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Cited by 252Adipokines, Inflammation, and Metabolic DiseasesLiver Disease Diagnosis and TreatmentLiver physiology and pathology

Hepatokines and metabolism: Deciphering communication from the liver

Open access
Jensen-Cody, Sharon O., Potthoff, Matthew J.·2021·Molecular Metabolism
DOI 10.1016/j.molmet.2020.101138PMC PMC7788242
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Abstract

BACKGROUND: The liver is a key regulator of systemic energy homeostasis and can sense and respond to nutrient excess and deficiency through crosstalk with multiple tissues. Regulation of systemic energy homeostasis by the liver is mediated in part through regulation of glucose and lipid metabolism. Dysregulation of either process may result in metabolic dysfunction and contribute to the development of insulin resistance or fatty liver disease. SCOPE OF REVIEW: The liver has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors that can signal to and communicate with distant tissues. Dysregulation of liver-centered inter-organ pathways may contribute to improper regulation of energy homeostasis and ultimately metabolic dysfunction. Deciphering the mechanisms that regulate hepatokine expression and communication with distant tissues is essential for understanding inter-organ communication and for the development of therapeutic strategies to treat metabolic dysfunction. MAJOR CONCLUSIONS: In this review, we discuss liver-centric regulation of energy homeostasis through hepatokine secretion. We highlight key hepatokines and their roles in metabolic control, examine the molecular mechanisms of each hepatokine, and discuss their potential as therapeutic targets for metabolic disease. We also discuss important areas of future studies that may contribute to understanding hepatokine signaling under healthy and pathophysiological conditions.

AI snapshot

Written from the paper’s full text.

TL;DR

This review describes the liver as an endocrine organ that secretes hepatokines to regulate systemic energy, glucose, and lipid homeostasis. It summarizes key hepatokines, their target tissues and metabolic roles, and discusses their therapeutic potential and unresolved questions in metabolic disease.

Key findings

  • The review classifies hepatokines by metabolic impact: beneficial hepatokines include activin-E, ANGPTL4, ANGPTL6, FGF21, GDF15, IGF-1, LCN13, SMOC1, and TSK; detrimental hepatokines include ANGPTL3, ANGPTL8, fetuin-A, hepassocin, LECT-2, and selenoprotein-P.
  • Table 1 reports human serum concentration changes in insulin resistance: increased for activin-E, ANGPTL3, ANGPTL6, fetuin-A, FGF21, follistatin, GDF15, hepassocin, LECT2, selenoprotein-P, and Tsukushi; decreased for IGF1, LCN13, and SMOC1; debated for ANGPTL4 and ANGPTL8.
  • Several mechanisms are highlighted, including FGF21 signaling through FGFR1c/β-klotho, GDF15 signaling through GFRAL/RET, and ANGPTL3/ANGPTL8 complex inhibition of lipoprotein lipase.
  • The review notes that elevated levels of some hepatokines in obesity and diabetes may reflect endocrine resistance, similar to insulin or leptin resistance, and that hepatokines are promising but incompletely validated therapeutic targets.

Methods

  • Narrative review; no primary experiments, systematic search strategy, or meta-analysis are described.
  • The paper synthesizes published rodent and human literature, including genetic, pharmacological, and clinical trial findings, and presents a summary table of hepatokines with target organs, metabolic roles, and human serum concentration changes in insulin resistance.
  • Main analysis is qualitative: mechanisms, target tissues, physiological contexts, and therapeutic implications are discussed for each selected hepatokine.

Limitations

  • Stated: the review is “not meant to be an exhaustive list”; future studies are needed to determine how hepatokines integrate with other organokines, how preclinical evidence translates to humans, how hepatokines contribute to disease progression, and how each hepatokine is regulated and acts under healthy and pathophysiological conditions.
  • Stated/evident: conflicting findings exist for some hepatokines, such as debated circulating ANGPTL4 and ANGPTL8 levels in metabolic disease and non-reproduced TSK knockout results in a subsequent study.
  • Evident: as a narrative review, it lacks systematic search, quantitative synthesis, and primary data to establish causality or effect sizes.

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

Integrity signals

Registry

Crossref · 10.1016/j.molmet.2020.101138

Cites

276 of 276 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 225 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Pharmacological administration of FGF21 increases energy expenditure in mice.

    “Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [131] Coskun, 2008, Fibroblast growth factor 21 corrects obesity in mice, Endocrinology source

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    • cites [132] Xu, 2009, Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models--association with liver and adipose tissue effects, American Journal of Physiology. Endocrinology and Metabolism source

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    • cites [133] Xu, 2009, Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice, Diabetes source

      Not checked in the free run.

  • Premisecitation

    Pharmacological administration of FGF21 decreases sugar and alcohol intake in mice.

    “Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [137] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metabolism source

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    • cites [138] Talukdar, 2016, FGF21 regulates sweet and alcohol preference, Cell Metabolism source

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    • cites [139] Tanaka, 2013, Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake, American Journal of Clinical Nutrition source

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  • Premisecitation

    The liver has more recently been identified to contribute to the endocrine control of metabolism by producing liver-derived factors or hepatokines.

    “While adipose tissues and pancreas are well known for their endocrine function, the liver has more recently been identified to contribute to the endocrine control of metabolism by producing liver-derived factors or hepatokines [[7], [8], [9], [10], [11], [12], [13]].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7], [8], [9], [10], [11], [12], [13]

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  • Premisecitation

    FGF21 signals to a receptor complex comprised of FGFR1c and KLB.

    “FGF21 signals to a receptor complex comprised of FGF receptor 1c (FGFR1c) and its co-receptor β-klotho (KLB) [[143], [144], [145], [146]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [143] Kurosu, 2007, Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21, Journal of Biological Chemistry source

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    • cites [144] Suzuki, 2008, betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c, Molecular Endocrinology source

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    • cites [145] Adams, 2012, The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue, Mol Metab source

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  • Premisecitation

    Pharmacological administration of FGF21 decreases plasma glucose and lipid levels in mice.

    “Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [131] Coskun, 2008, Fibroblast growth factor 21 corrects obesity in mice, Endocrinology source

      Not checked in the free run.

    • cites [132] Xu, 2009, Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models--association with liver and adipose tissue effects, American Journal of Physiology. Endocrinology and Metabolism source

      Not checked in the free run.

    • cites [133] Xu, 2009, Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice, Diabetes source

      Not checked in the free run.

