FGF21 regulates metabolism and circadian behavior by acting on the nervous system

Nat Med. 2013 Sep;19(9):1147-52. doi: 10.1038/nm.3249. Epub 2013 Aug 11.


Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth; however, the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell-surface receptor composed of one of three FGF receptors (FGFR1c, FGFR2c or FGFR3c) in complex with β-Klotho, a single-pass transmembrane protein that is enriched in metabolic tissues. Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response. These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding β-Klotho (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Rhythm / physiology*
  • Energy Metabolism*
  • Fibroblast Growth Factors / metabolism*
  • Glucocorticoids / metabolism
  • Hypothalamus / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity
  • Nervous System / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Signal Transduction
  • Starvation
  • Suprachiasmatic Nucleus / metabolism


  • Glucocorticoids
  • Klb protein, mouse
  • Membrane Proteins
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Fgfr1 protein, mouse
  • Fgfr2 protein, mouse
  • Fgfr3 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, Fibroblast Growth Factor, Type 3