Component

Mouse fibroblast growth factor 21 / Fgf21

Context-specific entity; species, compartment and exposure are stated on each claim.

12 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. Whole-body Fgf21 deletion blunted low-isoleucine-induced energy expenditure and hyperphagia but did not abolish improved glucose tolerance.

    Mouse fibroblast growth factor 21 / Fgf21 → Energy-expenditure response to low-isoleucine diet source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Fgf21-knockout mice and littermate diet comparisons.
    limitations
    Do not label FGF21 a required mediator of all isoleucine-restriction effects.
    nutrient_topic
    L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine
    plain_language
    Different outcomes used partly different routes.
    primary_references
    The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 386–392

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fgf21-knockout mice and littermate diet comparisons. · source_derived_draft · unverified_draft

    ## isoleucine-restriction-fgf21-loss Different outcomes used partly different routes. Whole-body Fgf21 deletion blunted low-isoleucine-induced energy expenditure and hyperphagia but did not abolish improved glucose tolerance. Model: Fgf21-knockout mice and littermate diet comparisons. Limitations: Do not label FGF21 a required mediator of all isoleucine-restriction effects. Evidence access: Primary full text The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025
    Complete structured claim and evidence

  2. Fgf21 knockout attenuated weight loss in mice fed a diet lacking both methionine and cysteine.

    Mouse fibroblast growth factor 21 / Fgf21 → Weight loss during systemic cysteine depletion in mice source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    nutrient_deficiency Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Fgf21-null versus control mice on no-methionine/no-cysteine diets; separate from the Cse-null cysteine-only experiment.
    limitations
    Do not silently replace the combined restriction with cysteine-only restriction. Correction record: Author correction published 12 December 2025 (2026 issue), PMID 41388205, DOI 10.1038/s41586-025-09780-8: two incorrect day-3 muscle histology panels in Extended Data Fig. 2f,g duplicated day-7 panels and were replaced. The authors state that figure and paper conclusions were unaffected. This is a figure correction, not independent validation. https://www.nature.com/articles/s41586-025-09780-8
    nutrient_topic
    L-Cysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Cysteine
    plain_language
    A stress hormone contributed under combined sulfur-amino-acid withdrawal.
    primary_references
    Unravelling cysteine-deficiency-associated rapid weight loss. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40399674/ · DOI 10.1038/s41586-025-08996-y
    trigger_kind
    nutrient_deficiency Imported condition classification; unverified.

    L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 340–346

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fgf21-null versus control mice on no-methionine/no-cysteine diets; separate from the Cse-null cysteine-only experiment. · source_derived_draft · unverified_draft

    ## l-cysteine-fgf21-combined-restriction A stress hormone contributed under combined sulfur-amino-acid withdrawal. Fgf21 knockout attenuated weight loss in mice fed a diet lacking both methionine and cysteine. Model: Fgf21-null versus control mice on no-methionine/no-cysteine diets; separate from the Cse-null cysteine-only experiment. Limitations: Do not silently replace the combined restriction with cysteine-only restriction. Correction record: Author correction published 12 December 2025 (2026 issue), PMID 41388205, DOI 10.1038/s41586-025-09780-8: two incorrect day-3 muscle histology panels in Extended Data Fig. 2f,g duplicated day-7 panels and were replaced. The authors state that figure and paper conclusions were unaffected. This is a figure correction, not independent validation. https://www.nature.com/articles/s41586-025-09780-8 Evidence access: Primary full text Unravelling cysteine-deficiency-associated rapid weight loss. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40399674/ · DOI 10.1038/s41586-025-08996-y
    Complete structured claim and evidence

  3. Additional Fgf21 deletion in Cth-null mice did not prevent the rapid weight-loss phenotype during cysteine-free feeding.

    Mouse fibroblast growth factor 21 / Fgf21 → Weight loss during systemic cysteine depletion in mice source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    nutrient_deficiency Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Cth-null versus Cth/Fgf21 double-null mice on cysteine-free diet for five days.
    limitations
    Different genotype and diet from the combined methionine/cysteine restriction study; no universal FGF21 dependence is assigned.
    nutrient_topic
    L-Cysteine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Cysteine
    plain_language
    An increased hormone level did not make that hormone necessary for this outcome.
    primary_references
    Cysteine depletion triggers adipose tissue thermogenesis and weight loss. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40461845/ · DOI 10.1038/s42255-025-01297-8
    trigger_kind
    nutrient_deficiency Imported condition classification; unverified.

