ABOVE: Mice fed a low-fat diet (left), a high-fat diet containing fish oil (middle), and a high-fat diet containing cocoa butter (right) Bing Li

Bing Li studies cancer, not hair loss. But when his research on diet-related obesity and cancer resulted in an accidental crop of balding mice, the University of Iowa Carver College of Medicine immunologist knew he had to investigate. In a paper published December 13 in Cell Reports, Li and his colleagues detail the mechanism through which the ingestion of fish oil can cause hair loss in mice. The finding raises questions about fish oil intake, which is considered beneficial for humans.

“It’s an interesting paper,” says Rui Yi, a stem cell biologist at the Northwestern University Feinberg School of Medicine who wasn’t involved in the research. “It’s probably the first report that a fish oil, high-fat diet can cause hair loss.”

Fish oil is mostly made of fatty acids, particularly omega-3 fatty acids—a group of polyunsaturated fatty acids marketed as supplements to reduce the risk of ailments such as heart disease and asthma and to ease arthritic pains.

See “Omega-3s: Fishing for a Mechanism

Li sought to investigate how different kinds of fat affect obesity and obesity-related tumor growth. So, he fed some mice a high-fat diet containing lots of fish oil while others received a high-fat diet containing the plant-based oil cocoa butter, both of which he compared to a low-fat diet control group. Soon, he noticed something unexpected: The mice fed the omega-3–rich fish oil lost a considerable amount of hair along their shoulders. Meanwhile, the mice fed cocoa butter (which contains saturated fats) and the low-fat diet control mice exhibited no hair loss at all. Li and the other researchers double-checked this result by running experiments with different types of mice, and each time the outcome was the same.

Li couldn’t find other research describing this phenomenon in the literature, so he decided to explore the connection himself. He and his team used fluorescence to track both the omega-3 fatty acids from the fish oil and the saturated fatty acids from the cocoa butter after ingestion. While the saturated fats from the cocoa butter moved through various parts of the body, the omega-3 fats accumulated on the skin.

Because hair loss diseases such as alopecia areata in humans are triggered by immune responses, Li decided to perform an immune phenotype analysis on fluorescent omega-3–containing cells to determine what immune cells were interacting with them in the skin of the mice. That revealed that dermal macrophages were accumulating in the skin and taking up the omega-3s. When macrophages take up omega-3s, they generate reactive oxygen species (ROS), which can activate various cellular pathways and even be toxic.

If you think about it, it’s kind of scary. How did [the acids] get there?

-Rui Yi, Northwestern University Feinberg School of Medicine 

Li suspected that in this case, the ROS could be generating a cytokine response. So, he performed an RNA sequencing analysis on the mice’s skin tissues and found that the cells that had taken up fish oil expressed a well-known inflammatory cytokine called IL-36, which attracted macrophages from other parts of the body. By staining and analyzing the cells, Li and his team found that these macrophages were generating high levels of a second cytokine called TNF-a, which can cause apoptosis, or cell death. In this case, TNF-a was inducing the death of hair follicle stem cells therefore resulted in hair loss. Further staining tests confirmed that these high TNF-a levels were only present in mice that had consumed fish oil, and when a new round of fish-oil–fed mice were treated with anti-TNF-a antibodies, they exhibited significantly less hair loss.

Yi is intrigued by the idea that ingested fatty acids could accumulate in unexpected areas of the body. “If you think about it, it’s kind of scary,” he says. “How did [the acids] get there?” However, he adds that more research is needed both in mice and humans to see whether this pattern is consistent and how exactly macrophages trigger the immune response.

See “Fanning the Flames

Valerie Horsley, a tissue biologist at Yale University, emphasizes that because there is still so much unknown about the way lipids interact with the body, it’s hard to draw any concrete conclusions. “We need to further understand how these different fatty acids are influencing the different phenotypes that they’re seeing here,” she says. “We have a lot more to learn.”

Li notes that the way fatty acids interact with the body is complicated. In his ongoing cancer research, for example, fish oil appears to help reduce mammary tumors in mice. “Everything has two sides,” he says. “I hope people can do [research] in similar settings, then we can all understand [what] the fat we eat every day [is] doing to our body.”