FGF21 regulates metabolism and circadian behavior by acting on the nervous system
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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.
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KLB expression is primarily restricted to specific metabolic tissues (liver, pancreas, adipose) and lower in brain; KLB is not expressed in muscle.
“KLB expression is primarily restricted to specific metabolic tissues (for example, the liver, pancreas and adipose tissue)5, and lower expression is observed in the brain22,48–50. Despite some reports to the contrary51,52, KLB is not expressed in muscle5,41.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [49]
KLB is expressed in numerous cell types and regions throughout the hypothalamus and CNS, in contrast to reported restriction to the suprachiasmatic nucleus.
“In contrast to the reported restriction of KLB expression to the suprachiasmatic nucleus49, KLB is expressed in numerous cell types and regions throughout the hypothalamus48 (and CNS).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [49]
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A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21
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- Authors
- Bookout, A. L., de Groot, M. H. M., Owen, B. M., Lee, S., Gautron, L., Lawrence, H. L., Ding, X., Elmquist, J. K., Takahashi, J. S., Mangelsdorf, D. J., & Kliewer, S. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mangelsdorf, David J
- Kliewer, Steven A
- Venue
- Nature Medicine
- Published
- 2013-08-11
- Volume
- 19
- Issue
- 9
- Pages
- 1147-1152
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3769420
- OpenAlex
- W1966181749
- Cited by
- 545
- References
- 38
- Citations by year
- 2026: 36 · 2025: 36 · 2024: 35 · 2023: 38 · 2022: 50 · 2021: 40 · 2020: 59 · 2019: 49 · 2018: 43 · 2017: 42 · 2016: 42 · 2015: 32 · 2014: 36 · 2013: 6
- FWCI
- 17.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (I-1275, I-1558, U19DK62434)
- National Institute of General Medical Sciences (T32GM007062, GM007062, RL1GM084436)
- National Institute of Diabetes and Digestive and Kidney Diseases (RL1DK081185, U19 DK-62434, P01DK088761, U19DK062434, R01DK067158)
- National Center for Research Resources (P20RR20691, P20RR020691)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- FGF21, β-Klotho, suprachiasmatic nucleus, circadian rhythm, circadian activity, whole-body metabolism, glucocorticoid signaling, physical activity, starvation response, dorsal vagal complex, hypothalamus, fibroblast growth factor receptor, insulin signaling, reproductive function
- MeSH terms
- Klotho Proteins, Animals, Circadian Rhythm, Energy Metabolism, Fibroblast Growth Factors, Glucocorticoids, Hypothalamus, Male, Membrane Proteins, Mice, Inbred C57BL, Motor Activity, Nervous System, Starvation, Suprachiasmatic Nucleus, Signal Transduction, Mice, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptor, Fibroblast Growth Factor, Type 3
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