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