.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D008136:Longevity; D051379:Mice; D009243:NAD / Q000096:biosynthesis; D050903:Nicotinamide N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D016271:Proto-Oncogene Proteins c-myc; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D009243:NAD; D050903:Nicotinamide N-Methyltransferase; D051736:Proto-Oncogene Proteins c-mdm2; D056564:Sirtuin 1
keywords: MDM2; NAD(+); energy expenditure; high-fat diet; p53; ribosomal protein