Adipogenesis
One of the earliest recognized functions of PPAR was its central role in adipocyte differentiation. Misexpression of PPARγ in NIH-3T3 fibroblasts suffices to drive these otherwise non-adipogenic cells into adipogenesis. More importantly, mice completely deficient for PPARγ lack all forms of adipose tissue.
Nevertheless, the absence of PPARγ does not seem to interfere with the initial steps of fat cell formation. A tissue patch which expresses a lacZ transgene knocked in-frame into the PPARγ gene forms at the interscapular region of late PPARγ null embryos (rescued from placental insufficiency by tetraploid chimeras), conceivably representing the brown adipose anlage. Thus, neonatal fat deficiency stems from a defect in the elaboration, rather than the initial specification of PPARγ null adipocytes.
Studies in chimeric mice showed that, given the opportunity, wild-type cells will invariably populate the mature fat tissue. In preliminary experiments with chimeric pre-term embryos, we were able to capture a transition in motion, observing growth-arrested, undifferentiated null brown adipose fat pads invaded and gradually displaced by wt cells. Our chimeric mouse system provides a potent differential platform to compare and contrast the cellular and molecular properties of wt and PPARγ null pre-adipocytes, which for a short period reside next to each other in the remodeling anlage. We use this system to define PPARγ -regulated processes and genes and their placement within the entire adipogenic program.
In a related effort, we use a combination of a floxed PPARγ allele and an adipose-specific CRE transgene to evaluate the roles of PPARγ in mature adipocytes. Preliminary data suggest that the effect of PPARγ deficiency varies, and depends on the fat depot in question. This observation suggests that PPARγ plays distinct roles in various fat forms.
