Consumption of fish oil high-fat diet induces murine hair loss via epidermal fatty acid binding protein in skin macrophages

Highlights•Consumption of fish oil HFD, but not cocoa butter HFD, induces murine hair loss•TNF-α signaling in CD207− macrophages mediates fish oil HFD-induced hair loss•E-FABP is essential in the n-3 fatty acid-induced ROS/IL-36/TNF-α axis in skin macrophages•E-FABP deficiency protects mice from fish oil HFD-induced hair lossSummaryFats are essential in healthy diets, but how dietary fats affect immune cell function and overall health is not well understood. Mimicking human high-fat diets (HFDs), which are rich in different fatty acid (FA) components, we fed mice various HFDs from different fat sources, including fish oil and cocoa butter. Mice consuming the fish oil HFD exhibit a hair-loss phenotype. Further studies show that omega-3 (n-3) FAs in fish oil promote atypical infiltration of CD207− (langerin−) myeloid macrophages in skin dermis, which induce hair loss through elevated TNF-α signaling. Mechanistically, epidermal fatty acid binding protein (E-FABP) is demonstrated to play an essential role in inducing TNF-α-mediated hair loss by activating the n-3 FA/ROS/IL-36 signaling pathway in dermal resident macrophages. Absence of E-FABP abrogates fish oil HFD-induced murine hair loss. Altogether, these findings support a role for E-FABP as a lipid sensor mediating n-3 FA-regulated macrophage function and skin health.Graphical abstract