Affinage

FGF21

Fibroblast growth factor 21 · UniProt Q9NSA1

Length
209 aa
Mass
22.3 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGF21 is a stress- and nutrient-responsive endocrine factor secreted by multiple tissues—liver, brown adipose tissue, skeletal muscle, and exocrine pancreas—that signals through FGFR–β-Klotho (KLB) receptor complexes to coordinate systemic glucose homeostasis, lipid oxidation, thermoregulation, and central behavioral responses to diet (PMID:21317437, PMID:18948104, PMID:28089565, PMID:31167139, PMID:30679672). Its C-terminal sequence is the primary determinant of KLB binding and receptor activation, and its non-canonical flexible β-trefoil fold governs stability—features exploited to engineer super-agonist and chimeric variants with improved metabolic efficacy (PMID:29789271, PMID:33295692). In the periphery, FGF21 acts largely through adiponectin: it raises adipocyte adiponectin secretion to mediate insulin sensitization, cardioprotection (suppressing cardiomyocyte PDK4 via PI3K/AKT), and inhibition of retinal/choroidal neovascularization, with these effects lost in adiponectin-null mice (PMID:23663741, PMID:39955281, PMID:28199833). FGF21 also drives glucose disposal through UCP1-dependent BAT thermogenesis, while a separate UCP1-independent pyrexic action raises body temperature by reducing heat loss (PMID:26586424, PMID:34418595). In the brain, FGF21 signals through CNS β-Klotho to reduce sweet and alcohol preference, shift macronutrient preference during dietary protein restriction, and drive sympathetic outflow to BAT for thermoregulation; distinct circuits include locus coeruleus noradrenergic neurons (counteracting ethanol intoxication) and retrosplenial-cortex-derived FGF21 that enhances hippocampal LTP and spatial memory (PMID:26724861, PMID:31167139, PMID:30679672, PMID:36889282, PMID:36001982). FGF21 transcription is controlled by multiple inputs—PPARα (including PPARα-dependent promoter DNA demethylation), MyoD and ROS→p38→ATF2 in muscle, β-adrenergic/cAMP/PKA/p38/ATF2 in BAT, HRI→eIF2α→ATF4 in hepatocytes, and the integrated stress response acting through ATF3 (a repressor) in pancreas—while the CREBH transcription factor is gated by HRD1-ERAD ubiquitination and Fgf21 mRNA stability is set by the CNOT6L deadenylase (PMID:21317437, PMID:30389664, PMID:25055037, PMID:31915301, PMID:35385705, PMID:27486236, PMID:32198422). Dietary protein restriction extends lifespan and improves metabolic health in an FGF21-dependent manner (PMID:28811495, PMID:35393401).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2008 Medium

    Established that skeletal muscle is an FGF21 source and that PI3K/Akt1 signaling drives its muscle expression, broadening FGF21 beyond a liver-only hepatokine.

    Evidence Akt1 muscle-specific transgenic mice plus PI3K inhibition in cultured myocytes

    PMID:18948104

    Open questions at the time
    • Physiological stimulus driving muscle Akt1/FGF21 in vivo not defined
    • Systemic role of muscle-derived FGF21 not isolated from liver source
  2. 2011 High

    Identified BAT as a thermogenically activated FGF21 source and defined the β-adrenergic/cAMP/PKA/p38/ATF2 transcriptional pathway, linking sympathetic tone to FGF21 production.

    Evidence Arteriovenous difference across BAT, β-adrenergic pharmacology, p38 inhibition, ATF2 promoter binding, in vivo cold exposure

    PMID:21317437

    Open questions at the time
    • Relative contribution of BAT vs liver FGF21 to circulating pool not resolved here
  3. 2013 High

    Defined adiponectin as an obligatory downstream effector of FGF21's systemic insulin-sensitizing action, separating it from direct adipose ERK signaling.

    Evidence Adiponectin-knockout mice with FGF21 administration and metabolic readouts

    PMID:23663741

    Open questions at the time
    • Mechanism by which FGF21 induces adiponectin transcription not detailed
    • Adiponectin-independent FGF21 actions not enumerated
  4. 2014 High

    Showed MyoD is the major muscle transcriptional regulator of FGF21 and that mitochondrial dysfunction induces FGF21 via ROS→p38→ATF2, casting FGF21 as a mitochondrial-stress signal.

    Evidence OXPHOS inhibitors, MyoD knockdown, ROS measurement, p38 inhibition, ATF2 promoter binding in muscle cells

    PMID:25055037

    Open questions at the time
    • In vivo confirmation of MyoD requirement not shown
    • Single-lab data
  5. 2015 High

    Demonstrated CNS β-Klotho-dependent FGF21 signaling reduces sweet and alcohol preference with reduced accumbal dopamine, establishing a central behavioral axis for FGF21.

    Evidence FGF21 administration in mice and monkeys, CNS-specific KLB knockout, accumbal dopamine measurement, preference assays

    PMID:26724861

    Open questions at the time
    • Specific neuronal targets and circuit not mapped here
    • Link between dopamine change and preference is correlative
  6. 2015 High

    Separated FGF21's weight-lowering effect from its glucose-clearance effect, showing the latter requires UCP1-dependent BAT thermogenesis.

    Evidence Ucp1-knockout mice with FGF21 administration, glucose tolerance tests, BAT temperature

    PMID:26586424

    Open questions at the time
    • How UCP1 thermogenesis mechanistically drives glucose disposal not detailed
  7. 2016 Medium

    Expanded transcriptional control of hepatic FGF21 to the HRI→eIF2α→ATF4 integrated-stress arm (de-repressed upon PPARβ/δ loss) and to AMPK (metformin), STAT3 (leptin), and metabolite sensing.

