Two UConn Health researchers will investigate the regulators of a cell type that plays a critical role in metabolic diseases associated with obesity. Beiyan Zhou, associate professor of immunology, and Anthony Vella, professor and chair of immunology, have received a $2 million grant from the National Institutions of Health for this five-year project.
B cells are the second most abundant type of immune cell in adipose (fat) tissue under obese conditions. These cells are present in about the same proportion as other kinds of immune cells under healthy conditions. Under obese conditions, however, the number of B cells in fat tissue increases.
In normal conditions, they are responsible for producing antibodies to fight pathogens. But in obese individuals, B cells undergo functional changes with the result that they play a pathogenic role in inflammation and insulin resistance. This can lead to a host of metabolic syndromes.
These changes may also have a systemic impact on how immune cells respond to other diseases leading to worse outcomes after infection, weaker vaccine response, and increased risk for cardiovascular diseases and some cancers.
While the link between adipose tissue B cells and metabolic syndromes appears clear, scientists lack an understanding of the mechanisms underlying their function. Without understanding the precise cellular mechanisms at work, it has been difficult to translate this knowledge into therapeutic approaches for metabolic diseases.
Through this project, Zhou and Vella will define the key regulators for these B cells during obesity.
“We are very excited to investigate how B cells regulate by a small RNA molecule and how that regulation can impact how our body responds to obesity stress,” Zhou says.
Their data point to microRNAs, specifically miR-150, as a potential target. A microRNA is a cellular RNA fragment that prevents the production of a protein by binding to the messenger RNA and thus blocking the function of the protein molecule for which it was created. In this case, miR-150 is responsible for either blocking or allowing the action of B cells.
The researchers believe under the stress of obesity, miR-150 is a key regulator of adipose tissue B cell activation. The dysregulation, of these microRNAs facilitates pro-inflammatory responses of these B cells. This dysregulation corrupts B cells’ ability to interact with other cells in the adipose tissue. This results in exacerbated adipose tissue inflammation and insulin resistance.
Vella and Zhou will demonstrate how miR-150 regulates normal B cell function during different stages of development. They will test the effect of knocking out B cell function in lean mice versus overexpression of B cells in obese mice.
This microRNA regulates B cell behavior and function through specific genes. The researchers have screened dozens of potential genes and successfully identified several targets.
This project will test the hypothesis that the disruption of miR-150 in adipose tissue B cells interferes with their ability to control cell-to-cell interactions. They will determine the mechanisms through which miR-150 regulates interactions between B cells and other immune cell populations including T cells and macrophages in adipose tissue.
This work will elucidate the critical regulatory mechanism of microRNA on adipose tissue B cells and their contribution in orchestrating the adipose tissue metabolic and immunological responses to obesity.
With a better understanding of this mechanism, scientists can work on developing more effective treatments for metabolic diseases that result from obesity.
“Although B cells are the second most abundant immune population in an obese fat tissue, the complex yet highly orchestrated actions of these cells were poorly elucidated,” Zhou says. “I hope our findings will provide valuable information to fill this knowledge gap and provide new targetable molecules for future drug development and therapeutic treatments to mitigate health risks induced by obesity.”
Beiyan Zhou holds a Ph.D. in biochemistry/molecular biology from Northwestern University. She completed a postdoctoral fellowship in cell and molecular biology at the Whitehead Institute for Biomedical Science at the Massachusetts Institute of Technology. Her research focuses on understanding the systemic regulatory networks governed by epigenetic factors in controlling immune cell formation and their functions in various tissue niches.
Anthony Vella holds a Ph.D. in immunology from Cornell University. He completed postdoctoral training at the National Jewish Center for Immunology and Respiratory Medicine. His research interests include co-stimulation, adjuvants, and inflammatory responses during T cell-priming, effector differentiation and memory formation.
This grant is NIH No.: 1 R01 DK121805-01A1