    L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 364–370

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cth-null versus Cth/Fgf21 double-null mice on cysteine-free diet for five days. · source_derived_draft · unverified_draft

    ## l-cysteine-fgf21-cysteine-only-limit An increased hormone level did not make that hormone necessary for this outcome. Additional Fgf21 deletion in Cth-null mice did not prevent the rapid weight-loss phenotype during cysteine-free feeding. Model: Cth-null versus Cth/Fgf21 double-null mice on cysteine-free diet for five days. Limitations: Different genotype and diet from the combined methionine/cysteine restriction study; no universal FGF21 dependence is assigned. Evidence access: Primary full text Cysteine depletion triggers adipose tissue thermogenesis and weight loss. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40461845/ · DOI 10.1038/s42255-025-01297-8
    Complete structured claim and evidence

  4. FGF21 induced hepatic IGFBP1 and SOCS2, regulators that blunt GH/IGF signaling.

    Mouse fibroblast growth factor 21 / Fgf21 → Mouse IGF binding protein 1 / Igfbp1 source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Mouse endocrine experiments.
    limitations
    No universal human growth-hormone response is inferred.
    nutrient_topic
    Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake
    plain_language
    Additional regulators restrained growth signaling.
    primary_references
    Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18585098/ · DOI 10.1016/j.cmet.2008.05.006

    Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 272–278

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse endocrine experiments. · source_derived_draft · unverified_draft

    ## fast-mouse-gh-brakes Additional regulators restrained growth signaling. FGF21 induced hepatic IGFBP1 and SOCS2, regulators that blunt GH/IGF signaling. Model: Mouse endocrine experiments. Limitations: No universal human growth-hormone response is inferred. Evidence access: Primary abstract Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18585098/ · DOI 10.1016/j.cmet.2008.05.006
    Complete structured claim and evidence

  5. FGF21 stimulated liver ketogenesis and white-adipose lipolysis.

    Mouse fibroblast growth factor 21 / Fgf21 → Ketone-body production source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Mouse experiments.
    limitations
    Human timing differs; shared pathway labels retain mouse context.
    nutrient_topic
    Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake
    plain_language
    The endocrine signal altered fuel mobilization.
    primary_references
    Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17550777/ · DOI 10.1016/j.cmet.2007.05.003

    Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 248–254

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse experiments. · source_derived_draft · unverified_draft

    ## fast-mouse-ketones The endocrine signal altered fuel mobilization. FGF21 stimulated liver ketogenesis and white-adipose lipolysis. Model: Mouse experiments. Limitations: Human timing differs; shared pathway labels retain mouse context. Evidence access: Primary abstract Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17550777/ · DOI 10.1016/j.cmet.2007.05.003
    Complete structured claim and evidence

  6. FGF21 reduced active hepatic STAT5 and expression of its target Igf1.

    Mouse fibroblast growth factor 21 / Fgf21 → Mouse STAT5 transcription factors source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Mouse FGF21 exposure experiments.
    limitations
    Chronic experimental exposure is not an ordinary human overnight fast.
    nutrient_topic
    Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake
    plain_language
    A starvation signal weakened growth-hormone action.
    primary_references
    Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18585098/ · DOI 10.1016/j.cmet.2008.05.006

    Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 264–270

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse FGF21 exposure experiments. · source_derived_draft · unverified_draft

    ## fast-mouse-stat5 A starvation signal weakened growth-hormone action. FGF21 reduced active hepatic STAT5 and expression of its target Igf1. Model: Mouse FGF21 exposure experiments. Limitations: Chronic experimental exposure is not an ordinary human overnight fast. Evidence access: Primary abstract Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18585098/ · DOI 10.1016/j.cmet.2008.05.006
    Complete structured claim and evidence

  7. FGF21 reduced activity and promoted torpor.

    Mouse fibroblast growth factor 21 / Fgf21 → Mouse torpor and reduced activity source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Mouse experiments.
    limitations
    Torpor in this model is not a demonstrated human fasting response.
    nutrient_topic
    Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake
    plain_language
    Energy conservation involved behavior and temperature.
    primary_references
    Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17550777/ · DOI 10.1016/j.cmet.2007.05.003

    Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 256–262

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse experiments. · source_derived_draft · unverified_draft

    ## fast-mouse-torpor Energy conservation involved behavior and temperature. FGF21 reduced activity and promoted torpor. Model: Mouse experiments. Limitations: Torpor in this model is not a demonstrated human fasting response. Evidence access: Primary abstract Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17550777/ · DOI 10.1016/j.cmet.2007.05.003
    Complete structured claim and evidence

What acts on it

  1. The reduced-isoleucine diet increased hepatic FGF21 expression and circulating FGF21, with adipose UCP1-associated changes and increased energy expenditure.

