Researchers discover why obesity impacts males and females differently

An immune cell best known for its role in allergies may help explain why obesity affects male and female mice differently. New research suggests that eosinophils living in fat tissue take on several distinct roles, with some linked to protection and others associated with inflammation.

Scientists at the University of California, Riverside, led by biomedical researchers Meera Nair and Adam Godzik, examined these cells individually. Their study in PNAS Nexus maps differences in gene activity and predicted communication with macrophages, another important immune cell in fat.

The team identified six eosinophil groups with different molecular signatures. Their distribution and signaling patterns varied with biological sex and a protein called RELM alpha. The findings add another layer to research on sex differences in obesity, while leaving important questions about cause and effect open.

The message is that immune cells in fat cannot be understood simply by counting them. Their functional state and cellular neighbors may matter just as much. That perspective could guide research into healthier fat tissue, although the mouse findings do not establish a treatment for people. The next step is to test whether these molecular patterns correspond to reproducible, protective functions.

Eosinophils are white blood cells often associated with asthma, allergies and responses to parasitic worms. They can release potent substances that damage tissue. However, previous research also links them to maintaining healthy tissues, including helping regulate immune activity within fat under certain conditions.

“Eosinophils are more complex than we once thought,” said Nair, a professor of biomedical sciences in UCR’s 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.”

Fat tissue contains much more than energy-storing cells. Blood vessels, nerves and immune cells help shape its behavior. Studies of tissue inflammation illustrate why researchers increasingly examine this broader cellular environment when investigating obesity and its complications.

Macrophages are part of that environment. They clear debris and respond to tissue changes, but some states can contribute to persistent inflammation. Research on macrophages in other metabolic conditions reinforces the importance of identifying what immune cells are doing, rather than treating every member of a cell type alike.

The researchers used single-cell RNA profiling to examine gene activity in cells collected from mouse fat. Their comparisons included males and females fed a high-fat diet, mice lacking RELM alpha, and a group of female mice challenged with parasitic worms to investigate another immune stimulus.

One analysis resolved 7,461 eosinophils into six clusters, labeled C0 through C5. These were groups defined by gene-expression patterns, rather than six newly proven, permanently separate cell types. The researchers also used protein-marker measurements to support distinctions among several of the groups identified through sequencing.

Male mice had more cells in groups associated with antigen presentation, stress responses and metabolic adaptation. Female mice had greater representation in groups with migration-related or activation-limiting signatures. Such molecular differences offer clues about function, but gene activity alone cannot establish every cell’s actual effect on metabolism.

This approach complements broader efforts to understand fat-cell changes and the cellular memory associated with obesity. Here, the new contribution is a detailed view of an immune population that has been difficult to study because its cells are scarce and fragile.

RELM alpha emerged as a candidate regulator of the relationship between eosinophils and macrophages. Earlier work from the team found higher levels of this protein in female mouse fat. Removing it disrupted a protective immune environment, while treatment with RELM alpha or eosinophils improved outcomes in those earlier experiments.

The new study examined that relationship at higher resolution. Computational analysis predicted communication pathways based on the signaling molecules and receptors expressed by different cells. One eosinophil group, C3, appeared especially important in a network involving CCL6, a chemical messenger that can help direct immune-cell behavior.

Tissue imaging added spatial evidence. Female mice showed closer associations between markers linked to eosinophils and macrophages, and RELM alpha deficiency disrupted that arrangement. These observations support a communication model, but they do not directly prove every predicted message. Efforts to map inflammation show why cellular location also matters.

“This means the relationship between eosinophils and obesity is not simply a matter of how many eosinophils are present,” said co-first author Rebecca E. Ruggiero-Ruff. “Their functional characteristics and how they communicate with other immune cells are also critical.” Understanding those relationships could inform research on controlling chronic inflammation.

The results do not mean that females are universally protected from obesity or that all male eosinophils are harmful. They describe differences within a particular experimental setting. Human metabolic health reflects many interacting factors, and this study did not test whether the same six groups exist in people.

The authors also acknowledge limited biological replication and small sample sizes. They say larger independent studies are needed to confirm the proposed eosinophil states. They note that additional correction for technical batch effects could strengthen comparisons, even though the biological replicates were processed together within the experiment.

Several mechanistic questions remain unresolved. Researchers still need to determine whether specific eosinophil states directly change macrophage behavior, how stable those states are, and exactly how RELM alpha supports the network. Evidence that sex and age influence obesity biology does not answer those particular questions.

“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. Other studies of metabolic responses also examine differences across participants, underscoring why future experiments should assess biological sex explicitly.

The immediate benefit is a more specific set of questions about immune cells in fat. Future experiments can test which communication pathways preserve healthier tissue responses and which accompany damaging inflammation. That could help researchers avoid assuming that increasing or decreasing all eosinophils would produce the same result.

The UCR team is developing three-dimensional human adipose organoids, laboratory structures that reproduce selected features of fat tissue. Such tissue models could let researchers alter one signal at a time and observe how eosinophils, macrophages and fat cells respond under controlled conditions.

Including relevant immune cells is important. Work with heart organoids illustrates the broader value of building models that capture interactions among multiple cell types. For this obesity project, human experiments must establish whether the protective communication patterns suggested by mice can be reproduced at all.

“We ultimately hope to develop human adipose organoids that will allow us to investigate whether manipulating immune-cell communication can promote healthier tissue responses,” Godzik said. For now, the study offers a research map: identify the cells’ states, test their conversations, and determine which findings carry over to human biology.

This article is for informational purposes and does not provide medical advice. Consult a qualified health care professional about obesity or treatment decisions.

These resources explain adipose cell diversity and the research behind eosinophil–macrophage interactions, listed newest first.

Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution
Researchers outline standards and approaches for mapping the many cell types and states found in fat tissue. (Nature Metabolism, May 2025)

Probing connections between obesity and parasitic worms
UCR describes a research program examining RELM alpha, sex differences and communication between macrophages and eosinophils. (University of California, Riverside, January 2025)

Protein found to protect females against obesity
The team’s earlier mouse research investigates how RELM alpha influences immune cells and diet-induced obesity. (University of California, Riverside, July 2023)

A single-cell atlas of human and mouse white adipose tissue
A cellular atlas compares white fat across species, tissue locations and body weights. (Nature, March 2022)

Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis
Foundational mouse experiments connect eosinophils in fat with macrophage activity and glucose regulation. (Science, April 2011)

Research findings are available online in the journal PNAS Nexus.

The original story "Researchers discover why obesity impacts males and females differently" is published in The Brighter Side of News.

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