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Cell Rep. 2017 Jan 24;18(4):1005-1018. doi: 10.1016/j.celrep.2016.12.086.

Protection against High-Fat-Diet-Induced Obesity in MDM2C305F Mice Due to Reduced p53 Activity and Enhanced Energy Expenditure.

Author information

1
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.
2
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.
3
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.

Abstract

The RPL11-MDM2 interaction constitutes a p53 signaling pathway activated by deregulated ribosomal biosynthesis in response to stress. Mice bearing an MDM2C305F mutation that disrupts RPL11-MDM2 binding were analyzed on a high-fat diet (HFD). The Mdm2C305F/C305F mice, 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/C305F mice; however, p53 was induced in WT but not in Mdm2C305F/C305F mice. Reduced p53 activity in HFD-fed Mdm2C305F/C305F mice 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.

KEYWORDS:

MDM2; NAD(+); energy expenditure; high-fat diet; p53; ribosomal protein

PMID:
28122227
PMCID:
PMC5560502
DOI:
10.1016/j.celrep.2016.12.086
[Indexed for MEDLINE]
Free PMC Article

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