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. TITLE=Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.860446 DOI=10.3389/fonc.2022.860446 ISSN=2234-943X 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.