    Evidence PPARβ/δ KO mice and HRI siRNA with eIF2α/ATF4 readout; metformin/Compound C in hepatocytes; leptin/STAT3 in rats and HepG2; lactate/p38 in adipocytes

    PMID:23118742 PMID:26769382 PMID:26982498 PMID:27486236

    Open questions at the time
    • Leptin/STAT3 link is Low-confidence single cell line
    • Integration of these inputs into a unified regulatory logic not established
  8. 2017 High

    Revealed an autocrine/paracrine FGF21 function in exocrine pancreas, stimulating digestive enzyme secretion via FGFR–β-Klotho and PLC-IP3R calcium signaling, with loss causing zymogen accumulation and ER stress.

    Evidence FGF21 and β-Klotho KO, acinar-specific KLB deletion, recombinant FGF21 rescue, calcium imaging, PLC-IP3R pharmacology

    PMID:28089565

    Open questions at the time
    • Whether circulating vs locally produced FGF21 dominates acinar action not fully resolved
  9. 2017 High

    Established FGF21 as essential for the lifespan-extending and metabolic benefits of dietary protein restriction, linking the hormone to healthy aging.

    Evidence FGF21 global knockout, long-term protein restriction, lifespan and frailty assessment

    PMID:28811495 PMID:35393401

    Open questions at the time
    • Tissue source and target circuit mediating longevity effect not isolated here
  10. 2018 High

    Defined upstream control of FGF21 production by HRD1-ERAD ubiquitination of the ER-tethered transcription factor CREBH at K294, coupling nutrient state (refeeding) to FGF21 suppression.

    Evidence Liver-specific HRD1 KO, in vitro ubiquitination with K294 mutagenesis, proteasome inhibition, refeeding

    PMID:30389664

    Open questions at the time
    • Signal triggering CREBH activation versus degradation balance not fully mapped
  11. 2018 High

    Mapped the C-terminal sequence as the primary KLB-binding/receptor-activation determinant, enabling antagonist peptides and engineered super-agonists.

    Evidence In vitro signaling assays, alanine-scanning mutagenesis, KLB binding assays, obese mouse pharmacology

    PMID:29789271

    Open questions at the time
    • Structural basis of the C-terminus–KLB contact not solved here
  12. 2019 High

    Showed brain KLB signaling, not direct adipose action, mediates the adaptive response to protein restriction (macronutrient preference, energy expenditure, glucose), centralizing FGF21's site of action.

    Evidence Brain-specific KLB KO and whole-body FGF21 KO with protein restriction phenotyping

    PMID:31167139

    Open questions at the time
    • Specific brain neuronal population not identified in this study
  13. 2019 High

    Demonstrated liver, not adipose, is the cold-induced circulating FGF21 source, and central KLB signaling drives sympathetic BAT activation while adipose-direct FGF21 signaling is dispensable for thermoregulation.

    Evidence Liver-, adipose-, and adipose-KLB-specific KO mice, CNS FGF21 blockade, cold exposure, temperature monitoring

    PMID:30679672

    Open questions at the time
    • Identity of CNS thermoregulatory FGF21-target neurons not defined here
  14. 2020 High

    Solved the FGF21 NMR structure, attributing its instability to a non-canonical flexible β-trefoil and engineering a folding-stabilized chimera with better glycemic efficacy and no mitogenic effect.

    Evidence NMR spectroscopy, chimera design, thermostability assays, ob/ob mouse glucose/insulin

    PMID:33295692

    Open questions at the time
    • Receptor-bound structure not determined
    • Single lab
  15. 2020 High

    Added PPARα-dependent Fgf21 promoter DNA demethylation as a determinant of FGF21 expression magnitude, demonstrated causally by targeted dCas9-TET1 demethylation.

    Evidence CRISPR/dCas9-TET1 epigenome editing at the Fgf21 promoter in PPARα-deficient mice and Hepa1-6 cells, bisulfite sequencing

    PMID:32198422

    Open questions at the time
    • Developmental timing and enzymes setting methylation not fully defined
  16. 2020 High

    Identified ATF3 as an integrated-stress-response repressor that directly silences the Fgf21 promoter in pancreatitis, with FGF21 replacement resolving disease and conserved human ATF3 sites.

    Evidence ATF3 ChIP on Fgf21 promoter, three pancreatitis mouse models, recombinant FGF21 rescue, PERK inhibition, human tissue

    PMID:31915301

    Open questions at the time
    • Whether ATF3 repression operates in other FGF21-producing tissues not tested
  17. 2021 High

    Dissociated FGF21's pyrexic action from thermogenesis, showing a UCP1-independent rise in body temperature achieved by reducing heat loss.

    Evidence UCP1-KO mice, FGF21 across ambient temperatures, calorimetry, telemetry, tail thermography

    PMID:34418595

    Open questions at the time
    • Effector mechanism for reduced heat loss (e.g. vasomotor control) not specified
  18. 2022 High

    Defined CNOT6L deadenylase as a post-transcriptional brake on Fgf21 mRNA stability, providing a druggable node to raise circulating FGF21.

    Evidence Genetic and pharmacological CNOT6L inhibition, mRNA stability assays, small-molecule validation in diet-induced obese mice

    PMID:35385705

    Open questions at the time
    • Specificity of CNOT6L for Fgf21 versus other transcripts not bounded
  19. 2022 High

    Resolved central FGF21 circuit diversity: liver-derived FGF21 acts on hypothalamic GABAergic DR2 neurons (gated by tanycytes) for breastfeeding-induced obesity protection, while RSC-derived FGF21 enhances hippocampal LTP and spatial memory independent of energy homeostasis.

