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Cited by 222Fibroblast Growth Factor ResearchFolate and B Vitamins ResearchPeptidase Inhibition and Analysis

Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis

Open access
BonDurant, Lucas D., Potthoff, Matthew J.·2018·Annual Review of Nutrition
DOI 10.1146/annurev-nutr-071816-064800PMC PMC6964258
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Abstract

Fibroblast growth factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis. During the past decade, there has been an enormous effort made to understand the physiological roles of FGF21 in regulating metabolism and to identify the mechanism for its potent pharmacological effects to reverse diabetes and obesity. Through both human and rodent studies, it is now evident that FGF21 levels are dynamically regulated by nutrient sensing, and consequently FGF21 functions as a critical regulator of nutrient homeostasis. In addition, recent studies using new genetic and molecular tools have provided critical insight into the actions of this endocrine factor. This review examines the numerous functions of FGF21 and highlights the therapeutic potential of FGF21-targeted pathways for treating metabolic disease.

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Written from the paper’s full text.

TL;DR

This review synthesizes human and rodent evidence that fibroblast growth factor 21 (FGF21) is a liver-derived endocrine hormone that regulates nutrient homeostasis, macronutrient preference, thermogenesis, and stress responses, with potent pharmacological effects against obesity and diabetes. It highlights central nervous system actions as key to FGF21’s chronic metabolic benefits and discusses therapeutic promise alongside unresolved safety and mechanism questions.

Key findings

  • FGF21 is dynamically regulated by nutritional state: fasting, low-protein diets, carbohydrate/fructose intake, ketogenic diets, and alcohol all alter circulating FGF21, while liver-derived FGF21 coordinates fasting/refeeding, protein restriction, and sweet-taste preference.
  • Pharmacological FGF21 has strong metabolic effects: a single injection lowered plasma glucose by more than 50% in diabetic/obese animal models, and repeated administration increased metabolic rate and promoted weight loss; human trials with analogs LY2405319 and PF-05231023 reduced body weight and improved lipid profiles, though effects on glucose/insulin varied.
  • The chronic metabolic effects of FGF21 on body weight and glucose homeostasis require CNS β-klotho, not adipose β-klotho; acute insulin sensitization instead requires direct FGF21 signaling to brown adipocytes.
  • Human genetics link FGF21 variants to macronutrient intake and sweet preference: rs838133 and rs838145 associate with higher carbohydrate intake, and a UK Biobank analysis of 451,000 individuals found rs838133 associated with higher carbohydrate intake, body fat distribution, and blood pressure. Other reported numbers include an approximately eightfold increase in circulating FGF21 with excess carbohydrate, a half-life of approximately 0.4–2 hours, and human FGF21 cleavage between Pro-171 and Ser-172 by FAP.

Methods

  • Narrative review of human and rodent studies, including genetic loss- and gain-of-function models, pharmacological FGF21 administration, clinical trials with FGF21 analogs, and human genetic association data.
  • The paper synthesizes findings thematically across fasting/refeeding, ketogenic diets, protein restriction, macronutrient preference, alcohol, thermogenesis, cellular stress, CNS signaling, and translational trials; no primary experimental methods or systematic review protocol are reported.

Limitations

  • The review states several unresolved controversies: whether FGF21 resistance exists in obesity, whether FGF21 is required for ketogenic-diet effects, whether FGF21 directly affects bone loss or female fertility, and whether extrahepatic FGF21 production has physiological relevance.
  • It notes that mechanisms for adverse effects, including gastrointestinal issues, blood pressure changes, and the CNS–adipose circuit, remain unclear and require further study.
  • Evident from the text: this is a narrative review without a stated systematic search strategy, inclusion criteria, or quantitative synthesis, and many conclusions rely on rodent models with acknowledged species differences in FGF21 biology and thermogenesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1146/annurev-nutr-071816-064800

Cites

153 of 153 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingown data

    Liver-specific, but not adipose-specific, Fgf21 knockout mice are susceptible to acute cold exposure lasting 1-3 days.

