Chemicals can work differently through the same biological receptor to generate different types of fat cells and disrupt healthy metabolic functions, according to Stephanie Kim, Ph.D., in an Oct. 21 lecture at NIEHS.

Kim described how two chemicals, tributyltin (TBT) and triphenyl phosphate (TPhP), affect the process that triggers pre-fat cells to develop into different types of fat cells, called adipocytes. The chemicals bind to a type of receptor protein called peroxisome proliferator activated receptor (PPAR) gamma, which is essential in regulating adipocyte development.

“Different fat cells have different functions,” said Kim, a former Superfund Research Program (SRP) trainee at Boston University (BU) and winner of the 2018 SRP Karen Wetterhahn Award. “The white adipocyte is the fat cell that we are familiar with, which stores excess energy and generates hormones,” she explained. “When there is an abnormal increase in the number and size of white adipocytes, it can lead to metabolic dysfunction. But we also have other types of fat cells, and they support healthy metabolic function.”

These other fat cells, known as brown adipocytes, have more mitochondria and smaller lipid droplets. Recently, researchers identified a third type, called brown-in-white, or brite, fat cells, which are similar to brown fat but form in areas with white adipocytes.

Because brite and brown adipocytes have more mitochondria, they increase base metabolism. This may be the reason they are associated with healthier metabolic functions.

Same receptor, different effects

Kim studied how fat cells differentiate into either white or brite cells, in response to exposure to TBT and TPhP. She compared her results with the effects of rosiglitazone, a diabetes medication that also binds to PPAR gamma.

Although the two chemicals and rosiglitazone both bind to PPAR gamma, she found that exposure to rosiglitazone affected pathways associated with development of brite fat cells. Exposure to TBT and TPhP did not influence those pathways.

Kim validated her findings by computationally evaluating large sets of publicly available gene-related data.

SRP Director Bill Suk, Ph.D., kicked off the talk with a tribute to Karen Wetterhahn, Ph.D. SRP created the annual award to recognize outstanding young trainees in the program. (Photo courtesy of Steve McCaw)

Gene switch determines fate of fat cell

Further study revealed that TPhP exposure makes PPAR gamma remain phosphorylated at a specific protein building block known as serine 273, Kim said. Phosphorylation can influence which genes are turned on ― in this case, those genes favored white fat cells.

To test the direct effects of phosphorylation status, Kim and her research team used cells in which serine 273 was mutated to another protein building block, so that PPAR gamma could not remain phosphorylated. In these cells, TPhP and rosiglitazone both induced expression of genes associated with brite adipocytes. In normal cells without the the serine 273 mutation, only rosiglitazone induced more of the brite genes.

“By identifying this mechanism associated with PPAR gamma phosphorylation, we were able to show one way that environmental metabolic disruptors bind to PPAR gamma but do not enhance healthy fat differentiation and metabolic functions, while therapeutic PPAR gamma ligands can,” said Kim.

SRP Program Administrator Heather Henry, Ph.D., left, introduced Kim and moderated questions, which focused on how effects of cells may translate to animals and humans. (Photo courtesy of Steve McCaw)

Combining disciplines to answer questions

At BU, Kim studied under the mentorship of BU SRP Center Project Leader Jennifer Schlezinger, Ph.D., and Bioinformatics Core Leader Stefano Monti, Ph.D.

“When I arrived at BU, I wanted to learn more about toxicology and bioinformatic analyses of hazardous chemical exposures and was lucky enough to find interdisciplinary research projects within the BU SRP Center,” said Kim. “My SRP training helped me understand how to take a multidisciplinary approach to investigate and address complex questions about the role of hazardous contaminants in human disease.”

She is now using her SRP training at the U.S. Environmental Protection Agency to combine exposure data and large-scale datasets from epidemiology studies that contain genetic and molecular profiles of humans, to better understand risks of potentially hazardous chemicals.

Citation: Kim S, Li A, Monti S, Schlezinger JJ. 2018. Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models. Arch Toxicol 92(9):2859–2874.

(Sara Amolegbe is a research and communication specialist for MDB Inc., a contractor for the NIEHS Superfund Research Program.)