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Cited by 311Fibroblast Growth Factor ResearchRegulation of Appetite and ObesityPeptidase Inhibition and Analysis

Metabolic messengers: FGF21

Open access
Flippo, Kyle H., Potthoff, Matthew J.·2021·Nature Metabolism
DOI 10.1038/s42255-021-00354-2PMC PMC8620721
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Abstract

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. Interest in therapeutic applications for FGF21 was initially sparked by its ability to correct metabolic dysfunction and decrease body weight associated with diabetes and obesity. More recently, new functions for FGF21 signalling have emerged, thus indicating that FGF21 is a dynamic molecule capable of regulating macronutrient preference and energy balance. Here, we highlight the major physiological and pharmacological effects of FGF21 related to nutrient and energy homeostasis and summarize current knowledge regarding FGF21’s pharmacodynamic properties. In addition, we provide new perspectives and highlight critical unanswered questions surrounding this unique metabolic messenger. Flippo and Potthoff provide a concise overview of the major physiological and pharmacological effects of FGF21 in nutrient and energy homeostasis.

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TL;DR

FGF21 is a liver-derived endocrine hormone that signals through an FGFR1c–KLB receptor complex to regulate insulin sensitivity, energy balance, hepatic lipids, and macronutrient preference. This review synthesizes rodent, non-human primate, and human data, proposing FGF21 as a “master sensitizer” of metabolic signals while highlighting unresolved mechanisms and analogue-specific clinical effects.

Key findings

  • FGF21 is primarily liver-derived under physiological conditions and acts via the obligate co-receptor β-klotho (KLB) and FGFR1c; loss of KLB abolishes FGF21 effects. Its half-life is approximately 0.5–1.5 hours, and human FGF21 is cleaved/inactivated by FAP at residue 171, whereas mouse FGF21 is not.
  • Acute FGF21 is a potent insulin sensitizer: a single injection decreases plasma glucose by more than 50% in genetically and diet-induced obese animal models, and coadministration with insulin synergistically increases glucose disposal. This effect requires direct FGF21 signaling to adipose tissue, particularly UCP1+ adipocytes.
  • Prolonged FGF21 or FGF21-analogue administration increases energy expenditure and causes weight loss in obese rodents and non-human primates, with more modest body-weight effects in humans. All analogues consistently lower plasma triglycerides, often by as much as ~70%; in NASH, AKR-001 and pegbelfermin reduce liver fat by up to 70% and improve fibrosis.
  • FGF21 is induced by fasting, high sugar intake, and dietary protein restriction—but not by fat intake or ketogenic diets—and feeds back to suppress simple-sugar and sweet-taste intake via glutamatergic neurons in the ventromedial hypothalamus. It is also required for increased energy expenditure and weight loss during dietary protein dilution.

Methods

  • Narrative review; no primary experimental data are reported.
  • Synthesizes published rodent, non-human primate, and human studies, including clinical trials of FGF21 analogues.
  • Main analysis is a qualitative synthesis of FGF21 physiology, receptor signaling, pharmacological effects, and critical unanswered questions.

Limitations

  • Stated: mechanisms of FGF21 action within target cells, how it sensitizes diverse metabolic cues, cross-talk with FGF15/19, whether FGF21 signaling is impaired in obesity/diabetes, and the central neural circuits coordinating energy homeostasis remain unresolved.
  • Stated: human data largely involve FGF21 analogues rather than recombinant FGF21, so analogue-specific versus FGF21-specific effects are uncertain; species differences in brown adipose tissue may explain weaker glucose-lowering in humans.
  • Evident: conflicting results across analogues for body weight, insulin sensitivity, bone turnover, heart rate/blood pressure, and food intake; mouse bone-loss findings have not been independently validated in rodents or obese non-human primates; gastrointestinal adverse effects are common and their mechanism is unclear.

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Registry

Crossref · 10.1038/s42255-021-00354-2

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Fat intake does not significantly alter FGF21 expression in rodents.

    “a thorough analysis of macronutrient intake has revealed that fat intake does not significantly alter FGF21 expression in rodents28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Solon-Biet, S. M. et al. Defining the nutritional and metabolic context of FGF21 using the geometric framework. Cell Metab. 24, 555–565 (2016). source

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    Human but not mouse FGF21 is cleaved and processed by FAP.