  • May combine two claims. 78
  • Classified as probably not a substantial claim. 33

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    Premisenone given

    The liver can sense and respond to nutrient overabundance and deficit by secreting hepatokines, which signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system.

    “The liver can sense and respond to nutrient overabundance and deficit by secreting hepatokines, which signal energy status and help regulate nutrient availability to multiple peripheral tissues and the central nervous system (CNS).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In response to fasting, the liver increases hepatic glucose production via glycogenolysis and gluconeogenesis to supply glucose as a fuel source for non-hepatic tissues including the brain and skeletal muscle.

    “In response to fasting, however, the liver increases hepatic glucose production via glycogenolysis and gluconeogenesis to supply glucose as a fuel source for non-hepatic tissues including the brain and skeletal muscle [15,16].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Roden, 2003, Hepatic glucose metabolism in humans—its role in health and disease, Best Practice & Research Clinical Endocrinology & Metabolism source

      Not checked in the free run.

    • cites [16] Leone, 1999, A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders, Proceedings of the National Academy of Sciences of the U S A source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NAFLD is the most common chronic liver disease worldwide and a risk factor for type 2 diabetes, obesity, and cardiovascular disease.

    “NAFLD is the most common chronic liver disease worldwide and a risk factor for type 2 diabetes, obesity, and cardiovascular disease (CVD) [8,12,22].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Iroz, 2015, Hepatokines: unlocking the multi-organ network in metabolic diseases, Diabetologia source

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    • cites [12] Stefan, 2013, The role of hepatokines in metabolism, Nature Reviews Endocrinology source

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    • cites [22] Morrison, 2019, Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: a meta-analysis with bias analysis, Liver International source

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    Premisecitation

    ANGPTL3 is exclusively expressed and secreted by the liver and is an important regulator of plasma triglyceride levels due to its inhibition of LPL in oxidative tissues.

    “ANGPTL3 is exclusively expressed and secreted by the liver and has emerged as an important regulator of plasma triglyceride levels due to its inhibition of LPL in oxidative tissues [34] (Figure 3).”
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    • cites [34] Conklin, 1999, Identification of a mammalian angiopoietin-related protein expressed specifically in liver, Genomics source

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    Premisecitation

    Activin-E expression increases during fasting and is markedly suppressed by loss of the insulin receptor in the liver.

    “Activin-E expression increases during fasting and is markedly suppressed by loss of the insulin receptor in the liver [10], suggesting dynamic regulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Smati, 2020, Regulation of hepatokine gene expression in response to fasting and feeding: influence of PPAR-alpha and insulin-dependent signalling in hepatocytes, Diabetes & Metabolism source

      Not checked in the free run.

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    Premisecitation

    Circulating levels of activin-E are elevated in high-fat diet-fed mice and are thought to contribute to resistance to body weight gain.

    “Furthermore, circulating levels of activin-E are elevated in high-fat diet-fed mice and are thought to contribute to resistance to body weight gain [28,30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Chabicovsky, 2003, Overexpression of activin beta(C) or activin beta(E) in the mouse liver inhibits regenerative deoxyribonucleic acid synthesis of hepatic cells, Endocrinology source

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    • cites [30] Hashimoto, 2018, Activin E controls energy homeostasis in both Brown and white adipose tissues as a hepatokine, Cell Reports source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Insulin resistance occurs when insulin is unable to properly stimulate glucose uptake into metabolic tissues, suppress hepatic glucose production, and/or reduce adipose tissue lipolysis.

    “Insulin resistance occurs when insulin is unable to properly (1) stimulate glucose uptake into metabolic tissues (skeletal muscle and adipose tissues), (2) suppress hepatic glucose production, and/or (3) reduce adipose tissue lipolysis [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Hotamisligil, 2006, Inflammation and metabolic disorders, Nature source

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    Premisenone given

    Dysregulation of liver-centered inter-organ pathways may contribute to improper regulation of energy homeostasis and ultimately metabolic dysfunction.

    “Dysregulation of liver-centered inter-organ pathways may contribute to improper regulation of energy homeostasis and ultimately metabolic dysfunction.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    During hepatic insulin resistance, excess storage of ectopic fat in the liver can contribute to the development of non-alcoholic fatty liver disease (NAFLD).

    “During hepatic insulin resistance, excess storage of ectopic fat in the liver can contribute to the development of non-alcoholic fatty liver disease (NAFLD) [[17], [18], [19], [20]].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17], [18], [19], [20]

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    Premisenone given

    The liver regulates systemic glucose homeostasis through hepatic glucose production and glycogen storage.

    “The liver regulates systemic glucose homeostasis through hepatic glucose production and glycogen storage.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The liver has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors that can signal to and communicate with distant tissues.

    “The liver has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors that can signal to and communicate with distant tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FGF21 is an endocrine hormone produced and secreted predominantly by the liver, unlike traditional FGFs.

    “FGF21, unlike traditional FGFs, is an endocrine hormone produced and secreted predominantly by the liver [129,130].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [129] Nishimura, 2000, Identification of a novel FGF, FGF-21, preferentially expressed in the liver, Biochimica et Biophysica Acta source

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    • cites [130] Fon Tacer, 2010, Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse, Molecular Endocrinology source

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    Premisecitation

    FST acts as a multi-faceted hepatokine involved in reproduction, muscle growth, cancer development, and metabolism.

    “FST acts as a multi-faceted hepatokine that is involved in reproduction [181], muscle growth [182], cancer development [183], and metabolism [184].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [181] de Kretser, 2002, Inhibins, activins and follistatin in reproduction, Human Reproduction Update source

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    • cites [182] Rodino-Klapac, 2009, Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease, Muscle & Nerve source

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    • cites [183] Shi, 2016, Clinical and therapeutic implications of follistatin in solid tumours, CANCER GENOMICS and PROTEOMICS source

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    Premisecitation

    Most FST effects on reproductive health and cancer development are related to interactions with activins and follicle-stimulating hormone, while effects on muscle growth result from interactions with myostatin.

    “Most of FST's effects on reproductive health and cancer development are related to its interactions with activins and follicle-stimulating hormone, while its effects on muscle growth result from interactions with myostatin [186].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Brown, 2011, Follistatin and follistatin like-3 differentially regulate adiposity and glucose homeostasis, Obesity source

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    Premisecitation

    Under fasted conditions, FGF21 increases hepatic gluconeogenesis, β-oxidation, and ketogenesis in mice.

