Obesity affects approximately 1 in 4 adults and 1 in 5 children in the United States. As the epidemic of obesity continues to grow, so does the research effort aimed at understanding the molecular mechanisms of fat development. As published in the January 1 issue of Genes & Development, scientists have made a significant advance towards this goal.
Drs. Bruce Spiegelman and Heidi Camp from Harvard and Pfizer, respectively, have determined that the gene which encodes the PPARgamma protein is responsible for fat cell development, or adipogenesis. PPARgamma is a nuclear hormone receptor that regulates gene expression in response to extra-cellular signals. The determination that PPARgamma2 is necessary for fat cell development provides a molecular target for rational drug design in the battle against the bulge.
Adipogenesis is a two-step developmental process by which an undifferentiated mesenchymal cell differentiates into a pre-adipocyte cell, which then undergoes a secondary differentiation step to become a lipid-filled adipocyte. These two research groups have discovered that PPARgamma is responsible for the transition from pre-adipocyte to fat cell.
Dr. Spiegelman and colleagues created cells lacking PPARgamma and demonstrated that previously identified components of the adipogenic cascade were unable to induce adipogenesis in the absence of PPARgamma. This evidence suggests that PPARgamma is the critical player in the fat differentiation pathway.
Dr. Camp and colleagues at Sangamo Biosciences went one step further and identified exactly which form of PPARgamma is responsible for fat cell development. The PPARgamma gene encodes two different protein products, or isoforms, called gamma1 and gamma2. Using Sangamo's zinc finger protein (ZFP) technology to control gene expression, Dr. Camp generated two cell populations: one lacking the gamma2 isoform and another lacking both isoforms. Similar to Dr. Spiegelman's results, both cell populations were unable to differentiate into fat cells.
In order to test exactly which isoform is responsible for fat cell differentiation, Dr. Camp selectively expressed either gamma1 or gamma2 in the cells that lacked both isoforms. She discovered that PPARgamma2 is singularly responsible for adipogenesis. Until now, the differential functions of these two isoforms had remained a mystery.