There is a gap in our understanding of how the white, brown, and beige adipocyte subtypes are programmed to adopt their distinct phenotypic characteristics of storing or burning energy. The imbalance between energy intake and expenditure can lead to obesity and metabolic disorders such as type 2 diabetes. White adipocytes store and mobilize energy for peripheral tissue consumption, while brown adipocytes store and burn energy during cold exposure to generate heat. Beige adipocytes behave like brown adipocytes, but appear in white adipose tissue with prolonged cold exposure. Our long-term objective is to better understand how adipocyte precursors are programed to adopt these distinct phenotypic characteristics. Ultimately our goal is to shift the energy balance from storage to expenditure. We have identified opposing transcriptional programs that distinguish between energy storage and expenditure. We have evidence that supports that TLE3 and Prdm16 counter each other's actions. Our hypothesis is that TLE3 directly interacts with Prdm16 to form a mutually neutralized coactivator complex to regulate energy storage or expenditure. Where a bound TLE3-Prdm16 complex is inactive, and unbound TLE3 or Prdm16 are free to interact with PPAR to stimulate energy storage or energy expenditure, respectively. We expect that this interaction will be most important in beige adipocytes where TLE3 and Prdm16 expression is high. Furthermore, we've identified a cold inducible factor, AES, that we hypothesize interacts with TLE3 to disrupt the TLE3/Prdm16 complex. Guided by strong preliminary data, this hypothesis will be tested in the following aims:
Aim1 will determine the functional significance of the TLE3- Prdm16 interaction, Aim2 will determine whether TLE3 blocks the appearance of beige adipocytes, and Aim3 will test whether AES stimulates the appearance of beige adipocytes by disrupting the interaction between TLE3 and Prdm16.
Under Aim1, we've engineered several TLE3 and Prdm16 deletions to map the domains that mediate the TLE3-Prdm16 interaction and have developed a yeast-two-hybrid system to identify point mutations that disrupt the TLE3-Prdm16 interface, while maintaining intact interactions with PPAR. These experiments will allow us to test the biological significance of the TLE3-Prdm16 interaction in beige adipocytes.
Under Aim2, we will utilize our unique gain and loss of function mouse models to test whether TLE3 blocks the cold-induced appearance of beige cells in subcutaneous adipose tissue.
Under Aim3, using mice with conditional deletion of AES in adipocytes, we will test whether AES is required for programming of brown or beige adipocytes. Understanding the transcriptional mechanisms that distinguish between the adipocyte subtypes will be key to identifying novel therapeutic targets to program cells to adopt the favorable brown/beige adipocyte phenotype to treat obesity.
The proposed research is relevant to public health because obesity increases the risk of developing chronic diseases such as type 2 diabetes. A thorough understanding of how fat cells are programmed to store or burn energy will be key to identifying new treatment strategies for obesity.
