Roles of fibroblast growth factor 21 as a thermoregulatory hormone in cold adaptation

Abstract

Beige adipocytes are uncoupling protein-1 (UCP1) positive adipocytes with thermogenic capacity which are scattered in white adipose depots in response to different stimuli. It provides an important natural defence against hypothermia and a potential ideal strategy to prevent obesity in response to low temperature and nutrient surplus, respectively. Although recent studies have identified the involvement of several types of immune cells and type 2 cytokines in the biogenesis of beige adipocytes in response to cold challenge, the physiological stimulators that trigger the recruitment of immune cells and consequent type 2 immune responses are poorly understood. Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic beneficial effects on the regulation of energy homeostasis, including weight reduction, alleviation of hyperglycaemia and hyperlipidaemia. However, the mechanism remains obscure. Therefore, the aims of this study are to investigate: 1) whether FGF21 plays a physiological role in the regulation of cold-induced adaptive thermogenesis; 2) the mechanism underlying FGF21-mediated thermoregulation; 3) whether the autocrine actions of FGF21 in mature adipocytes is required for its thermoregulatory effects. In this study, by measuring the dynamic changes of FGF21 expression in various tissues and circulation during cold challenge, a selective induction of FGF21 in thermogenic adipose tissues, but not in the liver or circulation after cold exposure was observed. Genetic depletion of FGF21 in adipose tissues resulted in severely impaired cold-induced beiging and adaptive thermogenesis in subcutaneous white adipose tissue (scWAT), whereas liver-selective FGF21 knockout (L-FGF21KO) had no effects on beiging of scWAT. The defects in beiging and thermogenesis observed in mice with adipose-selective FGF21 knockout (A-FGF21KO) were accompanied by a marked reduction in the abundance of eosinophils and their effector cells, including M2 macrophages and adipocyte progenitor cells in scWAT. Conversely, local administration of recombinant FGF21 protein to A-FGF21KO mice increased the number of eosinophils, M2 macrophages and adipocyte progenitor cells, and hence reversed the impairment in beiging of scWAT. Adipose-derived and local administration of FGF21 acted directly on mature adipocytes through β-Klotho (KLB), a co-receptor of FGF21, in an autocrine manner to induce the production of a chemoattractant C-C motif chemokine ligand 11 (CCL11), which promoted the recruitment of eosinophils into scWAT, leading to the development of beige adipocytes in scWAT. Neutralization of endogenous CCL11 in scWAT by using monoclonal antibody against CCL11 abrogated the effects of FGF21 on beiging and thermogenesis during cold challenge; whereas replenishment with recombinant CCL11 protein reversed the defects of cold-induced beiging in A-FGF21KO mice. These findings collectively indicate that locally produced FGF21 in adipose tissues acts as a triggering factor for the initiation of type 2 immune responses through the production of CCL11. The FGF21-CCL11 axis facilitates the crosstalk between mature adipocytes and eosinophil-mediated type 2 cytokine signaling, thereby promoting the beiging process and adaptive thermogenesis in scWAT.