    “Under fasted conditions, FGF21 increases hepatic gluconeogenesis, β-oxidation, and ketogenesis in mice [142,154].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [142] Hotta, 2009, Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver, Endocrinology source

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    • cites [154] Potthoff, 2009, FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response, Proceedings of the National Academy of Sciences of the U S A source

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    Premisecitation

    FGF21 signaling to the VMH is required for its effects on lowering carbohydrate intake but not non-nutritive sweet-taste preference or body weight.

    “FGF21 signaling to the ventromedial hypothalamus (VMH) is required for its effects on lowering carbohydrate intake but not non-nutritive sweet-taste preference or body weight.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Jensen-Cody, 2020, FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake, Cell Metabolism source

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  • May combine two claims.

    Premisenone given

    FGF21 expression is regulated by nutrient signals and functions to regulate nutrient homeostasis.

    “FGF21 expression is regulated by nutrient signals and subsequently functions to regulate nutrient homeostasis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Administration of FGF21 analogs to obese and type 2 diabetic subjects improves dyslipidemia, decreases body weight, and improves fasting insulin levels.

    “Administration of FGF21 analogs to obese and type 2 diabetic subjects improves dyslipidemia, decreases body weight, improves fasting insulin levels, and was recently thoroughly reviewed [136] (Figure 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Gaich, 2013, The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes, Cell Metabolism source

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    Premisecitation

    The increase in FGF21 in response to low protein results in increased energy expenditure and lower body weight gain.

    “This robust increase in FGF21 results in increased energy expenditure and lower body weight gain [155,156,160,163] (Figure 2)”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [155] Laeger, 2014, FGF21 is an endocrine signal of protein restriction, Journal of Clinical Investigation source

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    • cites [156] Maida, 2016, A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution, Journal of Clinical Investigation source

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    • cites [160] Pérez-Martí, 2017, A low-protein diet induces body weight loss and browning of subcutaneous white adipose tissue through enhanced expression of hepatic fibroblast growth factor 21 (FGF21), Molecular Nutrition & Food Research source

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    • cites [163] Flippo, 2020, FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution, Scientific Reports source

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  • May combine two claims.

    Premisecitation

    FGF21 signals the CNS to increase energy expenditure and decrease body weight.

    “while it signals the CNS to increase energy expenditure and decrease body weight [169,171,172] (Figure 2).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [169] BonDurant, 2017, FGF21 regulates metabolism through adipose-dependent and -independent mechanisms, Cell Metabolism source

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    • cites [171] Ameka, 2019, Liver derived FGF21 maintains core body temperature during acute cold exposure, Scientific Reports source

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    • cites [172] Owen, 2014, FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss, Cell Metabolism source

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    Premisecitation

    In humans, circulating FGF21 levels increase with obesity, type 2 diabetes, and NAFLD.

    “In humans, circulating FGF21 levels also increase with obesity [[174], [175], [176]], type 2 diabetes [[176], [177], [178]], and NAFLD [179,180]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [174] Zhang, 2008, Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans, Diabetes source

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    • cites [175] Berti, 2015, Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes, Mol Metab source

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    • cites [176] Mraz, 2009, Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity, Clinical Endocrinology source

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    Premisecitation

    FGF21 is classically recognized as a fasting hormone regulated by PPARα.

    “Classically recognized as a fasting hormone regulated by the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) [150,151]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Badman, 2007, Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states, Cell Metabolism source

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    • cites [151] Inagaki, 2007, Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21, Cell Metabolism source

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  • May combine two claims.

    Premisecitation

    FST acts as an inhibitor of TGF-β superfamily members including myostatin and activins, and can promote skeletal muscle growth.

    “FST acts as an inhibitor of members of the TGF-β superfamily, including myostatin and activins [185,186], and can function as a promoter of skeletal muscle growth [187].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [185] Sidis, 2006, Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins, Endocrinology source

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    • cites [186] Brown, 2011, Follistatin and follistatin like-3 differentially regulate adiposity and glucose homeostasis, Obesity source

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    • cites [187] Lee, 2010, Regulation of muscle mass by follistatin and activins, Molecular Endocrinology source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FST is secreted by a broad range of cell types, and plasma levels are thought to result from paracrine/autocrine signaling spillover.

    “FST is secreted by a broad range of cell types, and plasma levels are thought to result from paracrine/autocrine signaling spillover [188].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Hansen, 2016, Circulating follistatin in relation to energy metabolism, Molecular and Cellular Endocrinology source

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    Premisecitation

    Administration of hGDF15 to GFRAL-deficient mice has no effect on body weight, energy expenditure, serum leptin and insulin levels, and food intake compared to wild-type mice given hGDF15.

    “Administration of hGDF15 to GFRAL-deficient mice had no effect on body weight, energy expenditure, serum leptin and insulin levels, and food intake compared to wild-type mice given hGDF15 [213].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [213] Yang, 2017, GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand, Natura Med source

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  • May combine two claims.

    Premisecitation

    Patients with type 2 diabetes have slightly elevated levels of circulating FST and plasma levels associated with glycemic parameters.

    “Patients with type 2 diabetes have slightly elevated levels of circulating FST and plasma levels associated with glycemic parameters in these patients [188,191,192] (Table 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [188] Hansen, 2016, Circulating follistatin in relation to energy metabolism, Molecular and Cellular Endocrinology source

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    • cites [191] Hansen, 2013, Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low-grade inflammation, Diabetes Metab Res Rev source

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    • cites [192] Hansen, 2016, Exercise-induced secretion of FGF21 and follistatin are blocked by pancreatic clamp and impaired in type 2 diabetes, Journal of Clinical Endocrinology & Metabolism source

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    Premisecitation

    Hepassocin has mitogenic activity on hepatocytes, serving as a regulator of hepatic growth and proliferation.

    “Hepassocin has mitogenic activity on hepatocytes, serving as a regulator of hepatic growth and proliferation [218].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Gao, 2014, Hepassocin activates the EGFR/ERK cascade and induces proliferation of L02 cells through the Src-dependent pathway, Cellular Signalling source

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    Premisecitation

    FST increases phosphorylation of MAPK/ERK1/2 proteins in WAT and increases expression of Myf5 protein in BAT, which increases UCP1 expression in both tissues.

    “FST functions to increase the phosphorylation of MAPK/ERK1/2 proteins in WAT and increase the expression of Myf5 protein in BAT, which increases UCP1 expression in both tissues [198].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] Singh, 2017, Follistatin targets distinct pathways to promote Brown adipocyte characteristics in Brown and white adipose tissues, Endocrinology source

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    Premisecitation

    GDF15 binds with high affinity to GFRAL and its co-receptor RET, inducing phosphorylation of RET and downstream signaling through AKT, ERK1/2, and PLCγ pathways.

