Author:
Araujo Nathalia,Sledziona James,Noothi Sunil K.,Burikhanov Ravshan,Hebbar Nikhil,Ganguly Saptadwipa,Shrestha-Bhattarai Tripti,Zhu Beibei,Katz Wendy S.,Zhang Yi,Taylor Barry S.,Liu Jinze,Chen Li,Weiss Heidi L.,He Daheng,Wang Chi,Morris Andrew J.,Cassis Lisa A.,Nikolova-Karakashian Mariana,Nagareddy Prabhakar R.,Melander Olle,Evers B. Mark,Kern Philip A.,Rangnekar Vivek M.
Abstract
Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.
Funder
National Institutes of Health
Cited by
1 articles.
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