    “Notably, human but not mouse FGF21 is cleaved and processed by FAP, because mouse FGF21 possesses a single–amino acid difference in the stringent FAP-recognition motif42,43.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Dunshee, D. R. et al. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J. Biol. Chem. 291, 5986–5996 (2016). source

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    • cites [43] Zhen, E. Y., Jin, Z., Ackermann, B. L., Thomas, M. K. & Gutierrez, J. A. Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem. J. 473, 605–614 (2016). source

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  • Premisecitation

    FGF21 has a short half-life of approximately 0.5-1.5 hours.

    “Once secreted, FGF21 has a short half-life of approximately 0.5–1.5 hours (refs. 40,41).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Kharitonenkov, A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148, 774–781 (2007). source

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    • cites [41] Xu, J. et al. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models: association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 297, E1105–E1114 (2009). source

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    Ketogenic diets do not induce plasma FGF21 levels in humans.

    “ketogenic diets do not induce plasma FGF21 levels in humans26,30,34”
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    • cites [26] Laeger, T. et al. FGF21 is an endocrine signal of protein restriction. J. Clin. Invest. 124, 3913–3922 (2014). source

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    • cites [30] Gälman, C. et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab. 8, 169–174 (2008). source

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    • cites [34] Christodoulides, C., Dyson, P., Sprecher, D., Tsintzas, K. & Karpe, F. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J. Clin. Endocrinol. Metab. 94, 3594–3601 (2009). source

      Not checked in the free run.

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    Obesogenic diets significantly elevate plasma FGF21 levels.

    “Obesogenic diets, which are termed high-fat diets but are actually high-fat/high-carbohydrate diets, also significantly elevate plasma FGF21 levels35.”
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    • cites [35] Vienberg, S. G. et al. Impact of short-term high-fat feeding and insulin-stimulated FGF21 levels in subjects with low birth weight and controls. Eur. J. Endocrinol. 167, 49–57 (2012). source

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    Premisecitation

    FGF21 is cleaved by FAP and DPP-IV; cleavage at residue 171 inactivates FGF21 because the last ten residues are critical for KLB interaction.

    “FGF21 is also subject to proteolytic cleavage by the serine proteases fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV)42,43.”
    • Also stated in: § Abstract · plain
      “cleavage at residue 171 inactivates FGF21, because the last ten residues of FGF21 are critical for its interaction with the obligate FGF21 co-receptor β-klotho (KLB)44,45.”
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    • cites [42] Dunshee, D. R. et al. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J. Biol. Chem. 291, 5986–5996 (2016). source

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    • cites [43] Zhen, E. Y., Jin, Z., Ackermann, B. L., Thomas, M. K. & Gutierrez, J. A. Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem. J. 473, 605–614 (2016). source

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    • cites [44] Micanovic, R. et al. Different roles of N- and C- termini in the functional activity of FGF21. J. Cell. Physiol. 219, 227–234 (2009). source

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    • cites [45] Yie, J. et al. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett. 583, 19–24 (2009). source

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    FGF21 is transcriptionally induced during extended fasting through a PPARα-dependent mechanism and regulates the adaptive fasting response.

    “FGF21 was initially proposed to be a late-fasting/starvation factor, because it is transcriptionally induced during extended fasting, through a mechanism dependent on the transcription factor PPARα, and it regulates the adaptive fasting response20,21.”
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    • cites [20] Inagaki, T. et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 5, 415–425 (2007). source

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    • cites [21] Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437 (2007). source

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    Starvation, high sugar intake, and dietary protein restriction all induce circulating FGF21 levels in humans.

    “Starvation30,31, high sugar intake32,33 and dietary protein restriction26 all induce circulating FGF21 levels in humans.”
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    • cites [30] Gälman, C. et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab. 8, 169–174 (2008). source

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    • cites [31] Fazeli, P. K. et al. FGF21 and the late adaptive response to starvation in humans. J. Clin. Invest. 125, 4601–4611 (2015). source

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    • cites [32] Dushay, J. R. et al. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol. Metab. 4, 51–57 (2014). source

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    • cites [33] Lundsgaard, A. M. et al. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol. Metab. 6, 22–29 (2016). source