    “Liver-specific, but not adipose-specific, Fgf21 knockout mice are susceptible to acute cold exposure (lasting 1–3 days) (M. Ameka, K.M. Markan & M.J. Potthoff, unpublished data).”
    Quote in the paperSubstantial claim
  • Findingown data

    Plasma FGF21 levels are induced acutely from the liver in response to cold exposure.

    “Plasma FGF21 levels are induced acutely from the liver in response to cold exposure and liver-derived FGF21 signals to the CNS to increase sympathetic nerve activity to BAT and regulate core body temperature (Figure 3b) (M. Ameka, K.M. Markan & M.J. Potthoff, unpublished data).”
    Quote in the paperSubstantial claim
  • Premisecitation

    The expression levels and metabolic functions of FGF21 are dynamically impacted by nutritional status.

    “The expression levels and metabolic functions of FGF21 are dynamically impacted by nutritional status (37, 102).”
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  • Premisecitation

    FGF21 functions in target tissues that express FGFR1c and the obligate coreceptor β-klotho.

    “FGF21 functions in target tissues that express the traditional FGF receptor FGFR1c and the obligate coreceptor β-klotho (2, 27, 71, 99, 124, 140).”
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  • Interpretationnone given

    FGF21 levels are dynamically regulated by nutrient sensing.

    “FGF21 levels are dynamically regulated by nutrient sensing”
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  • Classified as probably not a substantial claim. 4
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    Findingown data

    Liver-derived, but not adipose-derived, FGF21 regulates core body temperature during cold exposure.

    “In contrast to the studies supporting a role for adipose-derived FGF21 in regulating thermogenesis, recent work from our lab has found that liver-derived, but not adipose-derived, FGF21 regulates core body temperature during cold exposure.”
    Quote in the paperSubstantial claim

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    Findingown data

    Liver-derived FGF21 signals to the CNS to increase sympathetic nerve activity to BAT and regulate core body temperature.

    “Plasma FGF21 levels are induced acutely from the liver in response to cold exposure and liver-derived FGF21 signals to the CNS to increase sympathetic nerve activity to BAT and regulate core body temperature (Figure 3b) (M. Ameka, K.M. Markan & M.J. Potthoff, unpublished data).”
    Quote in the paperSubstantial claim

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    Interpretationnone given

    FGF21 is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis.

    “Fibroblast growth factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The FGF19 subfamily of FGFs has reduced affinity for HSGAGs and diffuses into circulation to act on distal tissues, thus functioning as endocrine hormones.

    “Unlike traditional FGFs, however, the FGF19 subfamily of FGFs, consisting of FGF19, FGF21, and FGF23, has reduced affinity for HSGAGs and diffuses into circulation to act on distal tissues (9, 106). Thus, these FGFs function as endocrine hormones.”
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    Premisecitation

    Administering FGF21 to obese or diabetic rodents and primates markedly reduced body weight and significantly improved carbohydrate and lipid homeostasis.

    “A myriad of studies ensued demonstrating that administering FGF21 to obese or diabetic rodents and primates markedly reduced body weight and significantly improved carbohydrate and lipid homeostasis (21, 64, 65, 141).”
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    Premisecitation

    Knockdown of hepatic Fgf21 results in significantly elevated hepatic triglyceride and plasma lipid levels, and impaired ketosis.

    “Knockdown of hepatic Fgf21 using adenovirus-mediated expression of short hairpin RNAs directed against Fgf21 mRNA resulted in significantly elevated hepatic triglyceride and plasma lipid levels, and impaired ketosis (7).”
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    Premisecitation

    The Fgf21 promoter has multiple ATF4 binding sites, and GCN2-mediated activation of ATF4 leads to induction of hepatic and circulating FGF21.

    “The Fgf21 promoter has multiple ATF4 binding sites, and GCN2-mediated activation of ATF4 leads to the induction of hepatic and circulating levels of FGF21 (24, 68, 72).”
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    Premisecitation

    Other groups have reported that FGF21 is not required for regulating glucose homeostasis and ketosis induced by ketogenic diets.

