Defining specific cellular and molecular mechanisms in most obesity-related diseases remains an important challenge. Here we report a serendipitous finding that consumption of a high-fat diet (HFD) greatly increased the occurrence of skin lesions in C57BL/6 mice. We demonstrated that HFD induced the accumulation of a specific type of CD11c+ macrophages in skin preceding detectable lesions. These cells primed skin to induce IL-1β and IL-18 signaling, which further promoted the cytokines IFN-γ- and IL-17-mediated skin inflammation. Mechanistically, epidermal fatty acid binding protein (E-FABP) was significantly upregulated in skin of obese mice, which coupled lipid droplet formation and NLRP3 inflammasome activation. Deficiency ofE-FABP in obese mice decreased recruitment ofCD11c+ macrophages in skin tissues, reduced production of IL-1β and IL-18, and consequently dampened activation of effector Tcells. Furthermore, E-FABP-deficient mice are completely resistant to HFD-induced skin lesions. Collectively, E-FABP represents a molecular sensor triggering HFD-induced skin inflammation.