When untethered, this signaling protein intensifies inflammation in obese mice, new study reveals
There’s more to fat tissue than just fat. Like other tissues in our bodies, fat tissue is composed of a variety of cell types that must communicate and balance their activities to keep the tissue, and our bodies, healthy.
Now, working with a mouse model of obesity, researchers have discovered how a protein that is overproduced by fat cells in an obese state may be contributing to the demise of two immune cell types — and driving further metabolic disorders in the process.
“My lab has been exploring how metabolic tissues talk to each other, and how different cells within tissues communicate and influence each other,” says Jiandie Lin, Ph.D., a professor at the University of Michigan Life Sciences Institute and senior author of a new study published May 13 in Science Advances. “There are two particular types of immune cells in fat tissue that help maintain tissue health. But in obesity, their abundance and function are impaired. We wanted to figure out why.”
The two cell types, called regulatory T cells (or Tregs) and group-2 innate lymphoid cells (or ILC2s), communicate with other immune cells to put a brake on inflammatory response in fat tissue. Their depletion in obese mammals, including humans, further worsens obesity-related inflammation and insulin resistance.
In healthy conditions, a receptor protein called ST2 (for suppression of tumorigenicity 2) sits on the surface of Treg and ILC2 cells. This protein acts as a sort of cellular satellite dish, receiving signals that keep the cells alive and healthy. If the Treg and ILC2 cells do not receive these signals, they cannot proliferate.
Lin and his colleagues noticed that, in obese states, fat tissue from mice surprisingly exhibited higher levels of expression for this receptor protein.
“We thought that was a bit odd. If there is more ST2 to receive signals, why would there be a defect?,” says Xu-Yun Zhao, Ph.D., a researcher investigator in Lin’s lab and the study’s lead author.
Upon further investigation, the research team discovered that obesity triggered fat cells to make a shorter form of the ST2 protein that was released out into the tissue, rather than remaining anchored to the cell surface. Once this soluble form of ST2 is released, it serves as a decoy that blocks signaling to the ST2 receptors on Treg and ILC2 cells.
“This is emerging as a powerful feedback loop,” explains Lin, who is also a professor of cell and developmental biology in the U-M Medical School. “Obesity triggers inflammation in fat tissue. The inflammatory signals stimulate secretion of soluble ST2 by fat cells, leading to diminished signaling to help maintain the immune cells in the fat tissue. That diminished signaling then further exacerbates obesity-associated inflammation and insulin resistance.”
If researchers could eventually find or develop a therapeutic agent that blocks soluble ST2, they may be able to restore signaling and immune balance to reduce obesity-driven inflammation and insulin resistance, Lin says.
Go to Article
The obesity-induced adipokine sST2 exacerbates adipose Treg and ILC2 depletion and promotes insulin resistance, Science Advances. DOI: 10.1126/sciadv.aay6191