    “However, these conclusions have been controversial because other groups have reported that FGF21 is not required for regulating glucose homeostasis and ketosis induced by ketogenic diets (97, 123).”
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    Interpretationcitation

    FGF21 functions as a metabolic switch to facilitate the transition to the refed state by enhancing insulin-stimulated glucose uptake while acutely maintaining the actions of the fasting response.

    “However, when nutrients become available following a prolonged fast, FGF21 functions as a metabolic switch to facilitate the transition to the refed state by enhancing insulin-stimulated glucose uptake while acutely maintaining the actions of the fasting response (86).”
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    Premisecitation

    Overexpression of FGF21 increases hepatic gluconeogenesis, β-oxidation, and ketogenesis, whereas loss of FGF21 prevents fasting-induced hepatic gluconeogenesis, β-oxidation, and ketogenesis in mice.

    “The overexpression of FGF21 was sufficient to increase hepatic gluconeogenesis, β-oxidation, and ketogenesis, whereas the loss of FGF21 prevented fasting-induced hepatic gluconeogenesis, β-oxidation, and ketogenesis in mice (105).”
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    Premisecitation

    Low-protein diets, amino acid starvation, and the amino acid-depleting drug asparaginase induce plasma FGF21 levels.

    “Low-protein diets (73, 85), amino acid starvation (25, 121), and the amino acid–depleting drug asparaginase (138) also induce plasma FGF21 levels.”
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    Fgf21 total knockout mice fed a ketogenic diet developed hepatosteatosis and exhibited impaired ketogenesis and glucose control.

    “Consistent with these data, Fgf21 total knockout mice fed a ketogenic diet developed hepatosteatosis and exhibited impaired ketogenesis and glucose control (6).”
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    Premisecitation

    FGF21 is markedly induced in response to protein restriction but not caloric restriction.

    “FGF21 is markedly induced in response to protein restriction (25, 73, 85) but not caloric restriction (73, 148).”
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    FGF21 is markedly induced by ketogenic diets in rodents and has been proposed to be a key mediator of hepatic lipid metabolism during ketotic states.

    “FGF21 is markedly induced by ketogenic diets in rodents and has been proposed to be a key mediator of hepatic lipid metabolism during ketotic states (6, 7).”
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    Premisenone given

    β-klotho expression is limited to metabolic tissues and confers specificity for FGF21 signaling.

    “While FGFR1c is ubiquitously expressed, β-klotho expression is limited to metabolic tissues and confers specificity for FGF21 signaling.”
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    Premisecitation

    Circulating FGF21 during fasting are derived from the liver, as liver-specific loss of Fgf21 ablates plasma FGF21 during fasting.

    “These circulating levels of FGF21 are derived from the liver, as the genetic loss of Fgf21 specifically from the liver ablates plasma FGF21 levels during fasting (86).”
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    Premisecitation

    Administration of FGF21 to the PVN of the hypothalamus restored corticosterone production and reversed impaired hepatic gluconeogenesis in Fgf21 knockout mice.

    “Administration of FGF21 to the PVN of the hypothalamus restored corticosterone production and reversed the impaired hepatic gluconeogenesis observed in Fgf21 knockout mice (81).”
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    Premisecitation

    Ad libitum feeding of sucrose for 6-24 hours gradually increases hepatic and plasma FGF21 levels in wild-type mice, and this effect is lost in liver-specific Fgf21 knockout mice.

    “Ad libitum feeding of sucrose for 6–24 hours gradually increases hepatic and plasma FGF21 levels in wild-type mice, and this effect is lost in liver-specific Fgf21 knockout mice (133).”
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    Premisecitation

    Mice lacking FGF21 develop marked liver steatosis and injury in response to chronic alcohol consumption despite being able to clear ethanol as effectively as wild-type controls.

    “Mice that lack FGF21 develop marked liver steatosis and injury in response to chronic alcohol consumption despite being able to clear ethanol as effectively as wild-type controls (26).”
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    Fructose markedly and acutely increased plasma FGF21 levels in humans, while glucose caused a delayed and gradual increase.