    Evidence FGF21-Cre lineage tracing, RSC mapping, hippocampal LTP electrophysiology, delayed-weaning models, behavioral and metabolic assays

    PMID:35879461 PMID:36001982

    Open questions at the time
    • RSC-derived FGF21 source mechanism is Medium-confidence single study for the hypothalamic circuit
    • How distinct FGF21 sources access separate circuits not unified
  20. 2022 Medium

    Extended the FGF21–adiponectin axis to cardioprotection, showing it suppresses cardiomyocyte PDK4 via PI3K/AKT to preserve mitochondrial bioenergetics in HFpEF, and revealed sex-dependent adrenergic-cAMP-EPAC control of adiponectin/hepatic lipid responses.

    Evidence FGF21, adipose-specific FGF21, adiponectin and PDK4 KO mice in HFpEF; sex-stratified obese models with ovariectomy and adrenergic-cAMP-EPAC assays

    PMID:35998055 PMID:39955281

    Open questions at the time
    • Whether cardiac protection is via circulating adiponectin or direct cardiomyocyte FGF21 not fully separated
    • Molecular basis of sex divergence in EPAC signaling unresolved
  21. 2023 High

    Identified locus coeruleus noradrenergic neurons as the substrate by which FGF21 counteracts ethanol intoxication through arousal, with specificity for ethanol over other sedatives.

    Evidence FGF21 KO and pharmacological rescue, righting/ataxia assays, LC neuronal activation, sedative-agent controls

    PMID:36889282

    Open questions at the time
    • Receptor and intracellular pathway in LC neurons not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse upstream transcriptional, epigenetic, and post-transcriptional inputs and the multiple tissue sources are integrated to set context-specific FGF21 output, and how distinct central circuits are selectively engaged, remains unresolved.
  • No unified model linking source tissue to specific peripheral/central target
  • Receptor-level structural basis of KLB engagement in each tissue not solved
  • Many disease-context mechanisms (atherosclerosis, OA, neuroinflammation, PAH) rest on single-lab studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-8953854 Metabolism of RNA 1
Partners
ADIPOQFGFR1KLB