    “GDF15 binds with high affinity to GFRAL and its co-receptor RET, which induces phosphorylation of RET, leading to downstream signaling through the AKT, ERK1/2, and phospholipase C (PLCγ) pathways [201,213,215].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source

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    • cites [213] Yang, 2017, GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand, Natura Med source

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    • cites [215] Hsu, 2017, Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15, Nature source

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    Interpretationreasoning

    The discrepancy in GDF15 food intake effects may be due to differences in mode and duration of elevated GDF15 levels.

    “This discrepancy may have been due to differences in the mode and duration of elevated GDF15 levels.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Plasma levels of hepassocin are associated with fasted plasma glucose, HOMA-IR, and prediabetes and increase in patients with type 2 diabetes.

    “Plasma levels of hepassocin are associated with fasted plasma glucose, HOMA-IR, and prediabetes and increase in patients with type 2 diabetes (Table 1) [217,220].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [217] Wu, 2016, A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes, Diabetologia source

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    • cites [220] Huang, 2020, Discovery of a role of the novel hepatokine, hepassocin, in obesity, BioFactors source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FST is present in three main isoforms, FST288, FST303, and FST315, with FST315 being the predominant isoform in circulation.

    “FST is present in three main isoforms, FST288, FST303, and FST315, with FST315 being the predominant isoform found in the circulation [185,194,195].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [185] Sidis, 2006, Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins, Endocrinology source

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    • cites [194] Shimasaki, 1988, Primary structure of the human follistatin precursor and its genomic organization, Proceedings of the National Academy of Sciences of the U S A source

      Not checked in the free run.

    • cites [195] Schneyer, 2004, Differential distribution of follistatin isoforms: application of a new FS315-specific immunoassay, Journal of Clinical Endocrinology & Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expression of human GDF15 improves glucose tolerance and insulin sensitivity, lowers body weight and leptin levels, and increases oxidative metabolism and energy expenditure in mice.

    “The expression of human GDF15 (hGDF15) improved glucose tolerance and insulin sensitivity, lowered body weight and leptin levels, and increased oxidative metabolism and energy expenditure in mice [207,208] (Figure 2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [207] Baek, 2006, Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia, Gastroenterology source

      Not checked in the free run.

    • cites [208] Chrysovergis, 2014, NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism, International Journal of Obesity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepassocin is secreted predominantly from the liver, but is also expressed in adipose tissue where it is suggested to regulate lipid metabolism.

    “Hepassocin is secreted predominantly from the liver, but is also expressed in adipose tissue where it is suggested to regulate lipid metabolism [219].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Demchev, 2013, Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GFRAL is exclusively expressed in the human brainstem and is responsible for the metabolic effects of GDF15 on regulating appetite.

    “GFRAL is exclusively expressed in the human brainstem and is responsible for the metabolic effects of GDF15 on regulating appetite [201,215].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source

      Not checked in the free run.

    • cites [215] Hsu, 2017, Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of GDF15 to wild-type mice produced responses similar to transgenic mice, but these mice exhibited consistent reduction in food intake.

    “Conversely, administration of GDF15 to wild-type mice produced responses similar to those in transgenic mice; however, these mice exhibited consistent reduction in food intake [201,213].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source

      Not checked in the free run.

    • cites [213] Yang, 2017, GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand, Natura Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GDF15 induces anorexia through nausea and emesis in mice and musk shrews, respectively.

    “A recent study found that GDF15 induced anorexia through nausea and emesis in mice and musk shrews, respectively [216].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] Borner, 2020, GDF15 induces anorexia through nausea and emesis, Cell Metabolism source

      Not checked in the free run.

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

    Premisecitation

    GDF15 is associated with numerous biological processes and diseases including cancer, cardiovascular disease, and obesity.

    “Growth differentiation factor 15 (GDF15), also called macrophage inhibitory cytokine-1, is associated with numerous biological processes and diseases including cancer, cardiovascular disease, and obesity [[199], [200], [201], [202]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [199] Bauskin, 2006, Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer, Cancer Research source

      Not checked in the free run.

    • cites [200] Breit, 2011, The TGF-β superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism, Growth Factors source

      Not checked in the free run.

    • cites [201] Mullican, 2018, Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond, Trends in Endocrinology and Metabolism source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    GDF15 belongs to the TGF-β superfamily and is upregulated by inflammatory or stress-related proteins including IL-1β, IL-2, and TNF alpha.

    “GDF15 belongs to the TGF-β superfamily and is upregulated by several inflammatory or stress-related proteins, including interleukin (IL)-1β, IL-2, and tumor necrosis factor (TNF) alpha.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Physiological levels of circulating GDF15 are low in healthy humans but increase in disease states and during pregnancy.

    “Physiological levels of circulating GDF15 are low in healthy humans but increase in disease states and during pregnancy [203] (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Li, 2000, Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression, Journal of Biological Chemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two studies found GDF15 transgenic mice were protected against obesity and had increased insulin sensitivity and energy expenditure without changes in food consumption compared to control mice.

    “Two studies found that GDF15 transgenic mice were protected against obesity and had increased insulin sensitivity and energy expenditure without any changes in food consumption compared to control mice [207,208].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [207] Baek, 2006, Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia, Gastroenterology source

      Not checked in the free run.

    • cites [208] Chrysovergis, 2014, NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism, International Journal of Obesity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GDF15 is not highly expressed in the human liver under basal conditions, but is highly expressed in the liver, adipose, and intestine in mice.

    “While GDF15 is not highly expressed in the human liver under basal conditions, it is highly expressed in the liver, adipose, and intestine in mice [[204], [205], [206]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [204] Hsiao, 2000, Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury, Molecular and Cellular Biology source

      Not checked in the free run.

    • cites [205] Baek, 2019, Growth differentiation factor 15 (GDF15): a survival protein with therapeutic potential in metabolic diseases, Pharmacology & Therapeutics source

      Not checked in the free run.

    • cites [206] Lockhart, 2020, GDF15: a hormone conveying somatic distress to the brain, Endocrine Reviews source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of FST in mice results in insulin resistance in WAT, increased hepatic glucose production, and impaired whole-body glucose tolerance.