    “While fructose markedly and acutely increased plasma FGF21 levels in humans, glucose caused a delayed and gradual increase in plasma FGF21 levels (31).”
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    Premisecitation

    Fgf21 knockout mice exhibit increased hepatic lipogenesis and decreased β-oxidation following alcohol exposure.

    “Fgf21 knockout mice exhibit increased hepatic lipogenesis and decreased β-oxidation following alcohol exposure (83).”
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    Fgf21 total knockout mice exhibit an increased preference for simple sugars, but not lipids or protein.

    “Consistent with these data in humans, Fgf21 total knockout mice exhibit an increased preference for simple sugars, but not lipids or protein (133).”
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    Premisecitation

    Variants rs838133 and rs838145 are associated with higher carbohydrate intake, and FGF21 is a candidate gene in the region.

    “Specifically, these studies reported that variants rs838133 and rs838145 were associated with higher carbohydrate intake and that FGF21 was a candidate gene in the region (20, 127).”
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    Klbfl/fl;CamK2a-Cre mice consume more alcohol and prefer alcohol more than wild-type control mice.

    “Finally, as would be predicted from the human SNP data, Klbfl/fl;CamK2a-Cre mice consume more alcohol and prefer alcohol more than wild-type control mice (116).”
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    In rodents, pharmacological levels of FGF21 increase energy expenditure, which results in increased food intake.

    “In rodents, pharmacological levels of FGF21 increase energy expenditure (64, 141), which results in increased food intake (54, 64).”
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    Administering recombinant FGF21 or overexpressing FGF21 significantly reduced alcohol preference but not plasma ethanol concentrations.

    “Interestingly, administering recombinant FGF21 (116) or the overexpression of FGF21 (125) significantly reduced alcohol preference but not plasma ethanol concentrations.”
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    Premisecitation

    Administration of recombinant FGF21 to mice markedly reduces carbohydrate preference without affecting preferences for lipid and protein.

    “Indeed, the administration of recombinant FGF21 to mice markedly reduces carbohydrate preference without affecting the preferences for lipid and protein (133).”
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    Premisecitation

    Variants around the FGF21 locus are not associated with obesity or type 2 diabetes.

    “Although variants around the FGF21 locus are associated with changes in macronutrient intake, they are not associated with obesity or type 2 diabetes (120).”
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    Premisecitation

    Xylulose-5-phosphate activates ChREBP and promotes its binding to carbohydrate response element sites in promoters of target genes, including FGF21.

    “An intermediate in this pathway, xylulose-5-phosphate, activates ChREBP (1) and promotes its binding to the carbohydrate response element sites in the promoters of target genes, including FGF21 (53, 130).”
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    Premisecitation

    FGF21 was elevated robustly by low protein and this induction was maximized when low-protein intake was coupled with high-carbohydrate intake.

    “This study found that FGF21 was elevated robustly by low protein and that this induction was maximized when low-protein intake was coupled with high-carbohydrate intake (121).”
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    Premisecitation

    Excess carbohydrate without affecting protein levels led to an approximately eightfold increase in circulating FGF21 levels, an effect not observed with increased fat intake.

    “Notably, without affecting protein levels, excess carbohydrate led to an approximately eightfold increase in circulating FGF21 levels, an effect not observed with increased fat intake (84).”
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    Interpretationcitation

    FGF21 is induced in response to excess levels of carbohydrate and loss of FGF21 signaling increases carbohydrate preference.

    “Together, these data reveal that FGF21 is induced in response to excess levels of carbohydrate and that the loss of FGF21 signaling increases carbohydrate preference.”
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    Premisecitation

    FGF21 administration increases energy expenditure and the browning of adipose tissues in vivo.

    “Since FGF21 administration increases energy expenditure and the browning of adipose tissues in vivo (21, 64, 141), it was hypothesized that FGF21 regulates adaptive thermogenesis in response to cold.”
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    FGF21 treatment increases both thermogenic gene expression and cellular respiration in human primary neck adipocytes.

