FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms
Open accessAbstract
FGF21 is an endocrine hormone that regulates energy homeostasis and insulin sensitivity. The mechanism of FGF21 action and the tissues responsible for these effects have been controversial, with both adipose tissues and the central nervous system having been identified as the target site mediating FGF21-dependent increases in insulin sensitivity, energy expenditure, and weight loss. Here we show that, while FGF21 signaling to adipose tissue is required for the acute insulin-sensitizing effects of FGF21, FGF21 signaling to adipose tissue is not required for its chronic effects to increase energy expenditure and lower body weight. Also, in contrast to previous studies, we found that adiponectin is dispensable for the metabolic effects of FGF21 in increasing insulin sensitivity and energy expenditure. Instead, FGF21 acutely enhances insulin sensitivity through actions on brown adipose tissue. Our data reveal that the acute and chronic effects of FGF21 can be dissociated through adipose-dependent and -independent mechanisms.
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Coadministration of FGF21 with insulin synergistically increases plasma glucose disposal many fold beyond insulin alone.
“coadministration of FGF21 with insulin synergistically increases plasma glucose disposal many fold beyond that induced by insulin administration alone65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
Loss of FGF21 signalling to adipose tissues abolishes the insulin-sensitizing effects of FGF21 in both lean and DIO mice.
“loss of FGF21 signalling to adipose tissues, as accomplished by crossing Klbfl/fl mice with adiponectin-Cre mice65,67, abolishes the insulin-sensitizing effects of FGF21 in both lean and diet-induced obese (DIO) mice”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
FGF21 acutely enhances insulin sensitivity through direct actions on adipose tissues.
“FGF21 acutely enhances insulin sensitivity through direct actions on adipose tissues65,67.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
The decrease in plasma glucose occurs primarily through increased peripheral glucose disposal, although decreases in hepatic glucose production have also been observed.
“This decrease in plasma glucose levels occurs primarily through increased peripheral glucose disposal41,56,65, although decreases in hepatic glucose production have also been observed66.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
Coadministration of FGF21 and insulin markedly increases glucose uptake in brown adipose tissue, but not muscle or white adipose tissue.
“coadministration of FGF21 and insulin markedly increases glucose uptake in brown adipose tissue, but not muscle or white adipose tissue65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
Thermogenic (UCP1+) adipocytes are particularly important; insulin-sensitizing effects of FGF21 are impaired in mice lacking KLB in UCP1+ adipocytes.
“Thermogenic (UCP1+) adipocytes are particularly important, because the insulin-sensitizing effects of FGF21 are also impaired in mice lacking KLB in UCP1+ adipocytes (Klbfl/fl;Ucp1-Cre)65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
In lean, ad libitum-fed wild-type mice, a single intraperitoneal injection of FGF21 has no effect on plasma glucose levels.
“in lean, ad libitum–fed wild-type mice, a single intraperitoneal injection of FGF21 has no effect on plasma glucose levels65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
A single injection of FGF21 can decrease plasma glucose levels by more than 50% in animal models with genetically induced and diet-induced obesity.
“A single injection of FGF21 can decrease plasma glucose levels by more than 50% in animal models with genetically induced and diet-induced obesity41,65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
The magnitude of glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents.
“the magnitude of the glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents81,87–91, perhaps because of differences in brown adipose tissue metabolism between species65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
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 [65]
FGF21 signalling to adipose tissues promotes the disposal of excess carbohydrates.
“FGF21 signalling to adipose tissues promotes the disposal of excess carbohydrates41,65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [65]
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 [169]
FGF21 directly signals adipose tissue to improve insulin sensitivity.
“FGF21 directly signals adipose tissue to improve insulin sensitivity [169,170]”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [169]
In wild-type lean mice, coinjection of FGF21 with insulin recapitulates the glucose-lowering effect.
“This effect of FGF21 can be recapitulated in wild-type lean mice through coinjection with insulin (11, 27), suggesting that FGF21 functions to directly enhance insulin sensitivity.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
FGF21 significantly increases insulin sensitivity in both lean and diet-induced obese wild-type mice, but this effect is completely lost in Klbfl/fl;Adiponectin-Cre mice.
“Consistent with the earlier studies, while FGF21 significantly increased insulin sensitivity in both lean and diet-induced obese wild-type mice, this effect was completely lost in Klbfl/fl;Adiponectin-Cre mice (11).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Adiponectin-Cre transgenic mice drive Cre expression specifically in adipose tissues.
“Thus, to explore the significance of FGF21 signaling directly to adipose tissues, investigators crossed mice with a conditional Klb allele with Adiponectin-Cre transgenic mice (11), which drive Cre expression specifically in adipose tissues (75).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
The potent effects of FGF21 on lipid metabolism are also present in adipose-specific Klb knockout mice.
“In addition, the potent effects of FGF21 on lipid metabolism (115) are also present in adipose-specific Klb knockout mice (11).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
The loss of β-klotho in hepatocytes or adipocytes does not impair FGF21-mediated effects on body weight.
“In contrast, the loss of β-klotho in hepatocytes (74) or adipocytes (11, 74) does not impair FGF21-mediated effects on body weight.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
The chronic effects of FGF21 on body weight and improved insulin sensitivity are retained in adipose-specific Klb knockout mice (Klbfl/fl;Adiponectin-Cre).
