Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Sep;19(9):1147-52.
doi: 10.1038/nm.3249. Epub 2013 Aug 11.

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

Angie L Bookout  1 , Marleen H M de Groot, Bryn M Owen, Syann Lee, Laurent Gautron, Heather L Lawrence, Xunshan Ding, Joel K Elmquist, Joseph S Takahashi, David J Mangelsdorf, Steven A Kliewer
Affiliations

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

Angie L Bookout et al. Nat Med. 2013 Sep.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Klb and Fgfr expression in the nervous system. (a) LCM mRNA expression in nonhypothalamic (CTX, Thal AD), hypothalamic (OVLT to PMV), midbrain (VTA to mPBN), hindbrain (AP to NTS), and peripheral nervous system (nodose, DRG) regions of male C57BL/6J mice (n = 4–5) harvested at the start of the light phase (see Supplementary Table 4 for abbreviations). (b) In situ hybridization of Klb from hypothalamus (top) and hindbrain (bottom) coronal sections (see Supplementary Fig. 1 for full panel of coronal sections; bar = 45 mm). (c) Klb expression in blunt-dissected SCN and DVC from Klbtm1(Camk2a) and Klbtm1(Phox2b) mice. Cycle time (Ct) values shown inside bars. Data represent the mean ± SEM. Asterisks indicate significant differences (P < 0.05) relative to –cre controls.
Figure 2
Figure 2
Transgenic overexpression of FGF21 alters wheel-running behavior through the SCN. Representative actograms are shown double-plotted for (a) wild-type (WT), (b) Tg(Fgf21), (e) Klbtm1∷Tg(Fgf21), and (f) Klbtm1(Camk2a)∷Tg(Fgf21) males. Yellow indicates light phase (LD, 12 hours light/12 hours dark; DD, constant darkness). (c, g) Average wave plots summarize wheel-running activity during days 6–15 of LD for indicated genotypes (n = 16–28). Time on x-axis refers to zeitgeber time (ZT) 0 at lights on. (d, h) Daily total and % light phase wheel-running activity for the indicated genotypes are plotted as mean ± SEM (*P < 0.05).
Figure 3
Figure 3
Endogenous FGF21 alters wheel-running behavior. Representative actograms are shown double-plotted for wild-type (WT) (a, b) and Fgf21−/− (d, e) males on standard chow (a, d) or ketogenic (b, e) diets. Yellow indicates light phase (LD, 12 hours light/12 hours dark; DD, constant darkness). (c, f) Average wave plots summarize wheel-running activity during days 6–15 of LD for indicated genotypes (n = 6–24). Time on x-axis refers to ZT0 at lights on. (g, h) Daily total and % light phase wheel-running activity for the indicated genotypes are plotted as mean ± SEM. Asterisks indicate significant differences (P < 0.05) compared to chow diets in (g) and as indicated in (h).
Figure 4
Figure 4
Klb expression in the SCN is required for FGF21 suppression of growth and insulin, and stimulation of glucocorticoid activity. (a – d) Male mice of indicated genotypes without (–) or with (Tg21) the Tg(Fgf21). (e – i) Male mice of indicated genotypes implanted with osmotic mini-pumps delivering vehicle (V) or human FGF21. Animals were sacrificed at ZT8 (a, c), ZT3 (e – i), or at ZT0 (b, d), and body weight, plasma hormone levels, and liver gene expression were determined. Data represent mean ± SEM, n = 5–9 for (a – d) and n = 6 for (e – i). Ct values shown inside bars. Asterisks indicate significant differences (P < 0.05) compared to (–) or (V) controls, or as indicated.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Potthoff MJ, Kliewer SA, Mangelsdorf DJ. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 2012;26:312–324. - PMC - PubMed
    1. Kharitonenkov A, et al. FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho. Journal of cellular physiology. 2008;215:1–7. - PubMed
    1. Ogawa Y, et al. BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:7432–7437. - PMC - PubMed
    1. Suzuki M, et al. betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol. 2008;22:1006–1014. - PMC - PubMed
    1. Fon Tacer K, et al. Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol. 2010;24:2050–2064. - PMC - PubMed

Publication types

MeSH terms