    “In addition, treating human primary neck adipocytes with FGF21 increases both thermogenic gene expression and cellular respiration (76).”
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    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).”
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    In animal models, FGF21 treatment not only prevents but also reverses diabetes and obesity.

    “Importantly, in animal models FGF21 treatment not only prevents (64) but also reverses diabetes and obesity (21, 141).”
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    During high-fat diet feeding, skeletal muscle does not contribute to circulating FGF21; circulating FGF21 is derived exclusively from the liver under these conditions.

    “For example, while chronic feeding of a high-fat diet clearly represents a state of cellular and mitochondrial stress for skeletal muscle, skeletal muscle does not contribute to circulating levels of FGF21 during feeding of a high-fat diet; instead, circulating levels of FGF21 are derived exclusively from the liver under these conditions (86).”
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    Premisecitation

    Repeated daily administration of FGF21 increases metabolic rate, promotes weight loss, and thus secondarily improves insulin sensitivity and glucose homeostasis.

    “In contrast to the acute metabolic effects, repeated daily administration of FGF21 increases metabolic rate, promotes weight loss, and thus secondarily improves insulin sensitivity and glucose homeostasis (141).”
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    Premisecitation

    In diabetic and obese animal models, FGF21 administration decreases blood glucose levels and body weight, improves insulin and leptin sensitivity, improves plasma lipid profiles, and decreases hepatic steatosis.

    “When administered to diabetic and obese animal models, FGF21 provides multiple metabolic benefits and has been shown to decrease blood glucose levels and body weight, improve insulin and leptin sensitivity, improve plasma lipid profiles, and decrease hepatic steatosis (21, 64, 141, 142).”
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    Acute pharmacological administration of FGF21 increases insulin sensitivity and lowers plasma glucose levels, primarily by stimulating peripheral glucose disposal, while also slightly reducing hepatic glucose production.

    “The acute pharmacological administration of FGF21 increases insulin sensitivity and lowers plasma glucose levels, primarily by stimulating peripheral glucose disposal, while also slightly reducing hepatic glucose production (27, 142).”
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    Both Fgf21 total knockout mice and adipose-specific Fgf21 knockout mice exhibit reduced body temperature in response to acute cold exposure.

    “Consistent with a functional role for FGF21 during cold, both Fgf21 total knockout mice (36) and adipose-specific Fgf21 knockout mice (52) exhibit reduced body temperature in response to acute cold exposure.”
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    FGF21 is induced under conditions of metabolic stress (e.g., fasting, cold) and under many conditions of cellular stress.

    “Although FGF21 is induced under conditions of metabolic stress (e.g., fasting, cold), it is also induced under many conditions of cellular stress, leading FGF21 to be referred to in some contexts as a stress hormone (69).”
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    Premisecitation

    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).”
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    Extended FGF21 administration increases energy expenditure, promotes lipid and glucose uptake in BAT, and increases adipose tissue metabolism.

    “Extended FGF21 administration increases energy expenditure, promotes lipid and glucose uptake in BAT, and increases adipose tissue metabolism (88).”
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    FGF21 crosses the blood-brain barrier and acts centrally to regulate multiple processes.

    “FGF21 crosses the blood–brain barrier and acts centrally to regulate multiple processes (50).”
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    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).”
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    FGF21 enhances insulin sensitivity in primary brown adipocytes but not in primary white adipocytes.

    “In addition, FGF21 enhances insulin sensitivity in primary brown adipocytes (86) but not in primary white adipocytes (64, 86).”
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    Administration of a bispecific FGFR1-β-klotho agonist to diet-induced obese wild-type mice promotes weight loss and improves glucose homeostasis, effects that are lost when β-klotho is removed from the CNS.

    “Consistent with recombinant FGF21 administration, the administration of a bispecific FGFR1–β-klotho agonist to diet-induced obese wild-type mice promotes weight loss and improves glucose homeostasis, effects that are lost when β-klotho is removed from the CNS (74).”
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    FGF21 administration increases sympathetic nerve activity to BAT and WAT, and browning of WAT depots.