“Although FGF21 signals directly to adipose tissues to acutely enhance insulin sensitivity, the chronic effects of FGF21 on body weight and improved insulin sensitivity are retained in adipose-specific Klb knockout mice (Klbfl/fl;Adiponectin-Cre) (11, 74), demonstrating that direct signaling to adipose tissues is not required for the chronic effects of FGF21 (Figure 4).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Both FGF21 and a bispecific activating antibody for the FGFR1-β-klotho receptor complex retain their acute insulin-sensitizing effects in adiponectin knockout mice.
“Moreover, in contrast to previous studies, both FGF21 (11) and a bispecific activating antibody for the FGFR1–β-klotho receptor complex (70) were found to efficiently retain their acute insulin-sensitizing effects in adiponectin knockout mice (Figure 4).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Activation of FGFR1-dependent signaling specifically in adipose tissues is not sufficient to induce the beneficial metabolic effects of FGF21 in vivo.
“In addition to the loss-of-function studies, independent groups also found that the activation of FGFR1-dependent signaling specifically in adipose tissues is not sufficient to induce the beneficial metabolic effects of FGF21 in vivo (11, 17).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Mice lacking the insulin receptor specifically in adipose tissues (IRfl/fl;Adiponectin-Cre) do not respond to the acute insulin-sensitizing effects of FGF21.
“Mice lacking the insulin receptor specifically in adipose tissues (IRfl/fl;Adiponectin-Cre) do not respond to the acute insulin-sensitizing effects of FGF21 (11).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Increased insulin sensitization in adipose tissues results in increased glucose uptake in BAT and attenuation of lipolysis in WAT.
“Increased insulin sensitization in adipose tissues results in increased glucose uptake in BAT (11) and attenuation of lipolysis in WAT (5).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Neither the inducible expression of a constitutively active FGFR1 protein specifically in adipose tissue nor antibody-mediated activation of a chimeric human FGFR1 receptor in brown adipocytes is sufficient to increase energy expenditure or affect body weight in vivo.
“Neither the inducible expression of a constitutively active FGFR1 protein specifically in adipose tissue (11) nor antibody-mediated activation of a chimeric human FGFR1 receptor in brown adipocytes (17) is sufficient to increase energy expenditure or affect body weight in vivo.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Mice lacking β-klotho in UCP1+ adipocytes (Klbfl/fl;UCP1-Cre) fail to show enhanced insulin sensitivity in response to acute FGF21 administration.
“Notably, as observed with Klbfl/fl;Adiponectin-Cre mice, mice lacking β-klotho in UCP1+ adipocytes (Klbfl/fl;UCP1-Cre) failed to show enhanced insulin sensitivity in response to acute FGF21 administration (11).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
FGF21 stimulates glucose uptake in BAT in vivo.
“Multiple studies have demonstrated that FGF21 stimulates glucose uptake in BAT in vivo (11, 27, 86, 115).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
More recent studies failed to observe increases in plasma adiponectin levels in response to acute FGF21 administration.
“However, more recent studies have challenged these findings by failing to observe increases in plasma adiponectin levels in response to acute FGF21 administration (11, 95).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Acute administration of FGF21 with insulin markedly induces glucose uptake in interscapular BAT compared to insulin alone, and this effect is impaired in mice lacking β-klotho in BAT.
“Positron emission tomography and computed tomography imaging revealed that acute administration of FGF21 with insulin markedly induced glucose uptake in interscapular BAT compared to insulin alone, and this effect is impaired in mice lacking β-klotho in BAT (11).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
Insulin sensitization specifically in adipose tissues is required for the acute insulin-sensitizing effects of FGF21.
“Instead, insulin sensitization specifically in adipose tissues is required for the acute insulin-sensitizing effects of FGF21 (11).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [11]
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Self-citationA feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21
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A Genetic Model to Study the Contribution of Brown and Brite Adipocytes to Metabolism
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- Authors
- BonDurant, L. D., Ameka, M., Naber, M. C., Markan, K. R., Idiga, S. O., Acevedo, M. R., Walsh, S. A., Ornitz, D. M., & Potthoff, M. J.
- Affiliations
- University of Iowa (US)
- Washington University in St. Louis (US)
- Corresponding author
- Potthoff, Matthew J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 25
- Issue
- 4
- Pages
- 935-944.e4
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5494834
- OpenAlex
- W2604914239
- Cited by
- 330
- References
- 32
- Citations by year
- 2026: 32 · 2025: 42 · 2024: 29 · 2023: 35 · 2022: 37 · 2021: 50 · 2020: 36 · 2019: 37 · 2018: 21 · 2017: 10
- FWCI
- 11.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01DK106104, T32 GM067795, R01 HL111190, K01DK111758)
- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- FGF21, insulin sensitivity, energy homeostasis, energy expenditure, brown adipose tissue, adipose tissue, adiponectin, central nervous system, weight loss
- MeSH terms
- Adipose Tissue, Animals, Energy Metabolism, Fibroblast Growth Factors, Insulin, Mice, Inbred C57BL, Signal Transduction, Weight Loss, Mice, Knockout, Adiponectin, Adipocytes, Brown
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