%0 Journal Article
%T Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.
%A Araujo N
%A Sledziona J
%A Noothi SK
%A Burikhanov R
%A Hebbar N
%A Ganguly S
%A Shrestha-Bhattarai T
%A Zhu B
%A Katz WS
%A Zhang Y
%A Taylor BS
%A Liu J
%A Chen L
%A Weiss HL
%A He D
%A Wang C
%A Morris AJ
%A Cassis LA
%A Nikolova-Karakashian M
%A Nagareddy PR
%A Melander O
%A Evers BM
%A Kern PA
%A Rangnekar VM
%J Front Oncol
%V 12
%N 0
%D 2022
%M 35425699
%F 5.738
%R 10.3389/fonc.2022.860446
%X 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.