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Adiponectin is a downstream effector of FGF21 in mediating its systemic insulin-sensitizing effects. FGF21 treatment enhanced adiponectin expression and secretion in adipocytes, raising serum adiponectin. Adiponectin knockout mice were refractory to FGF21-mediated alleviation of hyperglycemia, hypertriglyceridemia, insulin resistance, and hepatic steatosis, while FGF21-mediated ERK1/2 activation in adipose tissue remained intact. Adiponectin knockout mouse model, FGF21 administration, serum/tissue metabolic assays, Western blotting for insulin signaling Cell metabolism High 23663741
2011 Brown adipose tissue (BAT) is a source of circulating FGF21 upon thermogenic activation. Norepinephrine acts via β-adrenergic/cAMP/PKA/p38 MAPK signaling to induce FGF21 gene transcription, with ATF2 binding the FGF21 promoter as the mediating transcription factor. Cold exposure in rats caused direct FGF21 release from BAT measured by arteriovenous differences. Arteriovenous difference measurements across interscapular BAT, blood flow measurement, β-adrenergic pharmacology, p38 MAPK inhibitors, ATF2 chromatin binding assays, in vivo cold exposure The Journal of biological chemistry High 21317437
2008 Skeletal muscle is a source of FGF21, and FGF21 expression and secretion in muscle are regulated by the PI3K/Akt1 signaling pathway. Akt1 transgenic mice showed elevated muscle and serum FGF21; insulin and LY294002 regulated FGF21 in cultured muscle cells. Akt1 skeletal muscle-specific transgenic mice, PI3K inhibitor (LY294002), cultured myocytes, serum FGF21 measurement, protein/mRNA expression FEBS letters Medium 18948104
2015 FGF21 reduces sweet preference and alcohol preference via its co-receptor β-Klotho in the central nervous system, and correlates with reduced dopamine concentrations in the nucleus accumbens. FGF21 administration in mice and cynomolgus monkeys, CNS-specific β-Klotho knockout mice, dopamine measurement in nucleus accumbens, preference behavioral assays Cell metabolism High 26724861
2017 FGF21 acts as a secretagogue in pancreatic acinar cells, stimulating digestive enzyme secretion through an autocrine/paracrine mechanism requiring FGFR–β-Klotho signaling. FGF21 triggers intracellular calcium release via PLC-IP3R signaling. FGF21-deficient mice accumulate zymogen granules and show pancreatic ER stress; acinar-specific β-Klotho deletion also causes granule accumulation and prevents FGF21-stimulated secretion. FGF21 and β-Klotho knockout mice, acinar cell-specific β-Klotho deletion, recombinant FGF21 rescue, calcium imaging, PLC-IP3R pathway pharmacology, zymogen granule quantification Cell metabolism High 28089565
2019 FGF21 signaling in the brain via β-Klotho (KLB) is required for the adaptive physiological response to dietary protein restriction, including shifts in macronutrient preference toward protein, increased energy expenditure, and glucose homeostasis. Brain-specific KLB deletion or whole-body FGF21 deletion abolishes these responses. Brain-specific KLB knockout mice, whole-body FGF21 knockout mice, dietary protein restriction protocols, metabolic phenotyping, food preference assays Cell reports High 31167139
2018 HRD1-ERAD E3 ubiquitin ligase controls FGF21 production by catalyzing polyubiquitin conjugation onto the ER-tethered transcription factor CREBH at lysine 294, targeting it for proteasomal degradation. Liver-specific HRD1 deletion prevents FGF21 suppression during refeeding, phenocopying FGF21 gain-of-function mice. Liver-specific HRD1 knockout mice, polyubiquitination assay, site-specific mutagenesis (K294), proteasome inhibition, refeeding experiments, serum FGF21 measurement The EMBO journal High 30389664
2019 Liver-derived FGF21 (not adipose-derived) enters circulation during acute cold exposure and is critical for thermoregulation. Central FGF21 signaling (via CNS β-Klotho) is necessary for maximal sympathetic drive to BAT to maintain thermoregulation; direct FGF21 signaling to adipose tissue is dispensable. Liver-specific FGF21 KO mice, adipose-specific FGF21 KO mice, adipose-specific KLB KO mice, pharmacological CNS FGF21 blockade, cold exposure studies, body temperature monitoring Scientific reports High 30679672
2014 FGF21 expression and secretion in muscle cells is controlled by MyoD as a major transcriptional regulator, and is induced by mitochondrial dysfunction via increased ROS → p38 MAPK → ATF2 binding to the proximal FGF21 promoter. MyoD is required for mitochondrial dysfunction-induced FGF21 expression in myogenic cells. Respiratory chain/OXPHOS inhibitors in cultured muscle cells, MyoD knockdown, ROS measurement, p38 MAPK inhibition, ATF2 promoter binding assay, FGF21 mRNA/protein/secretion assays The Biochemical journal High 25055037
2015 FGF21-mediated improvements in glucose clearance require UCP1. While FGF21 can lower body weight in both wild-type and Ucp1-knockout mice, rapid clearance of a glucose challenge by FGF21 is defective in Ucp1-KO mice, implicating UCP1-dependent thermogenesis in BAT as a mechanism for FGF21-driven glucose disposal. Ucp1 knockout mice, FGF21 administration, glucose tolerance tests, BAT temperature measurement, UCP1 protein quantification Cell reports High 26586424