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    • cites [26] Laeger, T. et al. FGF21 is an endocrine signal of protein restriction. J. Clin. Invest. 124, 3913–3922 (2014). source

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    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.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [3] BonDurant, L. D. & Potthoff, M. J. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu. Rev. Nutr. 38, 173–196 (2018). source

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    • cites [40] Kharitonenkov, A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148, 774–781 (2007). source

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    • cites [58] Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005). source

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    • cites [77] Coskun, T. et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149, 6018–6027 (2008). source

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    • cites [78] Xu, J. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 (2009). source

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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.”
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    • cites [5] Fon Tacer, K. et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24, 2050–2064 (2010). source

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    • cites [22] von Holstein-Rathlou, S. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab. 23, 335–343 (2016). source

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    • cites [48] Jensen-Cody, S. O. et al. FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake. Cell Metab. 32, 273–286.e276 (2020). source

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    • cites [49] Bookout, A. L. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19, 1147–1152 (2013). source

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    • cites [50] Liang, Q. et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 63, 4064–4075 (2014). source

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    • cites [51] Patel, V. et al. Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts. PLoS ONE 9, e87102 (2014). source

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    • cites [52] Benoit, B. et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat. Med. 23, 990–996 (2017). source

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    • cites [41] Xu, J. et al. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models: association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 297, E1105–E1114 (2009). source

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    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] BonDurant, L. D. et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 25, 935–944.e4 (2017). source

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    Adiponectin is not required for FGF21 signalling; adiponectin may induce physiological FGF21 production from the liver.

    “more recent studies have confirmed that adiponectin is not required for FGF21 signalling but instead have suggested that adiponectin may induce physiological FGF21 production from the liver10.”
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    • cites [10] Han, M. S. et al. A feed-forward regulatory loop in adipose tissue promotes signalling by the hepatokine FGF21. Genes Dev. 35, 133–146 (2021). source

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    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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [41] Xu, J. et al. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models: association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 297, E1105–E1114 (2009). source

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    • cites [56] Ding, X. et al. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 16, 387–393 (2012). source

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    • cites [65] BonDurant, L. D. et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 25, 935–944.e4 (2017). source

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    • cites [66] Berglund, E. D. et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 150, 4084–4093 (2009). source

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    Premisecitation

    FGF21 binding promotes formation of a dimeric FGFR1c-KLB complex, activates tyrosine kinase domains and propagates signalling through ERK phosphorylation.

    “FGF21 binding promotes the formation of a dimeric FGFR1c–KLB signalling complex, which activates the intracellular tyrosine kinase domains of FGFR1c and propagates signalling through phosphorylation by the kinase ERK46,53,58,59”
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    • cites [46] Kurosu, H. et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687–26695 (2007). source

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    • cites [53] Ogawa, Y. et al. βKlotho is required for metabolic activity of fibroblast growth factor 21. Proc. Natl Acad. Sci. USA 104, 7432–7437 (2007). source

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    • cites [58] Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005). source

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    • cites [59] Yie, J. et al. Understanding the physical interactions in the FGF21/FGFR/β-Klotho complex: structural requirements and implications in FGF21 signalling. Chem. Biol. Drug Des. 79, 398–410 (2012). source

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    Administration of two FGF21 analogues PF-05231023 and LY2405319 to people with obesity and type 2 diabetes significantly decreases body weight and improves lipid profiles.

    “Independent administration of two different FGF21 analogues, PF-05231023 (ref. 81) and LY2405319 (ref. 87), to people with obesity and type 2 diabetes significantly decreases body weight and improves lipid profiles.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016). source

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    • cites [87] Gaich, G. et al. The effects of LY2405319, an FGF21 analogue, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013). source

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    Most FGF21 analogues are generally well tolerated; one discontinued FGF21 analogue increases heart rate and blood pressure.

    “while most FGF21 analogues are generally well tolerated, one discontinued FGF21 analogue increases heart rate and blood pressure92.”
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    • cites [92] Kim, A. M. et al. Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates. Diabetes Obes. Metab. 19, 1762–1772 (2017). source

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    In mice, FGF21 has been reported to promote bone loss, but this effect has not been independently validated in rodents or obese non-human primates.

