Study Explains Why Obesity Differs by Sex

Immune cells traditionally linked to asthma and allergies may help explain why obesity affects males and females differently. In a mouse study published in PNAS Nexus, a University of California, Riverside team reports that some populations of these cells, called eosinophils, in fat tissue may guard against obesity-related inflammation, while others may contribute to harmful metabolic changes. The cells also behaved differently depending on sex. 

The study was led by biomedical scientists Meera Nair and Adam Godzik. It challenges the conventional view that eosinophils are fairly uniform cells with a limited range of functions, and it suggests new possibilities for targeted treatments. Using high-resolution single-cell sequencing, the team found six distinct eosinophil populations in adipose tissue. Each had its own gene-expression pattern and potential functions.

“Eosinophils are more complex than we once thought,” said Nair. “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.”

Female mice had a protective eosinophil population that communicated more effectively with macrophages. According to Nair, this interaction may help maintain a healthier metabolic environment.

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

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

The team identified RELM alpha, a protein made by macrophages, as an important factor in keeping the protective relationship between the two cell types intact. In female mice, RELM alpha appeared to stabilize communication between macrophages and eosinophils. In earlier experiments, the group showed that giving RELM alpha to mice had protective effects, which further supports its possible role in regulating immune activity in fat tissue.

The work was done in mice, but it could still help explain human obesity. Eosinophils have been found in the adipose tissue of people with obesity, though exactly what they do in human fat tissue is still unclear. 

Nair stressed that more research is needed before the findings can lead to treatments. She said understanding sex-specific immune responses will be especially important as researchers explore 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. “We need to investigate sex-specific biology more thoroughly so that treatments can be optimized for different patients.”

Next, the team will try to determine whether the protective functions of eosinophil populations in humans can be reproduced in laboratory models. To study how eosinophils interact with adipose cells, the researchers are building three-dimensional adipose organoids.

“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.