Researchers at the University of Pittsburgh School of Medicine have found that protecting a subset of immune cells in visceral fat tissue can improve insulin sensitivity and may offer a new path for treating type 2 diabetes. The research, published in Nature Communications, found a special type of “good” immune cell in visceral fat tissue, VAT macrophages, that reduce inflammation, limit fat expansion and improve glucose tolerance in mouse models.
“One-third of our population is obese or overweight—over the next decade or so, obesity will drive increasing rates of many chronic diseases, including diabetes,” said senior author Partha Dutta, PhD, a cardiology professor and director of the Center for Cardiovascular Inflammation in Pitt’s department of medicine. “Our discovery could be the key to reversing insulin resistance and curing type 2 diabetes.”
Inflammation in visceral adipose tissue is strongly linked to insulin resistance. Previous research has shown that monocyte-derived macrophages that accumulate in fat during obesity promote inflammation and impair insulin signaling. The Pitt team, however, focused on a different macrophage population, VAT macrophages, that reside long term in visceral adipose tissue and help maintain tissue homeostasis.
VAT macrophages differ significantly from monocyte-derived macrophages. “VAT-resident macrophages, unlike monocyte-derived macrophages, are enriched with mitochondrial-specific antioxidant enzymes restraining inflammation and promoting VAT homeostasis and insulin sensitivity,” the researchers wrote.
In their research, the investigators discovered that VAT macrophages express high levels of SerpinB2, a protein that previously has received little attention for its role in macrophage metabolism. The Pitt team found that SerpinB2 supports macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing release of pro-apoptotic cytochrome c from mitochondria through production of the antioxidant glutathione.
This finding was surprising since inflammation is typically associated with immune activation, yet in this instance a subset of immune cells counteracted inflammation in fat. “What we found is that there is a subset of immune cells in our fat tissue that are actually helpful,” Dutta said. “Although they’re immune cells, they’re not inflammatory—rather, they actually suppress the inflammation that causes insulin resistance.”
The work builds on previous research efforts that have detailed the role adipose macrophages play in tissue homeostasis, metabolic inflammation, and insulin resistance, which uncovered that inflammation driven by monocyte-derived macrophages in visceral fat is causally linked to insulin resistance. Other research focused on plasminogen activator inhibitor-1 found that its inhibition lessened insulin resistance in mice fed a high-fat diet, but the physiological role of plasminogen activator inhibitor-2, encoded by SerpinB2, remained unknown.
To investigate this, the team analyzed both mouse models of diet-induced obesity and insulin resistance along with human visceral fat tissue samples. Their data showed that chronic inflammation in obesity diminished SerpinB2 expression in visceral adipose tissue macrophages in both people and mice, leading to a decline of the VAT macrophages.
Selective depletion of resident VAT macrophages in their mouse models worsened glucose intolerance and insulin resistance. Likewise, a method they used to protect these cells improved metabolic outcomes. “Selective depletion of the VAT resident macrophage subset enhanced glucose intolerance and insulin resistance in obese mice, accentuating the significance of this macrophage subset in promoting insulin sensitivity.”
Building on this finding, the researchers are working to translate the findings into a therapeutic a potential new therapeutic approach. Their focus is on identifying a small molecule that increases SerpinB2 levels that would protect resident macrophages.
“Our goal is to develop a drug that will stop and reverse the process that leads to bad fat accumulation and insulin-resistance by protecting and boosting the good immune cells that keep fat tissues healthy,” Dutta said. The team believes that drug able to achieve this could be used alongside GLP-1 medications, particularly as some patients develop reduced responsiveness over time.
If replicated in humans, targeting SerpinB2 pathways or enhancing glutathione production in adipose resident macrophages could shift the focus of diabetes therapy from weight loss alone to preservation of immune cell populations that maintain metabolic homeostasis.
