IL-25–induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice

Abstract

Beige fat dissipates energy and functions as a defense against cold and obesity, but the mechanism for its development is unclear. We found that interleukin (IL)-25 signaling through its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue after cold exposure and β3-adrenoceptor agonist stimulation. IL-25 induced beige fat formation in white adipose tissue (WAT) by releasing IL-4 and IL-13 and promoting alternative activation of macrophages that regulate innervation and up-regulate tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine (NE). Blockade of IL-4Rα or depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the beige fat formation in WAT. Mice fed with a high-fat diet (HFD) were protected from obesity and related metabolic disorders when given IL-25 through a process that involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling in WAT may have therapeutic potential for controlling obesity and its associated metabolic disorders. Beige fat dissipates energy and functions as a defense against cold and obesity, but the mechanism for its development is unclear. This study reveals that IL-25 is upregulated upon cold exposure and induces beige fat formation, with corresponding benefits to metabolic homeostasis; the effects of IL-25 are mediated by changes in macrophage polarization, which in turn influence tissue innervation.