Long-Term Cold Adaptation Does Not Require FGF21 or UCP1

Cell Metab. 2017 Aug 1;26(2):437-446.e5. doi: 10.1016/j.cmet.2017.07.016.


Brown adipose tissue (BAT)-dependent thermogenesis and its suggested augmenting hormone, FGF21, are potential therapeutic targets in current obesity and diabetes research. Here, we studied the role of UCP1 and FGF21 for metabolic homeostasis in the cold and dissected underlying molecular mechanisms using UCP1-FGF21 double-knockout mice. We report that neither UCP1 nor FGF21, nor even compensatory increases of FGF21 serum levels in UCP1 knockout mice, are required for defense of body temperature or for maintenance of energy metabolism and body weight. Remarkably, cold-induced browning of inguinal white adipose tissue (iWAT) is FGF21 independent. Global RNA sequencing reveals major changes in response to UCP1- but not FGF21-ablation in BAT, iWAT, and muscle. Markers of mitochondrial failure and inflammation are observed in BAT, but in particular the enhanced metabolic reprogramming in iWAT supports the thermogenic role of UCP1 and excludes an important thermogenic role of endogenous FGF21 in normal cold acclimation.

Keywords: Pm20d1; adaptive thermogenesis; beige adipose tissue; browning; cold exposure; endocrine cross talk; energy metabolism; mitochondrial respiration; uncoupling protein.

MeSH terms

  • Acclimatization / physiology*
  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / metabolism*
  • Animals
  • Cold Temperature*
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Mice
  • Mice, Knockout
  • Thermogenesis / physiology*
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism*


  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • fibroblast growth factor 21
  • Fibroblast Growth Factors