| First Author | Kon N | Year | 2018 |
| Journal | Oncotarget | Volume | 9 |
| Issue | 7 | Pages | 7282-7297 |
| PubMed ID | 29484110 | Mgi Jnum | J:286053 |
| Mgi Id | MGI:6390655 | Doi | 10.18632/oncotarget.23837 |
| Citation | Kon N, et al. (2018) Inhibition of Mdmx (Mdm4) in vivo induces anti-obesity effects. Oncotarget 9(7):7282-7297 |
| abstractText | Although cell-cycle arrest, senescence and apoptosis remain as major canonical activities of p53 in tumor suppression, the emerging role of p53 in metabolism has been a topic of great interest. Nevertheless, it is not completely understood how p53-mediated metabolic activities are regulated in vivo and whether this part of the activities has an independent role beyond tumor suppression. Mdmx (also called Mdm4), like Mdm2, acts as a major suppressor of p53 but the embryonic lethality of mdmx-null mice creates difficulties to evaluate its physiological significance in metabolism. Here, we report that the embryonic lethality caused by the deficiency of mdmx, in contrast to the case for mdm2, is fully rescued in the background of p53(3KR/3KR) , an acetylation-defective mutant unable to induce cell-cycle arrest, senescence and apoptosis. p53(3KR/3KR)/mdmx(-/-) mice are healthy but skinny without obvious developmental defects. p53(3KR/3KR)/mdmx(-/-) mice are resistant to fat accumulation in adipose tissues upon high fat diet. Notably, the levels of p53 protein are only slightly increased and can be further induced upon DNA damage in p53(3KR/3KR)/mdmx(-/-) mice, suggesting that Mdmx is only partially required for p53 degradation in vivo. Further analyses indicate that the anti-obesity phenotypes in p53(3KR/3KR)/mdmx(-/-) mice are caused by activation of lipid oxidation and thermogenic programs in adipose tissues. These results demonstrate the specific effects of the p53/Mdmx axis in lipid metabolism and adipose tissue remodeling and reveal a surprising role of Mdmx inhibition in anti-obesity effects beyond, commonly expected, tumor suppression. Thus, our study has significant implications regarding Mdmx inhibitors in the treatment of obesity related diseases. |