2017 Dietary protein restriction increases lifespan, reduces frailty, and improves metabolic health in mice in an FGF21-dependent manner. FGF21-knockout mice fail to exhibit these metabolic responses to protein restriction and show accelerated aging phenotypes. FGF21 global knockout mice, long-term dietary protein restriction, lifespan measurement, frailty assessment, metabolic phenotyping Scientific reports High 28811495 35393401
2018 The C-terminal sequence of FGF21 defines its binding to β-Klotho (KLB) and is the primary determinant of receptor activation. C-terminal FGF21 peptides potently inhibit FGF21/KLB-mediated signaling. Key residues are highly conserved with FGF19, and substituting native FGF21 C-terminal sequence with an optimized high-affinity peptide generates a super-agonist with enhanced metabolic efficacy in obese mice. In vitro functional signaling assays, alanine-scanning mutagenesis of C-terminal peptides, KLB binding assays, in vivo obese mouse pharmacology Molecular metabolism High 29789271
2020 FGF21 structure was determined by NMR spectroscopy; the non-canonical flexible β-trefoil conformation affects folding of the β2-β3 hairpin and overall protein stability. A chimeric FGF21-FGF19 variant (FGF21SS) with modulated folding dynamics showed better thermostability, improved insulin sensitivity, and reduced blood glucose in ob/ob mice without inducing hepatocyte proliferation. NMR spectroscopy, chimeric protein design, thermostability assays, in vitro adipocyte insulin signaling assay, ob/ob mouse blood glucose and insulin measurement EMBO reports High 33295692
2020 Pancreatitis is associated with loss of FGF21 expression in exocrine pancreas due to ISR activation inducing ATF3, a transcriptional repressor that directly binds specific sites on the Fgf21 promoter. FGF21 replacement mitigates ISR and resolves pancreatitis in three mouse models; ATF3 binding sites are conserved in human FGF21 promoter. ISR activation in cultured acinar cells and mouse pancreata, ATF3 chromatin immunoprecipitation on Fgf21 promoter, three mouse pancreatitis models, recombinant FGF21 pharmacological rescue, PERK inhibitor experiments, human pancreatitis tissue analysis Science translational medicine High 31915301
2023 FGF21 counteracts ethanol-induced intoxication by stimulating arousal via direct activation of noradrenergic neurons in the locus coeruleus, without changing ethanol catabolism. FGF21-deficient mice take longer to recover from ethanol; pharmacological FGF21 accelerates recovery. FGF21 does not counteract sedation by ketamine, diazepam, or pentobarbital, indicating ethanol specificity. FGF21 global knockout mice, pharmacological FGF21 administration, righting reflex and ataxia assays, locus coeruleus neuronal recording/activation studies, multiple sedative agent controls Cell metabolism High 36889282
2022 CNOT6L deadenylase controls FGF21 mRNA stability in hepatocytes. CNOT6L inhibition stabilizes Fgf21 mRNA, elevating serum FGF21 protein, which then acts on liver and adipose tissue to induce energy expenditure and lipid consumption. A small-molecule CNOT6L inhibitor that increases GDF15 and FGF21 improves diet-induced metabolic syndrome. CNOT6L inhibition (genetic and pharmacological), mRNA stability assays, serum hepatokine measurement, small-molecule screening, metabolic phenotyping in diet-induced obese mice Cell metabolism High 35385705
2022 FGF21 enhances adiponectin production, which in turn acts on cardiomyocytes (or FGF21 directly targets cardiomyocytes) to suppress PDK4 via PI3K/AKT signaling, thereby promoting mitochondrial bioenergetics and protecting against HFpEF. APN deletion abrogates FGF21's protective effects against HFpEF; genetic PDK4 inactivation mimics FGF21 protection. Global and adipose-specific FGF21 KO mice, HFD+L-NAME HFpEF model, FGF21 replenishment, adiponectin KO, PDK4 genetic inactivation, PI3K/AKT pathway assays, mitochondrial bioenergetics measurement Nature communications High 39955281
2022 Liver-derived FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta to mediate prolonged breastfeeding-induced protection against obesity, via enhanced BAT thermogenesis and energy expenditure. Tanycyte-controlled access to the hypothalamus gates FGF21 action. Delayed weaning rat model, transgenic mice, metabolic phenotyping, brain-specific pathway (tanycyte access), specific neuronal circuit identification (GABAergic DR2 neurons), hepatic FGF21 manipulation Nature metabolism Medium 35879461
2022 Central FGF21, produced not in the hypothalamus but in the retrosplenial cortex (RSC), enhances spatial memory by prolonging long-term potentiation in the hippocampus and activating hippocampal neurons, without regulating peripheral energy homeostasis or sugar intake. FGF21-Cre lineage tracing mouse model, RSC-specific FGF21 expression mapping, hippocampal LTP electrophysiology, spatial memory behavioral assays, energy homeostasis and sugar preference assays Cell reports High 36001982
