Researchers led by scientists at Harvard Medical School and Pfizer Inc. have independently discovered a gene that controls fat cell development. Their studies, published in the January 1 issue of Genes & Development, are significant because obesity affects approximately 1 in 4 adults and 1 in 5 children in the United States alone.
Drs. Bruce Spiegelman (Harvard Medical School) and Heidi Camp (Pfizer) 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 developing therapies to treat obesity.
Adipogenesis is a two-step developmental process by which undifferentiated "mesenchymal" cells differentiate into "pre-adipocytes" which then undergo a second differentiation step to become lipid-filled adipocytes (fat cells). The new studies show that PPARgamma triggers the transition from pre-adipocyte to fat cell.
Dr. Spiegelman and his colleagues created cells lacking PPARgamma and demonstrated that previously identified components of the adipogenic cascade were unable to trigger adipogenesis in the absence of PPARgamma. This evidence suggests that PPARgamma is the critical player in the fat cell differentiation pathway.
Dr. Camp and her colleagues at Sangamo Biosciences went one step further. They identified precisely 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. 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 different functions of these two isoforms had remained a mystery.