    “Overexpression of FST in mice resulted in insulin resistance in WAT, increased hepatic glucose production, and impaired whole-body glucose tolerance, consistent with higher expression in patients with type 2 diabetes [77,196].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] Gonzalez-Gil, 2020, The role of exercise in the interplay between myokines, hepatokines, osteokines, adipokines, and modulation of inflammation for energy substrate redistribution and fat mass loss: a review, Nutrients source

      Not checked in the free run.

    • cites [196] Tao, 2018, Inactivating hepatic follistatin alleviates hyperglycemia, Natura Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LECT2-deficient mice exhibit increased glucose tolerance and insulin sensitivity.

    “LECT2-deficient mice exhibited increased glucose tolerance and insulin sensitivity [239].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

      Not checked in the free run.

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

    Premisecitation

    IGF2 functions predominantly in early embryogenesis.

    “While IGF2 functions predominantly in early embryogenesis [226]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [226] Baker, 1993, Role of insulin-like growth factors in embryonic and postnatal growth, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LCN13 is secreted from multiple tissues including the liver to regulate glucose homeostasis and improve insulin sensitivity.

    “LCN13 in particular is secreted from multiple tissues including the liver to regulate glucose homeostasis and improve insulin sensitivity [254].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [254] Zhou, 2013, Lipocalin 13 regulation of glucose and lipid metabolism in obesity, Vitamins & Hormones source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of recombinant hepassocin or hepatic overexpression of hepassocin in mice induces insulin resistance in liver and skeletal muscle, while loss of hepassocin improves high-fat diet-induced insulin resistance in wild-type and ob/ob mice.

    “Administration of recombinant hepassocin or hepatic overexpression of hepassocin in mice induces insulin resistance in the liver and skeletal muscle, while loss of hepassocin improves high-fat diet-induced insulin resistance in wild-type and ob/ob mice [217] (Figure 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [217] Wu, 2016, A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Decreased expression of LECT2 is observed during tissue inflammation, fibrosis, or pathology, suggesting LECT2 functions positively under normal conditions.

    “Decreased expression of LECT2 is observed during tissue inflammation, fibrosis, or pathology, suggesting that LECT2 functions positively under normal conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LECT2-deficient mice exhibit increased insulin-stimulated AKT phosphorylation in skeletal muscle but not liver or adipose tissue, suggesting loss of LECT2 selectively improves insulin sensitivity in skeletal muscle.

    “These mice also exhibited increased insulin-stimulated AKT phosphorylation in skeletal muscle but not in the liver or adipose tissue, suggesting that loss of LECT2 selectively improves insulin sensitivity in skeletal muscle [239].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice fed high-fat diets or exercised have increased or decreased serum and hepatic levels of LECT2, respectively.

    “For example, mice that were fed high-fat diets or exercised had increased or decreased serum and hepatic levels of LECT2, respectively [239].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

      Not checked in the free run.

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

    Premisecitation

    LCN proteins are secreted proteins that bind small hydrophobic ligands through their conical β barrels.

    “Lipocalin (LCN) proteins are secreted proteins that bind small hydrophobic ligands through their conical β barrels [252,253].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [252] Grzyb, 2006, Lipocalins - a family portrait, Journal of Plant Physiology source

      Not checked in the free run.

    • cites [253] Flower, 1996, The lipocalin protein family: structure and function, Biochemical Journal source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IGFs are structurally and functionally related to insulin and play an important role in enhancing insulin sensitivity.

    “Insulin-like growth factors (IGFs) are structurally and functionally related to insulin and play an important role in enhancing insulin sensitivity [222].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [222] Moses, 1996, Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes, Diabetes source

      Not checked in the free run.

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

    Premisecitation

    IGF1 is secreted into the circulation by the liver in response to growth hormone stimulation.

    “IGF1 is secreted into the circulation by the liver in response to growth hormone stimulation [227].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [227] Van Wyk, 1999, Insulin-like growth factors and skeletal growth: possibilities for therapeutic interventions, Journal of Clinical Endocrinology & Metabolism source

      Not checked in the free run.

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

    Premisecitation

    IGFs are regulated by a family of IGF-binding proteins that can bind IGFs with equal or greater affinity than IGF1R.

    “IGFs are regulated by a family of IGF-binding proteins (IGFBP) that can bind IGFs with equal or greater affinity than IGF1R [224,225].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [224] Rajkumar, 1996, Impaired glucose homeostasis in insulin-like growth factor binding protein-1 transgenic mice, Journal of Clinical Investigation source

      Not checked in the free run.

    • cites [225] Jones, 1995, Insulin-like growth factors and their binding proteins: biological actions∗, Endocrine Reviews

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low plasma levels of IGF1 predict development of type 2 diabetes and correlate with insulin resistance and increased risk of metabolic syndrome and cardiovascular disease.

    “There is evidence that low plasma levels of IGF1 predict the development of type 2 diabetes and correlate with insulin resistance and increased risk of metabolic syndrome and cardiovascular disease [[231], [232], [233]] (Table 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [231] Sandhu, 2002, Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study, The Lancet source

      Not checked in the free run.

    • cites [232] Succurro, 2009, Low plasma insulin-like growth factor-1 levels are associated with reduced insulin sensitivity and increased insulin secretion in nondiabetic subjects, Nutrition, Metabolism, and Cardiovascular Diseases source

      Not checked in the free run.

    • cites [233] Juul, 2002, Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LECT2 functions in liver regeneration, immune modulation, bone growth, neural development, glucose metabolism, metabolic syndrome, and cancer.

    “LECT2 functions in liver regeneration, immune modulation, bone growth, neural development, glucose metabolism, metabolic syndrome, and cancer [[241], [242], [243], [244], [245], [246]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [241] Segawa, 2001, Possible changes in expression of chemotaxin LECT2 mRNA in mouse liver after concanavalin A-induced hepatic injury, Biological and Pharmaceutical Bulletin source

      Not checked in the free run.

    • cites [242] Yamagoe, 1996, Purification and primary amino acid sequence of a novel neutrophil chemotactic factor LECT2, Immunology Letters source

      Not checked in the free run.

    • cites [243] Ovejero, 2004, Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of beta-catenin in the liver, Hepatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of IGF1 in humans results in decreased blood glucose levels and improved insulin sensitivity in those with and without type 2 diabetes.

    “Administration of IGF1 in humans results in decreased blood glucose levels and improved insulin sensitivity in those with and without type 2 diabetes [[234], [235], [236]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [234] Laron, 1995, Carbohydrate metabolism in primary growth hormone resistance (Laron syndrome) before and during insulin-like growth factor-I treatment, Metabolism source

      Not checked in the free run.