2016 PPARβ/δ deficiency in hepatocytes increases FGF21 expression via upregulation of the heme-regulated eIF2α kinase (HRI), which causes enhanced phospho-eIF2α and ATF4, driving Fgf21 transcription. siRNA knockdown confirmed HRI as a regulator of hepatic FGF21 expression, and pharmacological HRI activation increased FGF21 and reduced hepatic steatosis in an FGF21-dependent manner. PPARβ/δ knockout mice, siRNA knockdown of HRI and PPARβ/δ in primary hepatocytes, eIF2α and ATF4 western blotting, HRI pharmacological activator, Fgf21-null mice as controls Diabetes High 27486236
2016 Lactate rapidly induces FGF21 expression and secretion in adipocytes via a p38-MAPK-dependent, NADH/NAD-independent pathway. Pyruvate and ketone bodies similarly activate FGF21, suggesting sensing of intermediate metabolites drives adipose FGF21 release. Lactate treatment of adipocytes, pharmacological p38-MAPK inhibition, knockout mouse models, NADH/NAD manipulation, FGF21 mRNA and secretion assays The Biochemical journal Medium 26769382
2012 Metformin stimulates FGF21 expression in primary rat and human hepatocytes via AMPK activation; this effect is blocked by the AMPK inhibitor Compound C. Primary rat and human hepatocyte cultures, metformin treatment, AMPK inhibitor (Compound C), FGF21 mRNA and protein measurement Experimental diabetes research Medium 23118742
2016 Leptin increases FGF21 expression in vivo in rats and in HepG2 hepatocytes, and this effect is mediated by STAT3 activation. Leptin injection in Wistar rats, HepG2 cell treatment, STAT3 inhibition/activation, FGF21 mRNA/protein measurement Cellular physiology and biochemistry Low 26982498
2020 In MDCK mechanical cell competition, scribble-knockdown (scribKD) cells secrete FGF21 via the ASK1-p38 pathway, which attracts surrounding wild-type cells and drives their mechanical elimination of scribKD cells through FGFR1 signaling in wild-type cells. FGF21 knockdown in scribKD MDCK cells, FGFR1 loss-of-function in WT cells, conditioned medium cell motility assays, ASK1-p38 pathway pharmacology Current biology Medium 33357449
2013 FGF21 enhances BMP-2-induced osteogenesis by upregulating BMP-2-dependent Smad signaling (not p44/42 MAPK). BMP-2 in turn decreases endogenous FGF21 mRNA expression, forming a negative feedback loop. C2C12 cell osteogenic differentiation assay, alkaline phosphatase activity, matrix mineralization, Smad and MAPK phosphorylation western blotting, FGF21 mRNA measurement Biochemical and biophysical research communications Low 23416071
2020 FGF21 impedes peripheral nervous system myelin development by activating the p38 MAPK/c-Jun signaling axis in Schwann cells (not ERK). Anti-FGF21 antibody accelerates peripheral myelination in neonatal rats. Primary Schwann cell culture, recombinant FGF21 treatment, p38 MAPK and ERK pharmacological inhibition, gene knockdown, neonatal rat FGF21 injection, anti-FGF21 antibody infusion, myelin gene expression analysis Journal of cellular physiology Medium 32657446
2020 FGF21 protects chondrocytes from apoptosis, senescence, and ECM catabolism by enhancing autophagy flux via TFEB nuclear translocation through activation of the SIRT1-mTOR signaling pathway, and reduces OA in a DMM mouse model. TBHP-induced chondrocyte stress model, FGF21 treatment, autophagy flux assay, TFEB nuclear translocation imaging, SIRT1-mTOR pathway western blotting, autophagy inhibitor (CQ), DMM mouse OA model Cell death & disease Medium 34556628
2022 FGF21 alleviates acute liver injury by enhancing SIRT1-mediated autophagy. Mechanistically, exogenous FGF21 upregulates LC3-II and Beclin1 (autophagy markers) via SIRT1 upregulation; SIRT1 knockdown by lentiviral RNAi reverses FGF21's hepatoprotective effect. CCl4-induced ALI mouse model, L02 hepatocyte cell line, FGF21 treatment, SIRT1 lentiviral RNAi knockdown in mice and cells, autophagy markers (LC3-II, Beclin1), ALT/AST/cytokine assays Journal of cellular and molecular medicine Medium 34984826
2024 Excess BCAA decreases hepatic FGF21 production by inhibiting PPARα signaling; reduced FGF21 leads to higher cardiac LAT1 expression via transcription factor Zbtb7c, increasing cardiac BCAA uptake and mTOR-driven mitochondrial damage and apoptosis. Fecal microbiota transplant from healthy mice alleviated cardiac dysfunction in T1D mice, but this was abolished by FGF21 knockdown. T1D mouse model, gut microbiota BCAA profiling, FGF21 knockdown, PPARα signaling pathway assay, LAT1 and Zbtb7c expression, mTOR signaling, fecal microbiota transplant, cardiac function assays Microbiome Medium 39182099
2021 FGF21 attenuates pulmonary arterial hypertension by suppressing miR-27b expression in HPAECs, which in turn de-represses PPARγ (a direct miR-27b target validated by luciferase assay), reducing NF-κB-driven inflammation and endothelial dysfunction. Hypoxia-induced HPAEC model, FGF21 treatment, miR-27b overexpression/inhibition, luciferase reporter assay for miR-27b/PPARγ targeting, NF-κB pathway assays, inflammatory cytokine measurement International journal of molecular medicine Medium 33907846
