Cell Reports
Volume 18, Issue 4, 24 January 2017, Pages 1005-1018
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Article
Protection against High-Fat-Diet-Induced Obesity in MDM2C305F Mice Due to Reduced p53 Activity and Enhanced Energy Expenditure

https://doi.org/10.1016/j.celrep.2016.12.086Get rights and content
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Highlights

  • Mdm2C305F mice exhibit longer lifespan and are resistant to HFD-induced obesity

  • HFD induces MYC- and RPL11-dependent p53 expression in WT but not Mdm2C305F mice

  • Lower p53 activity in HFD-fed Mdm2C305F mice increases levels of GLUT4 and SIRT1

  • Increased GLUT4 and SIRT1 enhances NAD+ biosynthesis and energy expenditure

Summary

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

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

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