Immune cell differences may explain sex-specific obesity responses

University of California, Riverside scientists have an explanation for why males and females respond differently to obesity. They report in PNAS Nexus that certain immune cell populations in fat tissue may protect against obesity-related inflammation while others may contribute to harmful metabolic changes. They found these immune cells, called eosinophils and traditionally associated with asthma and allergies, behave differently in males and females. 

The research, done in mice and led by biomedical scientists Meera Nair and Adam Godzik, challenges the conventional view that eosinophils are relatively uniform immune cells with a limited range of functions and suggests new possibilities for developing targeted treatments. 

Using high-resolution single-cell sequencing, the team identified six distinct eosinophil populations in adipose (fat) tissue, each with different gene-expression patterns and potential functions.

"Eosinophils are more complex than we once thought," said Nair, a professor of biomedical sciences in the UCR School of Medicine. "Some populations can protect against obesity, and if we can identify and activate the pathways that produce these protective cells, we may find new ways to improve metabolic health."

The researchers found that female mice had a protective eosinophil population that communicated more effectively with macrophages, another type of immune cell found in fat tissue. This interaction may help maintain a healthier metabolic environment, Nair said.

Male mice, by contrast, tended to develop more pro-inflammatory eosinophil populations when fed a high-fat diet. Nair and her colleagues found that the eosinophils in male adipose tissue had a less protective gene signature.

This means the relationship between eosinophils and obesity is not simply a matter of how many eosinophils are present. Their functional characteristics and how they communicate with other immune cells are also critical."

Rebecca E. Ruggiero-Ruff, postdoctoral researcher in Nair's lab and co-first author of the paper

The team identified RELM alpha, a protein produced by macrophages, as an important factor in maintaining the protective relationship between macrophages and eosinophils. In female mice, RELM alpha appeared to stabilize communication between the two cell types. The researchers' previous experiments showed that providing RELM alpha to mice had protective effects, further supporting its potential role in regulating immune activity in fat tissue. 

Although the research was conducted in mice, its findings could have implications for understanding human obesity. Eosinophils have been identified in the adipose tissue of people with obesity, but their precise functions in human fat tissue remain unclear.

Nair emphasized that further research is needed before the findings can be translated into treatments. Understanding sex-specific immune responses will be particularly important, she said, as researchers investigate new approaches to obesity and its complications.

"A drug may not activate the same pathways or produce the same effects in males and females, particularly when it targets the immune system," said co-first author Xinru Qiu, a postdoctoral researcher in Godzik's lab. "We need to investigate sex-specific biology more thoroughly so that treatments can be optimized for different patients."

The next phase of the research will focus on determining whether the protective functions of eosinophil populations in humans can be reproduced in laboratory models. The team is developing three-dimensional adipose organoids, structures that mimic aspects of real fat tissue, to study how eosinophils interact with adipose cells.

"We ultimately hope to develop human adipose organoids that will allow us to investigate whether manipulating immune-cell communication can promote healthier tissue responses," said Godzik, a professor of biomedical sciences and the Bruce D. and Nancy B. Varner Presidential Endowed Chair in Cancer Research.

Nair, Godzik, Ruggiero-Ruff, and Qiu were joined in the research by Lauren Vance, Yuxin He, and Djurdjica Coss.

The study was supported by the National Institutes of Health, UCR School of Medicine, and California Institute for Regenerative Medicine.