    “In mice, FGF21 has been reported to promote bone loss96,97, but this effect has not been independently validated in rodents98 or obese non-human primates99.”
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    • cites [96] Wei, W. et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc. Natl Acad. Sci. USA 109, 3143–3148 (2012). source

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    • cites [97] Wang, X., Wei, W., Krzeszinski, J. Y., Wang, Y. & Wan, Y. A liver-bone endocrine relay by IGFBP1 promotes osteoclastogenesis and mediates FGF21-induced bone resorption. Cell Metab. 22, 811–824 (2015). source

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    • cites [98] Li, X. et al. FGF21 is not a major mediator for bone homeostasis or metabolic actions of PPARα and PPARγ agonists. J. Bone Miner. Res. 32, 834–845 (2017). source

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    • cites [99] Andersen, B. et al. FGF21 decreases body weight without reducing food intake or bone mineral density in high-fat fed obese rhesus macaque monkeys. Int. J. Obes. (Lond.) 42, 1151–1160 (2018). source

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    Some studies report FGF21-mediated weight loss without effects on food intake; another study using PF-05231023 reports weight loss attributable to significant decreases in food intake.

    “whereas some studies have reported FGF21-mediated weight loss without effects on food intake40,86, another study using an FGF21 analogue (PF-05231023) in non-human primates has reported that the weight loss is attributable to significant decreases in food intake81.”
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    • cites [40] Kharitonenkov, A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148, 774–781 (2007). source

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    • cites [86] Murray, S. A. et al. Whole transcriptome analysis and validation of metabolic pathways in subcutaneous adipose tissues during FGF21-induced weight loss in non-human primates. Sci. Rep. 10, 7287 (2020). source

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    • cites [81] Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016). source

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    Effects of different FGF21 compounds on glucose homeostasis and insulin sensitivity vary: some do not significantly affect insulin sensitivity, while others significantly increase it in people with type 2 diabetes.

    “some compounds do not significantly affect insulin sensitivity81, while others significantly increase insulin sensitivity in people with type 2 diabetes87,88.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016). source

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    • cites [87] Gaich, G. et al. The effects of LY2405319, an FGF21 analogue, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013). source

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    • cites [88] Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J. & Rolph, T. AKR-001, an Fc-FGF21 analog, showed sustained pharmacodynamic effects on insulin sensitivity and lipid metabolism in type 2 diabetes patients. Cell Rep. Med. 1, 100057 (2020). source

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    Premisecitation

    Prolonged FGF21 administration to DIO mice significantly decreases body weight, adiposity, hepatic triglycerides and cholesterol; reverses hyperglycaemia and hypertriglyceridaemia; and secondarily increases insulin sensitivity.

    “Prolonged FGF21 administration to DIO mice significantly decreases body weight, adiposity, and hepatic triglycerides and cholesterol; reverses plasma hyperglycaemia and hypertriglyceridaemia; and secondarily increases insulin sensitivity78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Xu, J. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 (2009). source

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    Prolonged overexpression of FGF21 in mice increases insulin sensitivity and extends lifespan.

    “prolonged overexpression of FGF21 in mice increases insulin sensitivity and extends lifespan64,79.”
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    • cites [64] Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1, e00065 (2012). source

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    • cites [79] Youm, Y. H., Horvath, T. L., Mangelsdorf, D. J., Kliewer, S. A. & Dixit, V. D. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc. Natl Acad. Sci. USA 113, 1026–1031 (2016). source

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    In mice with acute ablation of thermogenic adipose tissues, FGF21 causes no increase in energy expenditure but still increased weight loss through increased physical activity and a trend towards decreased food intake.

    “mice with acute ablation of thermogenic adipose tissues exhibited no increase in energy expenditure but still exhibited increased weight loss through increased physical activity and a trend towards decreased food intake75.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Challa, T. D. et al. A genetic model to study the contribution of brown and brite adipocytes to metabolism. Cell Rep. 30, 3424–3433.e3424 (2020). source

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    Administration of high doses of FGF21 increases both energy expenditure and physical activity.

    “administration of high doses of FGF21 has been shown to increase both energy expenditure and physical activity78.”
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    • cites [78] Xu, J. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 (2009). source

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    Premisecitation

    In humans, administration of FGF21 analogues has conflicting effects on bone turnover: PF-05231023 increases markers of bone turnover, whereas AKR-001 and pegbelfermin have not.

