Protection against High-Fat-Diet-Induced Obesity in MDM2 C305F Mice Due to Reduced p53 Activity and Enhanced Energy Expenditure

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Cell Differentiation
  • Cell Line
  • Diet, High-Fat*
  • Energy Metabolism
  • Gene Expression Regulation
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Longevity
  • Mice
  • NAD / biosynthesis
  • Nicotinamide N-Methyltransferase / genetics
  • Nicotinamide N-Methyltransferase / metabolism
  • Obesity / etiology*
  • Obesity / metabolism
  • Obesity / mortality
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Ribosomal Proteins / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Survival Rate
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Glucose Transporter Type 4
  • Proto-Oncogene Proteins c-myc
  • Ribosomal Proteins
  • Tumor Suppressor Protein p53
  • NAD
  • Nicotinamide N-Methyltransferase
  • Proto-Oncogene Proteins c-mdm2
  • Sirtuin 1