Six kinds of immune cells in fat may explain why obesity differs by sex

A study in mice from the University of California, Riverside, has cracked open a question that has long puzzled obesity researchers: why the condition plays out differently in males and females. The answer, published in PNAS Nexus, may sit in fat tissue's immune cells. Using high-resolution single-cell sequencing, the team found six distinct populations of eosinophils — cells normally associated with asthma and allergies — each with its own gene-expression pattern and suspected job.

The split fell along sex lines. Female mice carried a protective eosinophil population that communicated more effectively with macrophages, another immune cell living in fat, according to the researchers. Male mice fed a high-fat diet instead trended toward pro-inflammatory eosinophils with a less protective gene signature. Rebecca E. Ruggiero-Ruff, a postdoctoral researcher in the lab and co-first author, said the numbers alone don't tell the story: how the cells function and talk to their neighbors matters just as much.

The team also flagged RELM alpha, a protein made by macrophages, as a key player in keeping macrophages and eosinophils on good terms. In female mice it appeared to stabilize the crosstalk between the two cell types. Earlier experiments from the same group showed that giving mice RELM alpha had protective effects.

Meera Nair, a professor of biomedical sciences in the UCR School of Medicine who led the work with Adam Godzik, said the findings upend the old assumption that eosinophils are a uniform bunch with limited duties. If researchers can identify and switch on the pathways that produce the protective cells, she said, new routes to better metabolic health may open up. Co-first author Xinru Qiu, a postdoctoral researcher in Godzik's lab, warned that a drug targeting the immune system may not flip the same switches in men and women.

Eosinophils have already been spotted in the fat tissue of people with obesity, but what they actually do there is still unclear. The next phase of the work will test whether the protective behavior seen in mice can be recreated in laboratory models. The team is building three-dimensional adipose organoids — structures that mimic real fat tissue — to watch how eosinophils interact with fat cells. Godzik said the goal is human versions that reveal whether tweaking immune-cell communication can push tissue toward healthier responses.

Nair, Godzik, Ruggiero-Ruff and Qiu were joined by Lauren Vance, Yuxin He and Djurdjica Coss on the paper. Nair stressed that more research is needed before any of this becomes a treatment.