    Experimentally reduced-isoleucine mouse diet → Mouse fibroblast growth factor 21 / Fgf21 source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    Mouse formulated-diet and tissue studies.
    limitations
    Co-change alone does not show that every metabolic benefit depends on FGF21.
    nutrient_topic
    L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine
    plain_language
    Dietary composition elicited a liver-to-adipose hormonal response.
    primary_references
    The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025

    L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 378–384

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse formulated-diet and tissue studies. · source_derived_draft · unverified_draft

    ## isoleucine-restriction-fgf21 Dietary composition elicited a liver-to-adipose hormonal response. The reduced-isoleucine diet increased hepatic FGF21 expression and circulating FGF21, with adipose UCP1-associated changes and increased energy expenditure. Model: Mouse formulated-diet and tissue studies. Limitations: Co-change alone does not show that every metabolic benefit depends on FGF21. Evidence access: Primary full text The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025
    Complete structured claim and evidence

  2. PPARalpha directly induced hepatic FGF21 in response to fasting or agonists.

    Mouse peroxisome proliferator-activated receptor alpha / Ppara → Mouse fibroblast growth factor 21 / Fgf21 source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Mouse fasting, agonist and FGF21 experiments.
    limitations
    Species-specific experimental evidence; not a human fasting timer.
    nutrient_topic
    Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake
    plain_language
    A fat-sensing regulator activated an endocrine signal.
    primary_references
    Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17550777/ · DOI 10.1016/j.cmet.2007.05.003

    Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 240–246

    AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse fasting, agonist and FGF21 experiments. · source_derived_draft · unverified_draft

    ## fast-mouse-fgf A fat-sensing regulator activated an endocrine signal. PPARalpha directly induced hepatic FGF21 in response to fasting or agonists. Model: Mouse fasting, agonist and FGF21 experiments. Limitations: Species-specific experimental evidence; not a human fasting timer. Evidence access: Primary abstract Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17550777/ · DOI 10.1016/j.cmet.2007.05.003
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Gcn2-null mice retained the methionine-restriction changes in adiposity, energy expenditure, insulin sensitivity and FGF21 induction.

    Experimentally methionine-restricted diet → Mouse GCN2 / Eif2ak4 source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Wild-type and Gcn2-knockout mice under the study diet.
    limitations
    Not a universal statement about GCN2 during total starvation or other amino-acid deficiencies.
    nutrient_topic
    L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
    plain_language
    This dietary response did not require the usual amino-acid stress sensor.
    primary_references
    Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 380–386

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Wild-type and Gcn2-knockout mice under the study diet. · source_derived_draft · unverified_draft

    ## methionine-gcn2-dispensability This dietary response did not require the usual amino-acid stress sensor. Gcn2-null mice retained the methionine-restriction changes in adiposity, energy expenditure, insulin sensitivity and FGF21 induction. Model: Wild-type and Gcn2-knockout mice under the study diet. Limitations: Not a universal statement about GCN2 during total starvation or other amino-acid deficiencies. Evidence access: Primary abstract Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26936965/ · DOI 10.2337/db15-1324
    Complete structured claim and evidence

  2. Dietary threonine restriction produced systemic metabolic remodeling in mice that required liver-derived FGF21.

    L-Threonine → Mouse threonine-restriction metabolic remodeling source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    nutrient_deficiency Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments.
    limitations
    Mouse metabolic responses are not evidence that restriction is appropriate for humans or developing animals.
    nutrient_topic
    L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
    plain_language
    A liver hormone mediates part of the organism-level response to restricted supply.
    primary_references
    Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
    trigger_kind
    nutrient_deficiency Imported condition classification; unverified.

    L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 346–352

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments. · source_derived_draft · unverified_draft

    ## l-threonine-fgf21-restriction A liver hormone mediates part of the organism-level response to restricted supply. Dietary threonine restriction produced systemic metabolic remodeling in mice that required liver-derived FGF21. Model: Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments. Limitations: Mouse metabolic responses are not evidence that restriction is appropriate for humans or developing animals. Evidence access: Primary abstract Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
    Complete structured claim and evidence

  3. Engineering threonine biosynthetic capacity selectively in hepatocytes reversed the systemic response to dietary threonine restriction.

    L-Threonine → Mouse threonine-restriction metabolic remodeling source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    nutrient_deficiency Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Engineered mouse hepatocyte threonine synthesis during dietary restriction.
    limitations
    This experimentally installed pathway is not a normal mammalian threonine-synthesis route.
    nutrient_topic
    L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
    plain_language
    Restoring supply in one organ changed a whole-body nutritional signal.
    primary_references
    Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
    trigger_kind
    nutrient_deficiency Imported condition classification; unverified.

    L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 354–360

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered mouse hepatocyte threonine synthesis during dietary restriction. · source_derived_draft · unverified_draft

    ## l-threonine-liver-supply-rescue Restoring supply in one organ changed a whole-body nutritional signal. Engineering threonine biosynthetic capacity selectively in hepatocytes reversed the systemic response to dietary threonine restriction. Model: Engineered mouse hepatocyte threonine synthesis during dietary restriction. Limitations: This experimentally installed pathway is not a normal mammalian threonine-synthesis route. Evidence access: Primary abstract Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

    Evidence, AI assistance and curation standards