    • cites [235] Laron, 1999, The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome, Journal of Clinical Endocrinology & Metabolism source

      Not checked in the free run.

    • cites [236] Hong, 2017, Central IGF1 improves glucose tolerance and insulin sensitivity in mice, Nutrition & Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IGFBP1 is elevated in patients with type 2 diabetes and counteracts the hypoglycemic effect of insulin through inhibition of IGF1.

    “IGFBP1 is elevated in patients with type 2 diabetes and has been shown to counteract the hypoglycemic effect of insulin through inhibition of IGF1 [224].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] Rajkumar, 1996, Impaired glucose homeostasis in insulin-like growth factor binding protein-1 transgenic mice, Journal of Clinical Investigation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LECT2-deficient mice show improved insulin sensitivity in skeletal muscle, while administration of recombinant LECT2 in mice leads to impaired insulin signaling and induced insulin resistance in skeletal muscle.

    “LECT2-deficient mice showed improved insulin sensitivity in skeletal muscle, while administration of recombinant LECT2 in mice led to impaired insulin signaling and induced insulin resistance in skeletal muscle [239] (Figure 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LECT2 alters insulin signaling through the JNK pathway in myocytes, and expression of LECT2 in liver is negatively regulated by AMPK.

    “LECT2 alters insulin signaling through the JNK pathway in myocytes, and the expression of LECT2 in the liver is negatively regulated by the energy-depletion sensor AMPK [239,248,249].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

      Not checked in the free run.

    • cites [248] Hwang, 2015, LECT2 induces atherosclerotic inflammatory reaction via CD209 receptor-mediated JNK phosphorylation in human endothelial cells, Metabolism source

      Not checked in the free run.

    • cites [249] Hwang, 2015, A dipeptidyl peptidase-IV inhibitor improves hepatic steatosis and insulin resistance by AMPK-dependent and JNK-dependent inhibition of LECT2 expression, Biochemical Pharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LCN13 regulates glucose metabolism in adipocytes and hepatocytes by enhancing insulin signaling, insulin-stimulated glucose uptake, and insulin suppression of glucose production.

    “it is well established that LCN13 regulates glucose metabolism in adipocytes and hepatocytes by enhancing insulin signaling, insulin-stimulated glucose uptake, and insulin suppression of glucose production [254,258].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [254] Zhou, 2013, Lipocalin 13 regulation of glucose and lipid metabolism in obesity, Vitamins & Hormones source

      Not checked in the free run.

    • cites [258] Cho, 2011, Lipocalin-13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms, Molecular and Cellular Biology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liver injury in mice enhances expression of hepassocin in adipose tissues, suggesting crosstalk between liver and adipose tissue.

    “Liver injury in mice enhances the expression of hepassocin in adipose tissues, suggesting crosstalk between the liver and adipose tissue, although its role in obesity remains obscure [219].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Demchev, 2013, Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    IGF1 plays an important role in maintaining insulin sensitivity, but the full mechanism is not completely resolved.

    “Altogether, it is clear that IGF1 plays an important role in maintaining insulin sensitivity; however, the full mechanism by which it does so has not been completely resolved.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IGF1 and IGF2 bind IGF1R, which elicits phosphorylation of intracellular adaptor proteins and activation of MAPK and PI3K/AKT signaling pathways.

    “The two main IGFs, IGF1 and IGF2, bind the IGF1 receptor (IGF1R), which elicits phosphorylation of intracellular adaptor proteins and activation of MAPK and PI3K/AKT signaling pathways [223].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] Menu, 2004, Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model, British Journal of Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tissues normally lacking LECT2 exhibit increased expression of LECT2 in disease settings, indicating improper upregulation of LECT2 may contribute to pathological conditions.

    “Interestingly, tissues normally lacking LECT2 exhibit increased expression of LECT2 in disease settings, indicating that improper upregulation of LECT2 may contribute to pathological conditions [246,247].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [246] Slowik, 2017, Leukocyte cell-derived chemotaxin-2: it's role in pathophysiology and future in clinical medicine, Clin Transl Sci source

      Not checked in the free run.

    • cites [247] Nagai, 1998, Systemic expression of a newly recognized protein, LECT2, in the human body, Pathology International source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    LECT2 is expressed in liver, adipose tissue, neurons, and white blood cells and is often found in circulation.

    “LECT2 is expressed in the liver, adipose tissue, neurons, and white blood cells and is often found in the circulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There is a positive relationship between circulating LECT2 levels, BMI, and insulin resistance in humans.

    “Interestingly, there is a positive relationship between circulating LECT2 levels, BMI, and insulin resistance in humans [239] (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LECT2 is an energy-sensing hepatokine positively associated with hepatic inflammatory signaling, obesity, NAFLD, and insulin resistance.

    “Leukocyte cell-derived chemotaxin 2 (LECT2) is an energy-sensing hepatokine that is positively associated with hepatic inflammatory signaling, obesity, NAFLD, and insulin resistance [239,240].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [239] Lan, 2014, LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance, Diabetes source

      Not checked in the free run.

    • cites [240] Jung, 2016, Implication of hepatokines in metabolic disorders and cardiovascular diseases, BBA Clin source

      Not checked in the free run.

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

    Premisenone given

    IGFs promote cell growth, proliferation, differentiation, and survival in an endocrine, paracrine, and autocrine fashion.

    “IGFs promotes cell growth, proliferation, differentiation, and survival in an endocrine, paracrine, and autocrine fashion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Expression and secretion of LCN13 in mice vary in response to changes in metabolic states, suggesting a role in nutrient sensing and regulation.

    “Expression and secretion of LCN13 in mice vary in response to changes in metabolic states, suggesting a role for this hepatokine in nutrient sensing and regulation [254].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [254] Zhou, 2013, Lipocalin 13 regulation of glucose and lipid metabolism in obesity, Vitamins & Hormones source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of a long-lasting SMOC1-Fc fusion protein improves glycemic control, cholesterol, and NAFLD activity scores in lean and obese mice up to 4 weeks following final administration.

    “Administration of a long-lasting SMOC1-Fc fusion protein improved glycemic control, cholesterol, and NAFLD activity scores in lean and obese mice up to 4 weeks following the final administration of SMOC1-Fc [266].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [266] Montgomery, 2020, SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control, Science Translational Medicine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SeP is a glycoprotein secreted predominantly from the liver and is upregulated by selenium and glucose supplies but downregulated by insulin and adiponectin.

