Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis

J Clin Endocrinol Metab. 2013 Jan;98(1):E98-102. doi: 10.1210/jc.2012-3107. Epub 2012 Nov 12.


Context: Cold exposure stimulates fibroblast growth factor 21 (FGF21) secretion in animals, enhancing the cold-induced thermogenesis (CIT) response through browning of white adipose tissue. In humans, the effects of cold exposure on circulating FGF21 levels are unknown.

Objective: Our objective was to evaluate the effects of mild cold exposure on circulating FGF21 and its relationship with CIT and lipolysis in humans.

Design and setting: We conducted a randomized, single-blind, crossover intervention study at the National Institutes of Health Clinical Center.

Participants: Participants were healthy adults.

Intervention: Subjects were exposed to a 12-h exposure to 24 or 19 C in a whole-room indirect calorimeter.

Outcome measures: Energy expenditure, plasma FGF 21, nonesterified fatty acid, and adipose tissue microdialysis glycerol concentrations were evaluated.

Results: At 24 C, plasma FGF21 exhibited a diurnal rhythm, peaking at 0800 h [110 (59-178) pg/ml], and progressively dropped to a nadir at 1700 h [41 (21-71) pg/ml, P < 0.0001] before rising at 1900 h [60 (11-81) pg/ml, P < 0.0001]. Exposure at 19 C lessened the diurnal reduction of FGF21 observed at 24 C from 0800-1700 h and augmented overall FGF21 levels by 37 ± 45% (P = 0.01). The change in area under the curve plasma FGF21 between 19 and 24 C correlated positively with the change in area under the curve adipose microdialysate glycerol (R(2) = 0.35, P = 0.04) but not with nonesterified fatty acid. Cold-induced increase in FGF21 predicted greater rise in energy expenditure during cold exposure (β = 0.66, P = 0.027), independent of age, gender, fat mass, and lean mass.

Conclusions: Mild cold exposure increased circulating FGF21 levels, predicting greater lipolysis and CIT. A small reduction in environmental temperature is sufficient to modulate FGF21 diurnal rhythm in humans, which may mediate cold-induced metabolic changes similar to those in animals.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Circadian Rhythm / physiology
  • Cold Temperature*
  • Cross-Over Studies
  • Female
  • Fibroblast Growth Factors / analysis
  • Fibroblast Growth Factors / blood*
  • Fibroblast Growth Factors / metabolism
  • Humans
  • Lipolysis / physiology*
  • Male
  • Middle Aged
  • Osmolar Concentration
  • Single-Blind Method
  • Thermogenesis / physiology*
  • Young Adult


  • fibroblast growth factor 21
  • Fibroblast Growth Factors