The activity of a protein called peroxisome proliferator-activated receptor gamma (or PPARγ for short) plays a central role in activating pathways required for adipocytes to form and function. "PPARγ is interesting because it is itself activated by lipids," said Saez. "When excess lipids are present in the body, the lipids turn on PPARγ so that it stimulates the formation of more fat cells to deal with these lipids."
In contrast, another pathway, regulated by proteins in a family called Wnt, blocks adipocyte differentiation, so it needs to be turned off for adipocytes to form.
A Dual Regulator of Differentiation
To find additional players in adipocyte formation, Saez, Tontonoz, and colleagues induced cells growing in a dish to differentiate into adipocytes. The scientists then individually tested the ability of 18,000 genes to augment the conversion of undifferentiated cells into fully functioning adipocytes, looking for genes that might play a role in this process.
In this way, they identified the gene encoding the TLE3 protein, which had never before been linked to fat development.
Saez, Tontonoz, and colleagues discovered that PPARγ turns on the production of TLE3. TLE3 then forms a complex with PPARγ and helps it turn on other genes and pathways needed for adipocyte formation.
In addition, TLE3 turns off Wnt signaling. "This is how Wnt gets shut off to allow differentiation to occur," said Saez. "TLE3 has a dual function: it is a positive regulator for PPARγ and a negative regulator for Wnt."
Novel Diabetes Drug Targets
A class of drugs introduced in the 1990s to treat diabetes, the thiazolidinediones, acts by stimulating PPARγ activity. But these drugs are far from optimal. Recently one of them, rosiglitazone (Avandia), wa
|Contact: Mika Ono|
Scripps Research Institute