The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity

Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT. [Display omitted] •Cold exposure selectively induces FGF21 expression in thermogenic adipose tissues•Autocrine actions of FGF21 are obligatory for type 2 immune activation and beiging•FGF21 induces CCL11 production in adipocytes to promote recruitment of eosinophils•The FGF21-CCL11 axis couples nervous and immune systems to induce beiging in scWAT Zhe Huang et al. show that cold activates type 2 immune responses and beiging in subcutaneous WAT through an FGF21-CCL11 axis which drives eosinophil recruitment, M2 macrophage accumulation and proliferation and commitment of beige adipocyte precursors. These findings explain how the immune system communicates with sympathetic nerves to control adaptive thermogenesis.