    “Selenoprotein P (SeP) is a glycoprotein that is secreted predominantly from the liver and is upregulated by selenium and glucose supplies but downregulated by insulin and adiponectin [260,261].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [260] Misu, 2010, A liver-derived secretory protein, selenoprotein P, causes insulin resistance, Cell Metabolism source

      Not checked in the free run.

    • cites [261] Misu, 2012, Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice overexpressing LCN13 are resistant to high-fat diet-induced hepatic steatosis and hyperlipidemia.

    “Mice overexpressing LCN13 are resistant to high-fat diet-induced hepatic steatosis and hyperlipidemia [259].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259] Sheng, 2011, Lipocalin 13 protein protects against hepatic steatosis by both inhibiting lipogenesis and stimulating fatty acid β-oxidation, Journal of Biological Chemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The liver responds to energy influx and demand by secreting hepatokines that act on various tissues to facilitate energy utilization or storage.

    “The liver responds to energy influx and demand by secreting hepatokines that act on various tissues to facilitate energy utilization or storage.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Hepatokines can act in isolation or in conjunction with other factors to coordinate systemic metabolic processes.

    “These hepatokines can act in isolation or in conjunction with other factors to coordinate systemic metabolic processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TSK is an inducible hepatokine that regulates energy expenditure and is strongly associated with NAFLD, NASH, and obesity.

    “Tsukushi (TSK) is an inducible hepatokine that regulates energy expenditure and is strongly associated with NAFLD, NASH, and obesity [269,270].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [269] Mouchiroud, 2019, The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis, JCI Insight source

      Not checked in the free run.

    • cites [270] Xiong, 2019, Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi, Mol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    SMOC1 has no effect on food intake, body weight, or energy expenditure.

    “Interestingly, SMOC1 has no effect on food intake, body weight, or energy expenditure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TSK-deficient mice are resistant to diet-induced obesity, insulin resistance, and hepatic steatosis as a result of enhanced sympathetic activation and brown fat thermogenesis.

    “TSK-deficient mice were resistant to diet-induced obesity, insulin resistance, and hepatic steatosis as a result of enhanced sympathetic activation and brown fat thermogenesis [271].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [271] Wang, 2019, The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation, Nat Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    LCN13 likely regulates lipid metabolism by downregulating expression of key liver lipogenic genes including ChREBP and PPARγ and upregulating hepatic expression of CPT1α to decrease lipogenesis and increase fatty acid β-oxidation.

    “LCN13 likely regulates lipid metabolism by downregulating the expression of key liver lipogenic genes including ChREBP and PPARγ and upregulating hepatic expression of carnitine palmitoyltransferase-1α (CPT1α) to decrease lipogenesis and increase fatty acid β-oxidation [259].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Sheng, 2011, Lipocalin 13 protein protects against hepatic steatosis by both inhibiting lipogenesis and stimulating fatty acid β-oxidation, Journal of Biological Chemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    SMOC1 is widely expressed in multiple tissues and generally localized at the basement membrane of cells.

    “SMOC1 is widely expressed in multiple tissues and generally localized at the basement membrane of cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Discrepancies in TSK findings may be due to differences in TSK knockout mouse models and/or variations in diet composition.

    “The discrepancies in findings between groups may have been due to the differences in TSK knockout mouse models that were generated and/or variations in diet composition that were used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Plasma levels of SMOC1 decrease in patients with insulin resistance compared with insulin-sensitive individuals and correlate with hepatic and peripheral insulin sensitivity.

    “Plasma levels of SMOC1 decrease in patients with insulin-resistance compared with insulin-sensitive individuals and correlate with hepatic and peripheral insulin sensitivity (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SMOC1 is a hepatokine recently identified to improve glucose homeostasis in rodents.

    “SPARC-related modular calcium-binding protein-1 (SMOC1) is a hepatokine recently identified to improve glucose homeostasis in rodents [266].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [266] Montgomery, 2020, SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control, Science Translational Medicine source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Beneficial hepatokines that improve metabolic dysfunction include activin-E, ANGPTL4, ANGPTL6, FGF21, GDF15, IGF-1, LCN13, SMOC1, and TSK.

    “Beneficial hepatokines that improve metabolic dysfunction include activin-E, ANGPTL4, ANGPTL6, FGF21, GDF15, IGF-1, LCN13, SMOC1, and TSK.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Hepatokine concentrations and effects are altered in response to metabolic stressors, and dysregulation in their signaling can result in pathologies including obesity, type 2 diabetes, and NAFLD.

    “Their concentrations and effects are altered in response to metabolic stressors, and dysregulation in their signaling can result in pathologies including obesity, type 2 diabetes, and NAFLD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Regulation of whole-body energy homeostasis by the liver is a complex process involving tissue crosstalk through production of hepatokines and changes in hepatic metabolism in response to metabolic cues and substrates.

    “The regulation of whole-body energy homeostasis by the liver is a complex process that involves tissue crosstalk through the production of hepatokines and changes in hepatic metabolism in response to metabolic cues and substrates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SeP knockout mice show improved glucose tolerance and insulin resistance.

    “whereas SeP knockout mice showed improved glucose tolerance and insulin resistance [260].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [260] Misu, 2010, A liver-derived secretory protein, selenoprotein P, causes insulin resistance, Cell Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SeP is associated with insulin resistance and increased serum triglyceride, and patients with NAFLD, obesity, and type 2 diabetes have high circulating levels of SeP.

    “SeP is associated with insulin resistance and increased serum triglyceride, and patients with NAFLD, obesity, and type 2 diabetes have high circulating levels of SeP [260,263,264] (Table 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [260] Misu, 2010, A liver-derived secretory protein, selenoprotein P, causes insulin resistance, Cell Metabolism source

      Not checked in the free run.

    • cites [263] Misu, 2019, Identification of hepatokines involved in pathology of type 2 diabetes and obesity, Endocrine Journal source

      Not checked in the free run.

    • cites [264] Yang, 2011, Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: implications for insulin resistance, inflammation, and atherosclerosis, Journal of Clinical Endocrinology & Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    These beneficial hepatokines improve whole organism energy homeostasis by increasing energy expenditure through brown and beige adipocyte activation, increasing insulin sensitivity, increasing glucose uptake, decreasing plasma triglyceride concentrations and regulating cholesterol homeostasis, decreasing body weight, and lowering food intake.

