Obesity is a well known risk factor for prostate, breast and colon cancer, but recent studies have shown that a protein responsible for generating fat cells also plays an important role in cancer. Researchers at the Genome Institute of Singapore have conducted, for the first time, a genome-wide analysis of how the protein, called perixosome proliferator-activated receptor gamma (PPARg), turns on various genes related to obesity.
Simply suppressing the protein entirely could prevent the generation of adipocytes – the precursors to fat cells – the researchers say, but it would decrease the protein’s beneficial properties. Instead, the researchers believe that by identifying the gene targets of PPARg, they could open up new targets for drug development against a number of diseases, including obesity, diabetes and cancer. They present their findings today at the AACR Centennial Conference on Translational Cancer Medicine.
“To date, only a limited number of direct targets for PPARg have been identified. Our findings provide a genome-wide map of PPARg binding sites during the course of adipocyte differentiation,” said M. Sabry Hamza, Ph.D, a postdoctoral research fellow at the Genome Institute of Singapore, a division of Singapore’s Agency for Science, Technology and Research (A*STAR). “These results together with the expression profile of genes that are dependent of PPARg expression provide us with clues into the transcriptional circuitry during adipogenesis, the process by which adipocytes differentiate into different types of fat tissue.”
With funding from A*STAR, “we have identified direct targets of PPARg, that when inhibited lead to a dramatic reduction of adipogenic potential,” Hamza said. “Ongoing analysis will help us decipher whether these direct targets control adipogenesis, insulin sensitization or determination of fat cell type.”
According to Hamza, PPARg inhibits the proliferation and lowers the threshold for apoptosis -- the process by which cancer cells destroy themselves. “In addition, significant increase in tumor suppressor BRCA1 is induced when breast cancer cells are exposed to PPARg agonists,” said Hamza. “Although indirect, the role of PPARg as it relates to obesity and cancer is intriguing.”
So far, Hamza and his colleagues have identified a number of new PPARg target genes which are connected to adipogenesis and insulin sensitivity. Currently available marketed oral hypoglycemic drugs, although very potent in treating type II diabetes, cause detrimental sides effects including weight gain, liver toxicity and heart disease, says Hamza. “Using drugs which target specifically those PPARg targets regulating insulin sensitivity could hence present a safer and more efficient therapeutical approach,” said Hamza.
According to Hamza, the researchers’ next step will be to apply their data to mouse models in order to compare PPARg activity in fat tissue of mice under high-fat and normal conditions and to further characterize the regulation of PPARg target genes identified in this study.