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 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 only induced in WT but not in Mdm2C305F/C305F mice. Reduced p53 activity in HFD-fed Mdm2C305F/C305F mice resulted in higher levels of p53 down-regulated 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