    “PF-05231023 has been found to increase markers of bone turnover in humans81, whereas AKR-001 (ref. 88) and pegbelfermin89 have not.”
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    • cites [81] Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016). source

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    • cites [88] Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J. & Rolph, T. AKR-001, an Fc-FGF21 analog, showed sustained pharmacodynamic effects on insulin sensitivity and lipid metabolism in type 2 diabetes patients. Cell Rep. Med. 1, 100057 (2020). source

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    • cites [89] Sanyal, A. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392, 2705–2717 (2019). source

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    FGF21's triglyceride-lowering effects are mediated by altered adipose and liver metabolism: accelerated lipoprotein catabolism, suppression of postprandial lipolysis, decreased hepatic ER and oxidative stress, and increased beta-oxidation of lipids in the liver.

    “Pharmacological administration of FGF21 or FGF21 analogues exerts lipid-lowering effects through accelerated lipoprotein catabolism108, suppression of postprandial lipolysis in adipose tissues88, decreased hepatic endoplasmic reticulum and oxidative stress109,110, and increased beta-oxidation of lipids in the liver62”
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    • cites [108] Schlein, C. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 23, 441–453 (2016). source

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    • cites [88] Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J. & Rolph, T. AKR-001, an Fc-FGF21 analog, showed sustained pharmacodynamic effects on insulin sensitivity and lipid metabolism in type 2 diabetes patients. Cell Rep. Med. 1, 100057 (2020). source

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    • cites [109] Ye, D. et al. Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice. Hepatology 60, 977–989 (2014). source

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    • cites [110] Kim, S. H. et al. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia 58, 809–818 (2015). source

      Not checked in the free run.

    • cites [62] Potthoff, M. J. et al. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc. Natl Acad. Sci. USA 106, 10853–10858 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] BonDurant, L. D. & Potthoff, M. J. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu. Rev. Nutr. 38, 173–196 (2018). source

      Not checked in the free run.

    • cites [104] Jensen-Cody, S. O. & Potthoff, M. J. Hepatokines and metabolism: deciphering communication from the liver. Mol. Metab. 44, 101138 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These SNPs are also associated with increases in sweet-taste preference and greater waist-to-hip ratios.

    “These single-nucleotide polymorphisms are also associated with increases in sweet-taste preference119 and greater waist-to-hip ratios120.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [119] Søberg, S. et al. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab. 25, 1045–1053.e6 (2017). source

      Not checked in the free run.

    • cites [120] Frayling, T. M. et al. A common allele in FGF21 associated with sugar intake is associated with body shape, lower total body-fat percentage, and higher blood pressure. Cell Rep. 23, 327–336 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [80] Owen, B. M. et al. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 20, 670–677 (2014). source

      Not checked in the free run.

    • cites [82] Ameka, M. et al. Liver derived FGF21 maintains core body temperature during acute cold exposure. Sci. Rep. 9, 630 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF21 is induced by simple-sugar intake in both mice and humans, and sugar-induced production of FGF21 from the liver occurs in a ChREBP-dependent manner.

    “FGF21 is induced by simple-sugar intake in both mice and humans22,32,33, and that sugar-induced production of FGF21 from the liver occurs in a ChREBP-dependent manner22,121.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [22] von Holstein-Rathlou, S. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab. 23, 335–343 (2016). source

      Not checked in the free run.

    • cites [32] Dushay, J. R. et al. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol. Metab. 4, 51–57 (2014). source

      Not checked in the free run.

    • cites [33] Lundsgaard, A. M. et al. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol. Metab. 6, 22–29 (2016). source

      Not checked in the free run.

    • cites [121] Fisher, F. M. et al. A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Mol. Metab. 6, 14–21 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF21 signals to the CNS and suppresses simple-sugar intake and sweet-taste preference, but not protein or lipid intake.

    “FGF21 signals to the CNS and consequently suppresses simple-sugar intake and sweet-taste preference22,122, but not protein or lipid intake22,84.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] von Holstein-Rathlou, S. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab. 23, 335–343 (2016). source

      Not checked in the free run.

    • cites [122] Talukdar, S. et al. FGF21 regulates sweet and alcohol preference. Cell Metab. 23, 344–349 (2016). source

      Not checked in the free run.

