A protective immune system cell disappears from a key form of fat, but only in those who are obese

The mammalian immune system is an evolutionary wonder. It’s capable of recognizing and destroying cancer cells, and it can deploy armies of antibodies against viruses, bacteria, parasites and fungi.

Among the lesser-spotlighted roles of the immune system is how a particular T cell helps maintain homeostasis—fostering a balanced and stable metabolic environment—in fat cells. It’s a role that has captured the investigatory eye of an elite team of immunologists.

Having a stronger understanding of the dynamic metabolic activities and signaling pathways in fat tissue can aid new strategies to treat obesity, a major global health concern. The condition affects more than 1 billion people worldwide, according to the World Health Organization.

In a new research paper reported in Science Immunology, investigators at Emory University in Atlanta have homed in on a subset of T cells that maintain homeostasis in fat cells: regulatory T cells, commonly known as Tregs.

These soldiers of the immune system play a dynamic role in the form of white fat known interchangeably as visceral fat—visceral adipose tissue, or just plain old VAT. Visceral adipose tissue is located in the abdominal cavity. It surrounds the liver, intestines and stomach.

While Tregs are critical to the healthy function of VAT, these vital immune system components are conspicuously diminished in the VAT of people affected by obesity. Some samples of VAT from obese individuals show no evidence of Tregs at all, scientists have found.

Exactly why Tregs decline in those with obesity has remained incompletely understood. But the Emory team has shed new light on the function of these critical immune system components. Their research was based on a deceptively simple question: Why do Tregs disappear from the VAT of the obese?

“Regulatory T cells accumulate in the visceral adipose tissue to maintain systemic metabolic homeostasis but decline during obesity,” writes Cody Elkins, first author of the new research. Elkins and colleagues tracked down why Tregs disappeared in obesity by studying animal models.

“We explored the metabolic pathways controlling the homeostasis, composition, and function of VAT Tregs,” Elkins declared, noting that the absence in visceral adipose tissue of these key immune system constituents was not a fluke.

Obesity is an inflammatory condition, especially in the abdominal cavity where VAT can drive systemic metabolic dysfunction. Moreover, chronic inflammation is a major hallmark of numerous afflictions in which obesity has a role, namely cardiovascular disease, type 2 diabetes and several forms of cancer.

The Tregs that have captured the attention of Emory immunologists are part of a broader population of tissue-resident T cells. These are T cells that reside in specific sites and don’t travel through the lymphatic system in search of invasive microbes or cancer cells.

Just as tissue resident T cells in VAT are there to maintain visceral fat’s homeostasis, so it is with tissue resident T cells in other sites: they’ve taken up residence to maintain tissue stability. Tissue-resident T cells have been identified in muscle, skin, nasal tissue, the lungs, intestines, the brain, and other sites.

A 2023 study, also published in Science Immunology, showed that tissue-resident Tregs are in abundant supply in muscle tissue. That research, conducted at Harvard Medical School, relied on animal-model experiments to demonstrate that Tregs protect the mitochondria and guard muscle tissue from exercise-induced stress.

For Elkins and colleagues, tracking down why Tregs were missing in the obese wasn’t a simple task, because as the team discovered, there were multiple reasons that explained why these immune cells diminished. The team found in their animal-model study that obesity disrupts cholesterol metabolism in Tregs, leading to increased inflammation and insulin resistance.

As part of their research, they focused on the master regulator of cholesterol homeostasis itself, and how it selectively reduced a critical subset of T cells in the obese, a population known as the St2^hi VAT Tregs.

Elkins and the Emory team examined these Tregs in mouse tissues and reanalyzed previously published data regarding St2^hi VAT Tregs from human visceral adipose tissue. The scientists observed that in VAT of the obese there is impaired expression of a gene known as Srebf2 as well as disrupted cholesterol homeostasis, which together diminished populations of St2^hi VAT Tregs.

That finding allowed the scientists to conclude that obesity affects regulatory T cells in visceral adipose tissue and disrupts cellular cholesterol homeostasis.

“Restoring Treg cholesterol homeostasis rescued VAT Treg accumulation in obese mice,” Elkins added. “This suggests that modulation of cholesterol homeostasis could be a promising strategy for Treg-targeted therapies in obesity-associated metabolic diseases.”

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