2020 FGF21 inhibits retinal and choroidal neovascularization, and this protective effect requires adiponectin (APN). FGF21 administration inhibited TNF-α but not VEGFA expression in neovascular eyes; APN-deficient mice were not protected by FGF21. Mouse oxygen-induced retinopathy model, VLDLR-deficient retinal angiomatous proliferation model, laser-induced choroidal neovascularization model, FGF21 administration, FGF21-KO, APN-KO mice, TNF-α and VEGFA measurement Cell reports High 28199833
2020 FGF21 attenuates neuroinflammation after subarachnoid hemorrhage by promoting AMPK-dependent mitophagy in microglia, preventing mitochondrial DNA release and thereby suppressing cGAS-STING pathway activation. Conditional STING knockout in microglia ameliorated SAH-induced inflammation. SAH mouse model, recombinant FGF21 treatment, AMPK pharmacological manipulation, mitophagy assay, mtDNA cytoplasmic release measurement, cGAS-STING pathway assays, microglial STING conditional knockout, RNA sequencing, behavioral assays Journal of translational medicine Medium 38720350
2021 FGF21 has a direct pyrexic effect on body temperature that is independent of UCP1 and can occur without changes in energy expenditure. In UCP1-knockout mice, FGF21 increases body temperature by reducing heat loss (e.g., reduced tail surface temperature) rather than increasing heat production. UCP1-knockout mice, FGF21 administration at multiple ambient temperatures, indirect calorimetry, body temperature telemetry, tail surface temperature (infrared thermography), BAT temperature measurement Molecular metabolism High 34418595
2022 FGF21 effects on hepatic lipid metabolism and adiponectin secretion are sex-dependent. FGF21 reduced liver triglycerides and stimulated adiponectin via the adrenergic receptor→cAMP→EPAC signaling pathway in obese male mice but inhibited this pathway in females. Ovariectomized and reproductively senescent old females did not respond to FGF21 for liver TG or adiponectin, indicating the sex dependence is not mediated by an active female reproductive system. Male and female obese mouse models, FGF21 treatment, adiponectin measurement, adrenergic receptor-cAMP-EPAC pathway assays, ovariectomy model, aged female mice, liver triglyceride quantification JCI insight Medium 35998055
2020 PPARα-dependent DNA demethylation of the Fgf21 promoter in postnatal mouse liver regulates FGF21 gene expression. Targeted DNA demethylation using CRISPR/dCas9-TET1 at the Fgf21 promoter in PPARα-deficient mice restored fasting- and PPARα ligand-induced Fgf21 expression, providing direct evidence that DNA methylation status at the Fgf21 promoter determines the magnitude of gene expression response. CRISPR/dCas9-SunTag-scFv-TET1CD system, Fgf21 promoter-specific demethylation, Hepa1-6 cells, PPARα-deficient mice, bisulfite sequencing, PPARα agonist treatment, fasting experiment Scientific reports High 32198422
2022 FGF21 reduces hypercholesterolaemia and atherosclerosis by promoting BAT activation and WAT browning, which enhances selective uptake of fatty acids from triglyceride-rich lipoproteins into thermogenic adipose tissues, accelerating clearance of cholesterol-enriched remnants by the liver. APOE*3-Leiden.CETP hypercholesterolaemic mouse model, pharmacological FGF21 administration, BAT activation measurement, WAT browning assessment, lipoprotein clearance assays, atherosclerotic lesion quantification, hepatic gene expression profiling Cardiovascular research Medium 33693480
2019 FGF21 and PPARγ mutually promote each other's expression in pulmonary artery smooth muscle cells via the AMPK/PGC-1α pathway and the FGF21 co-receptor KLB, attenuating hypoxia-induced pulmonary hypertension. Hypoxia-induced pulmonary hypertension mouse model, FGF21 and PPARγ expression assays, AMPK/PGC-1α pathway analysis, KLB protein assay, in vitro and in vivo experiments Experimental biology and medicine Low 30714402
2023 FGF21 inhibits FGF21 promoter via the FGFR-KLB-FGF21 autocrine axis to suppress CYP7A1 promoter activity in liver cells (hepatocyte autocrine mechanism). FGF21 protein directly inhibited CYP7A1 promoter activity in HepG2 cells, and this effect was mediated by conditioned medium from FGF21-overexpressing cells but not abolished by deletion of putative phosphorylated FGF21 effector response elements. HepG2 transfection with FGF21, luciferase reporter for CYP7A1 promoter, conditioned medium transfer, response element deletion mutants Biochimica et biophysica acta. Molecular basis of disease Low 29883717
2019 FGF21 mediates MSC senescence via AMPK signaling that regulates mitochondrial dynamics (fusion/fission balance). FGF21 depletion in MSCs enhanced mitochondrial fusion (via Mfn2) and mitochondrial ROS, driving senescence; AMPK activation or Mfn2 knockdown abrogated FGF21-depletion-induced senescence. FGF21 siRNA depletion in MSCs, Mfn2 siRNA knockdown, AMPK activator (AICAR), mitochondrial morphology (MitoTracker), ROS measurement (MitoSox), SA-β-gal staining Oxidative medicine and cellular longevity Medium 31178962

