Topic Overview:
Peroxisome proliferator-activated receptors (PPARs) are orphan nuclear hormone receptors that influence biological processes by regulating gene expression. These receptors are recognized primarily for their metabolic functions but appear to also play essential roles in cellular differentiation and embryonic development. PPARs are expressed in three major forms—alpha, gamma, and delta—each of which exhibits variable expression among different tissues of the body and carries out distinct physiological and biological functions. 

Dr. Barak studies PPAR function, especially as it relates to placental development and adipogenesis. His early studies of PPARγ knockout mice demonstrated that PPARγ is critical for placental development, but the mechanism was unclear. Further investigations showed that trophoblasts, specialized placental cells that play an integral role in implantation and formation of the maternal-fetal interface, require PPARγ to differentiate and establish a structurally and functionally sound placenta. More recent studies using differential mRNA screens have identified novel PPARγ target genes related to its role in placental development.    
           
In addition, PPARγ also has a well-established role in adipocyte differentiation (adipogenesis), which is demonstrated by its ability to promote adipogenesis when artificially introduced to cultured cells as well as by the complete absence of fat cells in PPARγ knockout mice. Dr. Barak found that PPARγ is not required to establish the adipose primordium but is essential for the primordium to expand and differentiate into full-fledged adipose tissue. In knockout mice, no fat cells develop; however, in chimeric mice, wild type progenitors infiltrate the PPARγ-null primordium and invariably replace the defective tissue. In addition, Dr. Barak’s studies in conditional knockouts have shown that mature adipocytes die upon loss of PPARγ, but the cell death is mitigated by the regeneration of new adipocytes from the progenitor pool. Combined, these studies demonstrate that PPARγ is important for every stage of the adipocyte life cycle and reveal the dynamic nature of adipose tissue.   

Dr. Barak’s research integrates gene targeting methods with in vivo phenotyping, stem and primary cell cultures, and multi-paradigm screens for native PPAR target genes followed by molecular genetics analyses of select targets. He is working to develop rational ways to validate these target genes, enabling his laboratory to dissect the mechanisms by which PPARs and associated factors and co-factors regulate transcription.