    “FGF21 administration increases sympathetic nerve activity to BAT (101) and WAT (28), and browning of WAT depots (28, 101).”
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    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] source

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  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] source

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    Premisecitation

    Transplantation of WAT from wild-type mice increases leptin levels and restores FGF21 responsiveness in lipodystrophic mice.

    “While lipodystrophic mice do not respond to FGF21 administration, the transplantation of WAT from wild-type mice increases leptin levels and restores FGF21 responsiveness (131).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] source

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    The infertility phenotype in FGF21-overexpressing mice is due to caloric insufficiency from chronic energy expenditure.

    “However, a separate study suggests that this phenotype is due to caloric insufficiency from chronic energy expenditure (119).”
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    Premisecitation

    When PF-05231023 was administered to obese cynomolgus monkeys, it decreased body weight and mean abdominal fat content but did not affect bone mineral content.

    “When PF-05231023 was administered to obese cynomolgus monkeys, it decreased body weight and mean abdominal fat content but did not affect bone mineral content (126).”
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    • cites [126] source

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    Premisecitation

    Adipose-derived circulating microRNAs are packaged into exosomes and regulate plasma FGF21 levels.

    “Although circulating levels of FGF21 are derived from the liver, adipose-derived circulating microRNAs are packaged into exosomes and regulate plasma FGF21 levels (129).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] source

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    Premisecitation

    In mice, FGF21 has been reported to promote bone loss, but this finding could not be replicated.

    “In mice, FGF21 has been reported to promote bone loss (134, 135); however, this finding could not be replicated (80).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [134] source

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    • cites [80] source

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  • May combine two claims.

    Premisecitation

    Once-weekly administration of PF-05231023 markedly improved plasma lipid profiles without significantly affecting fasting plasma glucose levels.

    “Similar to the previous study (126), once-weekly administration of PF-05231023 markedly improved plasma lipid profiles without significantly affecting fasting plasma glucose levels (66).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [126] source

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    • cites [66] source

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    Premisecitation

    Fgf21 transgenic mice are infertile on a chow diet, but this infertility is reversed by high-fat diet feeding.

    “While Fgf21 transgenic mice are infertile on a chow diet, this infertility is reversed by high-fat diet feeding (119).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FGF21 signals to the brain to suppress vasopressin-kisspeptin signaling, which impairs the proestrus surge in luteinizing hormone.

    “One study found that FGF21 signals to the brain to suppress vasopressin–kisspeptin signaling, which impairs the proestrus surge in luteinizing hormone (100).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another group failed to observe FGF21 resistance in mouse models of obesity and insulin resistance.

    “However, the concept of FGF21 resistance is controversial, with another group failing to observe FGF21 resistance in mouse models of obesity and insulin resistance (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] source

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    Premisecitation

    PF-05231023 significantly reduced body weight and metabolic profiles in nonhuman primates, but did so by reducing their food intake rather than by increasing the browning of subcutaneous WAT.

    “Notably, this FGF21 analog also significantly reduced body weight and metabolic profiles in nonhuman primates, but did so by reducing their food intake rather than by increasing the browning of subcutaneous WAT (126).”
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    Premisecitation

    The majority of adverse effects of PF-05231023 were gastrointestinal, and systolic and diastolic blood pressure and pulse rate increased in a dose-dependent manner.

    “The majority of adverse effects were gastrointestinal, but unlike the previous study, systolic and diastolic blood pressure, and pulse rate, increased in a dose-dependent manner (66).”
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    Premisenone given

    FGF21 regulates macronutrient preference, sweet taste preference, and alcohol intake through central mechanisms.

    “In addition, FGF21 regulates macronutrient preference, sweet taste preference, and alcohol intake through central mechanisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Administering LY2405319 for 28 days to obese subjects with type 2 diabetes resulted in decreased body weight, improved lipid profiles, lowered fasting insulin levels, and a trend toward reduced plasma glucose levels.