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell metabolism 585 23663741
2011 Thermogenic activation induces FGF21 expression and release in brown adipose tissue. The Journal of biological chemistry 516 21317437
2020 The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nature reviews. Endocrinology 485 32764725
2008 FGF21 is an Akt-regulated myokine. FEBS letters 357 18948104
2015 FGF21 Regulates Sweet and Alcohol Preference. Cell metabolism 284 26724861
2019 FGF21 as Modulator of Metabolism in Health and Disease. Frontiers in physiology 258 31057418
2014 Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends in endocrinology and metabolism: TEM 252 25476453
2013 Acute exercise induces FGF21 expression in mice and in healthy humans. PloS one 236 23667629
2018 FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO molecular medicine 231 29987000
2019 FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism. Cell reports 191 31167139
2020 FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases. Frontiers in endocrinology 168 33381084
2013 Inventing new medicines: The FGF21 story. Molecular metabolism 168 24749049
2014 FGF21 as a Hepatokine, Adipokine, and Myokine in Metabolism and Diseases. Frontiers in endocrinology 166 25071723
2013 Novel locus including FGF21 is associated with dietary macronutrient intake. Human molecular genetics 159 23372041
2014 FGF21-based pharmacotherapy--potential utility for metabolic disorders. Trends in endocrinology and metabolism: TEM 146 24709036
2019 Going Back to the Biology of FGF21: New Insights. Trends in endocrinology and metabolism: TEM 132 31248786
2014 FGF21 as a Stress Hormone: The Roles of FGF21 in Stress Adaptation and the Treatment of Metabolic Diseases. Diabetes & metabolism journal 126 25215270
2017 FGF21 Is an Exocrine Pancreas Secretagogue. Cell metabolism 112 28089565
2022 FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice. Nature communications 99 35393401
2017 Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses. Ageing research reviews 99 28552719
2015 FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties. Trends in endocrinology and metabolism: TEM 98 26490383
2016 FGF21 activates AMPK signaling: impact on metabolic regulation and the aging process. Journal of molecular medicine (Berlin, Germany) 97 27678528
2015 FGF21 and Cardiac Physiopathology. Frontiers in endocrinology 97 26379627
2021 Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway. Cell death & disease 95 34556628
2017 FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases. Hormone molecular biology and clinical investigation 95 28525362
2023 Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine. International journal of biological sciences 91 36594101
2020 FGF21 attenuates neurodegeneration through modulating neuroinflammation and oxidant-stress. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 90 32768941
2017 Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints. Scientific reports 90 28811495
2019 FGF21 Mediates Mesenchymal Stem Cell Senescence via Regulation of Mitochondrial Dynamics. Oxidative medicine and cellular longevity 85 31178962
2020 FGF21 and the Physiological Regulation of Macronutrient Preference. Endocrinology 79 32047920
2020 FGF19 and FGF21 for the Treatment of NASH-Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human. Frontiers in endocrinology 78 33414764
2020 FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation. Endocrine connections 77 32688339
2020 FGF21 in obesity and cancer: New insights. Cancer letters 77 33264641
2017 Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity. Cellular signalling 77 28844867
2019 Liver Derived FGF21 Maintains Core Body Temperature During Acute Cold Exposure. Scientific reports 74 30679672
2020 FGF19 and FGF21: In NASH we trust. Molecular metabolism 66 33383173
2020 Lack of FGF21 promotes NASH-HCC transition via hepatocyte-TLR4-IL-17A signaling. Theranostics 65 32929325
2017 FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice. Cell reports 63 28199833
2018 Homeostatic sensing of dietary protein restriction: A case for FGF21. Frontiers in neuroendocrinology 61 29890191
2015 FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1. Cell reports 61 26586424
2014 FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling. The Biochemical journal 61 25055037
2022 Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis. Cardiovascular research 60 33693480
2019 Circulating FGF21 Levels in Human Health and Metabolic Disease. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 59 31108554
2018 FGF21 Is a Hormonal Mediator of the Human "Thrifty" Metabolic Phenotype. Diabetes 59 30257977
2018 HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination. The EMBO journal 59 30389664
2016 The FGF21 Receptor Signaling Complex: Klothoβ, FGFR1c, and Other Regulatory Interactions. Vitamins and hormones 58 27125737
2012 FGF21: The center of a transcriptional nexus in metabolic regulation. Current diabetes reviews 57 22587513
2012 Metformin stimulates FGF21 expression in primary hepatocytes. Experimental diabetes research 57 23118742
2022 Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21. Nature metabolism 56 35879461
2023 FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis. eLife 55 36648330
2022 The potential function and clinical application of FGF21 in metabolic diseases. Frontiers in pharmacology 55 36618930
2016 Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway. The Biochemical journal 49 26769382
2023 Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho. Frontiers in endocrinology 44 37260446
2021 Association between serum FGF21 level and sarcopenia in older adults. Bone 44 33571698
2022 Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure. Cell metabolism 43 35385705
2023 FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system. Cell metabolism 42 36889282
2022 Hepatic hormone FGF21 and its analogues in clinical trials. Chronic diseases and translational medicine 42 35620160
2019 Dietary Methionine Restriction Reduces Inflammation Independent of FGF21 Action. Obesity (Silver Spring, Md.) 40 31207147
2018 Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificity. Molecular metabolism 39 29789271
2018 Interaction of glucocorticoids with FXR/FGF19/FGF21-mediated ileum-liver crosstalk. Biochimica et biophysica acta. Molecular basis of disease 39 29883717
2022 FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway. Journal of cellular and molecular medicine 38 34984826
2020 Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy. Science translational medicine 38 31915301
2015 Research Perspectives on the Regulation and Physiological Functions of FGF21 and its Association with NAFLD. Frontiers in endocrinology 38 26441837
2024 BCAA mediated microbiota-liver-heart crosstalk regulates diabetic cardiomyopathy via FGF21. Microbiome 37 39182099
2016 Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency. Diabetes 36 27486236
2022 Central FGF21 production regulates memory but not peripheral metabolism. Cell reports 35 36001982
2022 Aerobic exercise regulates FGF21 and NLRP3 inflammasome-mediated pyroptosis and inhibits atherosclerosis in mice. PloS one 32 36006939
2011 FGF10 and FGF21 as regulators in adipocyte development and metabolism. Endocrine, metabolic & immune disorders drug targets 32 21696361
2024 FGF21 attenuates neuroinflammation following subarachnoid hemorrhage through promoting mitophagy and inhibiting the cGAS-STING pathway. Journal of translational medicine 28 38720350
2020 Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing. Scientific reports 28 32198422
2016 Leptin as a Potential Regulator of FGF21. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 28 26982498
2023 Toward reconciling the roles of FGF21 in protein appetite, sweet preference, and energy expenditure. Cell reports 27 38060447
2022 Multi-organ FGF21-FGFR1 signaling in metabolic health and disease. Frontiers in cardiovascular medicine 27 35983184
2010 FGF21 signalling pathway and metabolic traits - genetic association analysis. European journal of human genetics : EJHG 27 20717167
2025 FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice. Nature communications 26 39955281
2013 Interactions between FGF21 and BMP-2 in osteogenesis. Biochemical and biophysical research communications 26 23416071
2012 FGF21 as a therapeutic reagent. Advances in experimental medicine and biology 26 22396172
2022 FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk. JCI insight 24 35998055
2016 Relationship between FGF21 and UCP1 levels under time-restricted feeding and high-fat diet. The Journal of nutritional biochemistry 24 27883936
2021 FGF21 attenuates hypoxia‑induced dysfunction and inflammation in HPAECs via the microRNA‑27b‑mediated PPARγ pathway. International journal of molecular medicine 23 33907846
2019 Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension. Experimental biology and medicine (Maywood, N.J.) 23 30714402
2018 FGF-21 as a Potential Biomarker for Mitochondrial Diseases. Current medicinal chemistry 23 29332568
2021 FGF21 ameliorates hepatic fibrosis by multiple mechanisms. Molecular biology reports 22 34536190
2020 Dynamic folding modulation generates FGF21 variant against diabetes. EMBO reports 22 33295692
2021 Neuroprotective Effects of the FGF21 Analogue LY2405319. Journal of Alzheimer's disease : JAD 21 33554901
2020 FGF21 Mimics a Fasting-Induced Metabolic State and Increases Appetite in Zebrafish. Scientific reports 21 32332781
2020 FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells. Current biology : CB 21 33357449
2020 The autocrine role of FGF21 in cultured adipocytes. The Biochemical journal 20 32648929
2021 Advances in Biological Functions and Clinical Studies of FGF21. Diabetes, metabolic syndrome and obesity : targets and therapy 19 34295169
2021 A pyrexic effect of FGF21 independent of energy expenditure and UCP1. Molecular metabolism 19 34418595
2020 Moderate-Intensity Continuous Training Improves FGF21 and KLB Expression in Obese Mice. Biochemistry. Biokhimiia 19 33045954
2023 CRISPRa-based activation of Fgf21 and Fndc5 ameliorates obesity by promoting adipocytes browning. Clinical and translational medicine 18 37462619
2022 FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ. Journal of cellular and molecular medicine 18 34989130
2022 FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19. Journal of cellular and molecular medicine 18 35437883
2021 Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine. Frontiers in endocrinology 18 34917032
2020 FGF21 impedes peripheral myelin development by stimulating p38 MAPK/c-Jun axis. Journal of cellular physiology 18 32657446
2015 Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress. Journal of nutritional science and vitaminology 18 26052146
2014 Molecular characterization and mapping of Fgf21 gene in a foodfish species asian seabass. PloS one 17 24587261
2024 Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21. Redox biology 16 39383602
2016 Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration. Molecular medicine reports 16 26934832

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