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

Cell Metab. 2017 Sep 5;26(3):493-508.e4. doi: 10.1016/j.cmet.2017.08.003. Epub 2017 Aug 24.

Abstract

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.

Keywords: adaptive thermogenesis; adipocyte precursor cells; adipose remodeling; beiging; eosinophils; eotaxin; macrophages; type 2 immunity.

MeSH terms

  • Adaptation, Physiological / drug effects
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue, Beige / drug effects
  • Adipose Tissue, Beige / metabolism
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism*
  • Animals
  • Autocrine Communication / drug effects
  • Cell Proliferation / drug effects
  • Chemokine CCL11 / metabolism*
  • Cold Temperature
  • Eosinophils / drug effects
  • Eosinophils / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factors / deficiency
  • Fibroblast Growth Factors / metabolism*
  • Glucuronidase / metabolism
  • Immunity* / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / metabolism*
  • Thermogenesis / drug effects

Substances

  • Ccl11 protein, mouse
  • Chemokine CCL11
  • Recombinant Proteins
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Extracellular Signal-Regulated MAP Kinases
  • Glucuronidase
  • klotho protein