A new study in mice reveals that certain immune cells may protect against obesity-related inflammation in one sex while promoting harmful changes in the other. Credit: Shutterstock

Scientists have discovered that immune cells in fat tissue behave differently in males and females, potentially helping explain sex-specific responses to obesity.

A type of immune cell best known for its role in allergies and asthma may help explain why obesity affects males and females differently. Researchers at the University of California, Riverside found that certain immune cells in fat tissue appear to protect female mice from obesity-related inflammation, while others become more inflammatory in males fed a high-fat diet.

The findings, published in PNAS Nexus, challenge the long-held assumption that these cells, called eosinophils, perform a relatively narrow range of functions. Instead, their effects may depend on their molecular characteristics, biological sex, and interactions with neighboring immune cells.

Six Distinct Immune Cell Populations Found in Fat Tissue

Using high-resolution single-cell sequencing, scientists identified six distinct eosinophil populations in adipose (fat) tissue. Each population displayed different patterns of gene activity, suggesting that eosinophils perform specialized functions rather than acting as a single, uniform group.

“Eosinophils are more complex than we once thought,” said Meera Nair, a professor of biomedical sciences at the UCR School of Medicine who co-led the research with biomedical scientist Adam Godzik. “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.”

Photo shows the research team. L-R bottom: Meera Nair, Rebecca Ruggiero-Ruff, Xinru Qiu, Adam Godzik. L-R top: Djurdjica Coss, Lauren Vance, Yuxin He. Credit: Nair lab, UC Riverside.

Why Male and Female Immune Responses Differ

In female mice, researchers identified a protective eosinophil population that communicated more effectively with macrophages, another class of immune cells found in fat tissue. This relationship appeared to be supported by RELM alpha, a protein produced by macrophages that may help maintain protective immune activity. Earlier experiments showed that supplying RELM alpha to mice had protective effects, providing additional evidence for its role in regulating the immune environment.

Male mice showed a different response to a high-fat diet. Their fat tissue tended to contain more eosinophil populations associated with inflammation, and these cells displayed gene-expression patterns that suggested weaker protective functions.

“This means the relationship between eosinophils and obesity is not simply a matter of how many eosinophils are present,” said Rebecca E. Ruggiero-Ruff, a postdoctoral researcher in Nair’s laboratory and co-first author of the study. “Their functional characteristics and how they communicate with other immune cells are also critical.”

Implications for Future Obesity Treatments

Although eosinophils have been detected in the fat tissue of people with obesity, scientists have not yet established whether they perform the same protective or inflammatory functions observed in mice. Determining whether similar cell populations exist in humans could help researchers investigate treatments that influence specific immune pathways rather than broadly altering immune activity.

“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 laboratory. “We need to investigate sex-specific biology more thoroughly so that treatments can be optimized for different patients.”

Testing Protective Immune Cells in Human Tissue Models

The researchers are now developing three-dimensional adipose organoids, laboratory-grown structures that reproduce certain features of human fat tissue. These models could allow scientists to examine how eosinophils interact with fat cells and macrophages, and whether modifying those interactions can encourage healthier tissue responses.

“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.

Reference: “Single-cell heterogeneity of adipose eosinophils is shaped by sex and RELMα and linked to macrophage communication networks in obesity” by Rebecca E Ruggiero-Ruff, Xinru Qiu, Lauren Vance, Yuxin He, Djurdjica Coss, Adam Godzik and Meera G Nair, 24 October 2026, PNAS Nexus.
DOI: 10.1093/pnasnexus/pgag365

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

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