    “These hepatokines improve whole organism energy homeostasis by accomplishing one or more of the following (1) increasing energy expenditure through brown and beige adipocyte activation, (2) increasing insulin sensitivity, (3) increasing glucose uptake, (4) decreasing plasma triglyceride concentrations and regulating cholesterol homeostasis, (5) decreasing body weight, and (6) lowering food intake.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Chronic decreased levels of detrimental hepatokines including ANGPTL3, ANGPTL8, fetuin-A, hepassocin, LECT-2, and SeP aid in maintaining insulin sensitivity, lipid homeostasis, and healthy body weight by decreasing systemic inflammation and insulin resistance.

    “Chronic decreased levels of detrimental hepatokines, including ANGPTL3, ANGPTL8, fetuin-A, hepassocin, LECT-2, and SeP aid in maintaining insulin sensitivity, lipid homeostasis, and healthy body weight by decreasing systemic inflammation and insulin resistance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mice lacking TSK exhibit elevated core body temperatures and are unable to adequately suppress energy expenditure during starvation, leading to greater body weight loss.

    “Mice lacking TSK exhibit elevated core body temperatures and are unable to adequately suppress energy expenditure during starvation, leading to greater body weight loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Loss of hepatic SMOC1 impairs glycemic control in lean mice, whereas acute SMOC1 administration and chronic hepatic SMOC1 overexpression improves glycemic control in lean and obese mice.

    “Loss of hepatic SMOC1 impairs glycemic control in lean mice, whereas acute SMOC1 administration and chronic hepatic SMOC1 overexpression improves glycemic control in lean and obese mice.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    SMOC1 regulates cell matrix interactions by binding to cell surface receptors, including laminins, C-reactive protein, and tenascin-C.

    “SMOC1 is known to regulate cell matrix interactions by binding to cell surface receptors, including laminins, C-reactive protein, and tenascin-C [266,268].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [266] Montgomery, 2020, SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control, Science Translational Medicine source

      Not checked in the free run.

    • cites [268] Wang, 2018, SMOC1 silencing suppresses the angiotensin II-induced myocardial fibrosis of mouse myocardial fibroblasts via affecting the BMP2/Smad pathway, Oncol Lett

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SMOC1 is highly expressed and secreted by the liver and regulates glucose homeostasis.

    “However, SMOC1 is highly expressed and secreted by the liver and regulates glucose homeostasis [266].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [266] Montgomery, 2020, SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control, Science Translational Medicine source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    SeP expression increases in mice in response to ER stress and JNK activation, while activation of AMPK protects against SeP production.

    “SeP expression increased in mice in response to ER stress and JNK activation, while activation of AMPK protected against SeP production (Figure 3).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    TSK was recently identified as an atypical member of the small leucine-rich proteoglycan family that regulates developmental processes in various organisms.

    “TSK was recently identified as an atypical member of the small leucine-rich proteoglycan family that regulates developmental processes in various organisms [[269], [270], [271]].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [269] Mouchiroud, 2019, The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis, JCI Insight source

      Not checked in the free run.

    • cites [270] Xiong, 2019, Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi, Mol Metab source

      Not checked in the free run.

    • cites [271] Wang, 2019, The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation, Nat Metab source

      Not checked in the free run.

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

    Premisecitation

    SMOC1 belongs to a family of matricellular proteins including SPARC, SMOC2, and testican-1.

    “SMOC1 belongs to a family of matricellular proteins including secreted protein acidic and rich in cysteine (SPARC), SMOC2, and testican-1 [267].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [267] Awwad, 2015, Role of secreted modular calcium-binding protein 1 (SMOC1) in transforming growth factor β signalling and angiogenesis, Cardiovascular Research source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Wild-type mice treated with SeP exhibit whole-body glucose intolerance and insulin resistance.

    “Wild-type mice treated with SeP exhibited whole-body glucose intolerance and insulin resistance [260]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [260] Misu, 2010, A liver-derived secretory protein, selenoprotein P, causes insulin resistance, Cell Metabolism source

      Not checked in the free run.

98 of 98

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?

  • Hepatic and plasma levels of tsukushi are strongly stimulated by stimuli that augment thermogenesis and energy expenditure, including adrenergic agonists and cold exposure.

    “Hepatic and plasma levels of this hepatokine are strongly stimulated by stimuli that augment thermogenesis and energy expenditure (including adrenergic agonists and cold exposure) [78,88,89].”

    From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [88]

  • Angptl8 is a hepatokine related to the reset of diurnal rhythms of the hepatic clock and metabolic genes in mice.

    “Angptl8 is a hepatokine related to the reset of diurnal rhythms of hepatic clock, and metabolic genes in mice [88,90,91].”

    From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [88]

  • The main hepatokines related to insulin resistance, a fundamental factor in the development of DM2 and obesity, are fetuin-A, hepassocin, LECT2, and selenoprotein.

    “The main hepatokines related to insulin resistance, a fundamental factor in the development of DM2 and obesity, are fetuin-A, hepassocin, LECT2, and selenoprotein.”

    From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [88]

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

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

    From Metabolic messengers: FGF21 (2021) · cites this paper as [104]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conclusion calls TSK beneficial despite reported benefits of TSK deficiency

    Major

    The conclusion lists TSK among hepatokines that improve metabolic dysfunction, but the TSK section reports that mice lacking TSK were resistant to obesity, insulin resistance, and hepatic steatosis. The section notes that a later study did not reproduce those results, leaving the claimed beneficial direction unsupported by its own account.

1 of 1

Cites

Flagged first, then by citations

2 of the 278 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Patrick Auberger, 1989, Jean olivier contreres, gilles pages, ginette le cam, bernard rossi, alphonse le cam, vol. 58

Cited by

Sorted by citations

Related

Authors
Jensen-Cody, S. O., & Potthoff, M. J.
Affiliations
University of Iowa (US)
Corresponding author
Potthoff, Matthew J.
ORCID
Potthoff, Matthew J.
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2021-02
Volume
44
Pages
101138
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2020.101138
PMC
PMC7788242
OpenAlex
W3112435365
Cited by
252
References
278
Citations by year
2026: 42 · 2025: 54 · 2024: 58 · 2023: 41 · 2022: 36 · 2021: 21
FWCI
3.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • U.S. Department of Veterans Affairs
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
hepatokines, energy homeostasis, inter-organ communication, glucose metabolism, lipid metabolism, insulin resistance, hepatic steatosis, metabolic dysfunction, therapeutic target
MeSH terms
Nutrients, Animals, Diabetes Mellitus, Type 2, Fatty Liver, Glucose, Homeostasis, Humans, Insulin Resistance, Liver, Metabolic Diseases, Obesity, Cytokines, Lipid Metabolism

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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