    • cites [84] Flippo, K. H., Jensen-Cody, S. O., Claflin, K. E. & Potthoff, M. J. FGF21 signalling in glutamatergic neurons is required for weight loss associated with dietary protein dilution. Sci. Rep. 10, 19521 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of FGF21 analogues AKR-001 and pegbelfermin in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis.

    “Administration of the FGF21 analogues AKR-001 (ref. 88) and pegbelfermin89 in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis88,89.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [88] Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J. & Rolph, T. AKR-001, an Fc-FGF21 analog, showed sustained pharmacodynamic effects on insulin sensitivity and lipid metabolism in type 2 diabetes patients. Cell Rep. Med. 1, 100057 (2020). source

      Not checked in the free run.

    • cites [89] Sanyal, A. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392, 2705–2717 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF21 is required for the increases in energy expenditure and the prevention of weight gain associated with low-protein diets.

    “FGF21 is required for the increases in energy expenditure and the prevention of weight gain associated with low-protein diets26,27.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Laeger, T. et al. FGF21 is an endocrine signal of protein restriction. J. Clin. Invest. 124, 3913–3922 (2014). source

      Not checked in the free run.

    • cites [27] Maida, A. et al. A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution. J. Clin. Invest. 126, 3263–3278 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    FGF21 signals through distinct populations of neurons, thereby mediating effects on macronutrient intake and energy expenditure.

    “These findings indicate that FGF21 signals through distinct populations of neurons, thereby mediating effects on macronutrient intake and energy expenditure48.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Jensen-Cody, S. O. et al. FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake. Cell Metab. 32, 273–286.e276 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physiological FGF21 signalling to glutamatergic neurons in the paraventricular nucleus regulates basal sucrose intake; FGF21 signalling to glutamatergic neurons in the VMH is required for FGF21-mediated suppression of simple-sugar intake.

    “While physiological FGF21 signalling to glutamatergic neurons in the paraventricular nucleus regulates basal sucrose intake22,48, FGF21 signalling to glutamatergic neurons in the ventromedial hypothalamus (VMH) is required for FGF21-mediated suppression of simple-sugar intake48.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] von Holstein-Rathlou, S. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab. 23, 335–343 (2016). source

      Not checked in the free run.

    • cites [48] Jensen-Cody, S. O. et al. FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake. Cell Metab. 32, 273–286.e276 (2020). source

      Not checked in the free run.

29 of 29

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?

  • The liver is the primary source of FGF-21 under physiological conditions, while adipose tissue and skeletal muscle may contribute to its levels under stress or with obesity.

    “Although the liver is the primary source of FGF-21 under physiological conditions, adipose tissue and skeletal muscle may contribute to its levels under stress or with obesity. 36”

    From Comprehensive Long-Term Changes in Cardiovascular Risk Biomarkers With Tirzepatide (2026) · cites this paper as [36]

    The opening section (page unavailable) says circulating FGF21 comes primarily, if not exclusively, from the liver under physiological conditions. It also reports FGF21 production by non-hepatic tissues in genetic models of altered mitochondrial function, but does not establish that adipose tissue and skeletal muscle contribute to circulating levels during obesity or stress generally. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Flippo, K. H., & Potthoff, M. J.
Affiliations
University of Iowa (US)
Corresponding author
Potthoff, Matthew J.
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2021-03-18
Volume
3
Issue
3
Pages
309-317
ISSN
2522-5812 (ISSN-L)
DOI
10.1038/s42255-021-00354-2
PMC
PMC8620721
OpenAlex
W3137710312
Semantic Scholar
05238b3ed4c58be5ccb6c9cc604530f700d3def7
Cited by
311
References
137
Citations by year
2026: 63 · 2025: 69 · 2024: 58 · 2023: 71 · 2022: 37 · 2021: 12
FWCI
4.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (T32 DK112751, T32 HL007121, R01DK106104, R01AA027654)
  • U.S. Department of Veterans Affairs (I01BX004634)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
Keywords
FGF21, energy homeostasis, nutrient homeostasis, obesity, diabetes mellitus, macronutrient preference
MeSH terms
Klotho Proteins, Animals, Energy Metabolism, Fibroblast Growth Factors, Homeostasis, Humans, Insulin Resistance, Membrane Proteins, Protein Binding, Signal Transduction, Receptor, Fibroblast Growth Factor, Type 1

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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