    “Administering this analog for 28 days resulted in decreased body weight, improved lipid profiles, lowered fasting insulin levels, and a trend toward reduced plasma glucose levels (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] source

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  • May combine two claims.

    Premisecitation

    Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP).

    “Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP) (29, 150).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] source

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    Premisecitation

    PF-05231023 did not affect systolic or diastolic blood pressure, pulse rate, or electrocardiogram readings.

    “In the same study, PF-05231023 did not affect systolic or diastolic blood pressure, pulse rate, or electrocardiogram readings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    PF-05231023 significantly decreased body weight and markedly reduced plasma cholesterol and lipid levels in subjects with type 2 diabetes.

    “PF-05231023 significantly decreased body weight and markedly reduced plasma cholesterol and lipid levels.”
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67 of 67

  • The paper relies on this without support.

    Humans possess relatively less BAT than rodents.

    “Since humans possess relatively less BAT than rodents, adipose tissue thermogenesis may contribute less to overall energy homeostasis in humans.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • FGF21 functions as an endocrine hormone that signals to distinct targets throughout the body.

    “As a non-canonical fibroblast growth factor, fibroblast growth factor 21 (FGF21) functions as an endocrine hormone that signals to distinct targets throughout the body.”

    From Metabolic messengers: FGF21 (2021) · cites this paper as [3]

  • Prolonged administration of FGF21 or FGF21 analogues decreases body weight in rodents and non-human primates, and has more modest effects on body weight in humans.

    “prolonged administration of FGF21 or FGF21 analogues has important metabolic effects, including a marked decrease in body weight in rodents and non-human primates, and more modest effects on body weight in humans3,40,58,77,78.”

    From Metabolic messengers: FGF21 (2021) · cites this paper as [3]

  • Physiological circulating levels of FGF21 are produced primarily by the liver in response to homeostatic imbalance, perhaps partly to protect the liver from metabolic or cellular stress.

    “Physiological circulating levels of FGF21 are produced primarily by the liver in response to homeostatic imbalance, perhaps partly to protect the liver itself from metabolic or cellular stress3,104.”

    From Metabolic messengers: FGF21 (2021) · cites this paper as [3]

  • Circulating levels of FGF21 are significantly elevated during obesity and diabetes.

    “Because circulating levels of FGF21 are significantly elevated during obesity and diabetes3, and given the known metabolic effects of FGF21, FGF21’s action might logically be reasoned to somehow be impaired, or ‘FGF21 resistant’, during obesity37.”

    From Metabolic messengers: FGF21 (2021) · cites this paper as [3]

  • Circulating FGF21 is a marker for metabolic disorders.

    “making it a marker for metabolic disorders [141] (Table 1).”

    From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [141]

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Related

Authors
BonDurant, L. D., & Potthoff, M. J.
Affiliations
University of Iowa (US)
ORCID
Potthoff, Matthew J.
Venue
Annual Review of Nutrition
Publisher
Annual Reviews
Published
2018-08-21
Volume
38
Issue
1
Pages
173-196
ISSN
  • 0199-9885 (ISSN-L)
  • 1545-4312
DOI
10.1146/annurev-nutr-071816-064800
PMC
PMC6964258
OpenAlex
W2799463911
Semantic Scholar
6a834338b1ae9b0e4c5e4a258c3655658f646629
Cited by
222
References
152
Citations by year
2026: 25 · 2025: 25 · 2024: 29 · 2023: 33 · 2022: 30 · 2021: 34 · 2020: 18 · 2019: 25 · 2018: 3
FWCI
1.96
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Nutrition (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Roy J. and Lucille A. Carver College of Medicine, University of Iowa
  • National Institute of General Medical Sciences (T32GM067795)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106104)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
  • Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
Keywords
FGF21, metabolic homeostasis, liver, nutrient sensing, nutrient homeostasis, diabetes mellitus, obesity, metabolic disease treatment
MeSH terms
Ethanol, Animals, Fibroblast Growth Factors, Food Deprivation, Gene Expression Regulation, Homeostasis, Humans, Lipid Metabolism

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