Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose by an integrin-dependent process and reconstitute AAMs through an IL-4/IL-13-dependent process. Mice on high-fat diet develop increased body fat, impaired glucose tolerance and insulin resistance in the absence of eosinophils, and helminth-induced adipose eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.

Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago,1 and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins, mediate eosinophil development and survival,2 and tissue recruitment,3 respectively, the processes underlying the basal regulation of these signals remain unknown. Here, we show that serum IL-5 is maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive,4 ILC2 co-express IL-5 and IL-13, which is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide (VIP) also stimulates ILC2 through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.

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