Inhibition of Mdmx (Mdm4) in vivo induces anti-obesity effects
Ning Kon1, Donglai Wang1, Tongyuan Li1
1Institute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Abstract:
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 , an acetylation-defective mutant unable to induce cell-cycle arrest, senescence and apoptosis. p53/mdmx mice are healthy but skinny without obvious developmental defects. p53/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/mdmx mice, suggesting that Mdmx is only partially required for p53 degradation in vivo. Further analyses indicate that the anti-obesity phenotypes in p53/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.
Insights
The p53/Mdmx pathway regulates metabolism and obesity. Inhibiting Mdmx in mice with defective p53 prevents obesity by activating fat burning, suggesting Mdmx inhibitors for metabolic diseases.
Area of Science:
- Molecular biology
- Metabolism
- Cancer biology
Background:
- The tumor suppressor p53 has canonical roles in cell-cycle arrest, senescence, and apoptosis.
- Emerging evidence suggests p53 also plays a significant role in regulating metabolism, but its in vivo regulation and independent functions are not fully understood.
- Mdmx (Mdm4) is a key suppressor of p53, similar to Mdm2, but its physiological role in metabolism is difficult to assess due to embryonic lethality in mdmx-null mice.
Purpose of the Study:
- To investigate the physiological significance of the p53/Mdmx axis in metabolism, particularly in lipid metabolism and adipose tissue remodeling.
- To determine if Mdmx inhibition has roles beyond tumor suppression, specifically in metabolic regulation.
- To explore the therapeutic potential of Mdmx inhibitors for obesity-related diseases.
Main Methods:
- Generation and analysis of p53 acetylation-defective mutant mice (p53(Af)) crossed with mdmx-deficient mice (mdmx(-/-)).
- Assessment of embryonic lethality rescue and physiological phenotypes, including body weight and adipose tissue accumulation under high-fat diet.
- Analysis of p53 protein levels, lipid oxidation, and thermogenic gene expression in adipose tissues.
Main Results:
- Embryonic lethality of mdmx deficiency was rescued by the p53(Af) mutation, yielding viable p53(Af)/mdmx(-/-) mice.
- These mice were resistant to diet-induced obesity, exhibiting activated lipid oxidation and thermogenic programs in adipose tissues.
- Mdmx was found to be only partially required for p53 degradation in vivo, and p53(Af)/mdmx(-/-) mice showed a lean phenotype without developmental defects.
Conclusions:
- The p53/Mdmx axis specifically influences lipid metabolism and adipose tissue remodeling.
- Mdmx inhibition demonstrates anti-obesity effects independent of canonical p53 tumor suppressor functions.
- These findings highlight the potential of targeting Mdmx for the treatment of obesity and related metabolic disorders.
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