Liver Derived FGF21 Maintains Core Body Temperature During Acute Cold Exposure
Open accessAbstract
Fibroblast Growth Factor 21 (FGF21) elicits an array of metabolic effects. However, the physiological role of FGF21 during thermal challenges is not clear. In this study, we assessed the tissue source of FGF21 and its site of action to regulate core body temperature in response to cold. Using mice lacking FGF21 specifically in the liver (FGF21 LivKO) or adipose tissues (FGF21 AdipoKO), we performed a series of cold exposure studies to examine the tissue specific induction of FGF21 in response to cold. We also examined the physiological site of FGF21 action during cold exposure by impairing FGF21 signaling to adipose tissues or the central nervous system (CNS) using genetic ablation of the FGF21 co-receptor β-klotho in adipose tissues (KLB AdipoKO) or pharmacological blockage of FGF21 signaling. We found that only liver-derived FGF21 enters circulation during acute cold exposure and is critical for thermoregulation. While FGF21 signaling directly to adipose tissues during cold is dispensable for thermoregulation, central FGF21 signaling is necessary for maximal sympathetic drive to brown adipose tissue to maintain thermoregulation during cold. These data demonstrate a previously unrecognized role for FGF21 in the maintenance of body temperature in response to cold.
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Effects of extended FGF21 signalling in promoting weight loss through increased energy expenditure are mediated through direct actions on the CNS, not adipose tissues.
“These effects of extended FGF21 signalling in promoting weight loss through increased energy expenditure are mediated through direct actions on the central nervous system67,80–84, not adipose tissues65,67,85”
From Metabolic messengers: FGF21 (2021) · cites this paper as [82]
FGF21 signals directly to the CNS, at least in rodents, and consequently regulates energy expenditure and improves glucose and lipid homeostasis.
“Instead, FGF21 signals directly to the CNS (Fig. 3a), at least in rodents, and consequently regulates energy expenditure and improves glucose and lipid homeostasis80,82.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [82]
FGF21 signals the CNS to increase energy expenditure and decrease body weight.
“while it signals the CNS to increase energy expenditure and decrease body weight [169,171,172] (Figure 2).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [171]
Hepatic FGF21 production can also be induced by cold, and blunted hepatic FGF21 secretion, but not adipocytic FGF21 secretion, results in impaired cold tolerance and decreased sympathetic nerve activity in BAT.
“Additionally, hepatic FGF21 production can also be induced by cold, and blunted hepatic FGF21 secretion, but not adipocytic FGF21 secretion, results in impaired cold tolerance and decreased sympathetic nerve activity in BAT 95.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [95]
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- Authors
- Ameka, M., Markan, K. R., Morgan, D. A., BonDurant, L. D., Idiga, S. O., Naber, M. C., Zhu, Z., Zingman, L. V., Grobe, J. L., Rahmouni, K., & Potthoff, M. J.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Potthoff, Matthew J.
- ORCID
- Venue
- Scientific Reports
- Published
- 2019-01-24
- Volume
- 9
- Issue
- 1
- Pages
- 630-630
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6345819
- OpenAlex
- W2913676190
- Cited by
- 93
- References
- 38
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 12 · 2023: 10 · 2022: 19 · 2021: 18 · 2020: 12 · 2019: 5
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (K01DK111758, HL134850,, HL084207, R01DK106104)
- American Heart Association (18EIA33890055, #14EIA18860041)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
- Keywords
- FGF21, thermoregulation, core body temperature, acute cold exposure, β-Klotho, adipose tissue, brown adipose tissue, sympathetic nervous system
- MeSH terms
- Animals, Body Temperature, Adipose Tissue, Brown, Cold Temperature, Fibroblast Growth Factors, Liver, Male, Mice, Inbred C57BL, Sympathetic Nervous System, Signal Transduction, Mice, Knockout, Mice, Adipose Tissue, White
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