A NOVEL ROLE FOR THE TUMOR-SUPPRESSOR PAR-4 IN REGULATION OF ADIPOGENESIS AND OBESITY

• Main Author: Sledziona, James
• Format: Others
• Published: UKnowledge 2018
• Subjects: Par-4; Adipogenesis; PPARγ; Obesity; Tumor Suppressor; Medicine and Health Sciences
• Online Access: https://uknowledge.uky.edu/toxicology_etds/20; https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1020&context=toxicology_etds

Prostate Apoptosis Response-4 (Par-4) is a conserved and ubiquitous tumor-suppressor factor which can selectively induce apoptosis in tumor cells, while leaving normal cells unaffected. While Par-4 is well established as a tumor-suppressor, there have yet been no formal investigations as to whether it has a physiologic role in normal tissues. Early observations of Par-4 knockout mouse lines yielded that the adult mice displayed significant weight gain and fat accumulation compared to their wild-type counterparts while on a conventional chow diet. Interestingly, obese mouse and human subjects were found to exhibit reduced expression of Par-4 in adipose tissue as well as lower levels of secreted Par-4 in their plasma, compared to samples collected from lean human subjects. Subsequent in vitro experiments would show that loss of Par-4 has significant impact upon adipogenesis. Mechanistically, Par-4 loss during adipogenesis in cell culture correlated inversely with expression of the adipogenic transcription factor PPARγ. Subsequent experiments would demonstrate that Par-4 transcriptionally represses PPARγ at the promoter level. Thereby, we conclude that Par-4 regulates adipogenesis and lipid accumulation through transcriptional repression of the PPARγ promoter. This research utilizes novel models and may be used as the basis for Par-4-mediated therapies for obesity and metabolic disease.