Loss of Adipocyte MDM2 Causes Lipodystrophy by Inducing P53-Dependent Apoptosis and Senescence

Abstract

Adipose tissue is crucial for the maintenance of metabolic health. Activation of tumor suppressor p53 is known to induce adipose tissue dysfunction and its related metabolic diseases in obesity and aging. Here we show that murine double minute 2 (MDM2) acts as a gatekeeper of adipose health by restraining p53-mediated apoptosis and senescence. Adipocyte-specific deletion of MDM2 induces chronic and unrestrained activation of p53, which in turn triggers progressive loss of adipose tissues. Similar to other mouse models with lipodystrophy, mice lacking of adipocyte MDM2 develop hyperglycemia, hyperinsulinemia, hyperlipidemia and massive nonalcoholic fatty liver. Adiponectin-Cre-mediated deletion of MDM2 has no obvious effect on adipogenesis in cell-autonomous manner but induces apoptotic and senescent program in white and brown adipocytes. To ascertain whether the activation of p53 is responsible for the MDM2-null phenotypes, we generated an adipocyte specific MDM2-p53 double knockout mouse model. As expected, lipodystrophy and its associated metabolic disorders are not observed in adipocyte-MDM2-p53 double knockout mice. In addition, transplantation of subcutaneous white adipose tissue largely reverses diabetes, dyslipidemia and nonalcoholic fatty liver in adipocyte-specific MDM2 knockout mice. Together, our data suggest that the balance of MDM2-p53 signaling axis is crucial for proper functions and turnover of adipose tissues. Disclosure Z. Liu: None. L. Jin: None. B. Wang: None. K.K.Y. Cheng: None. A. Xu: None.