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Cited by 99Fibroblast Growth Factor ResearchRegulation of Appetite and ObesityDietary Effects on Health

FGF21 and the physiological regulation of macronutrient preference

Open access
Hill, Cristal M, Qualls-Creekmore, Emily, Berthoud, Hans-Rudolf, Soto, Paul, Yu, Sangho, McDougal, David H, Münzberg, Heike, Morrison, Christopher D·2020·Endocrinology
DOI 10.1210/endocr/bqaa019PMC PMC7053867
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Abstract

The ability to respond to variations in nutritional status depends on regulatory systems that monitor nutrient intake and adaptively alter metabolism and feeding behavior during nutrient restriction. There is ample evidence that the restriction of water, sodium, or energy intake triggers adaptive responses that conserve existing nutrient stores and promote the ingestion of the missing nutrient, and that these homeostatic responses are mediated, at least in part, by nutritionally regulated hormones acting within the brain. This review highlights recent research that suggests that the metabolic hormone fibroblast growth factor 21 (FGF21) acts on the brain to homeostatically alter macronutrient preference. Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein, and exogenous FGF21 treatment reduces the consumption of sweet foods and alcohol while alternatively increasing the consumption of protein. In addition, while control mice adaptively shift macronutrient preference and increase protein intake in response to dietary protein restriction, mice that lack either FGF21 or FGF21 signaling in the brain fail to exhibit this homeostatic response. FGF21 therefore mediates a unique physiological niche, coordinating adaptive shifts in macronutrient preference that serve to maintain protein intake in the face of dietary protein restriction.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that FGF21 is a liver-derived endocrine signal of macronutrient imbalance, increased by high-carbohydrate/alcohol and low-protein intake, that acts in the brain to suppress sweet and alcohol consumption while increasing protein intake. It proposes that FGF21 mediates an adaptive protein appetite during dietary protein restriction.

Key findings

  • FGF21 is nutritionally regulated: high-carbohydrate and low-protein diets increase liver FGF21 mRNA and circulating FGF21, with protein restriction increasing FGF21 in mice, rats, and humans; alcohol also increases FGF21. Solon-Biet et al. found protein intake was the primary driver of circulating FGF21, but maximal FGF21 occurred with diets both low in protein and high in carbohydrate.
  • FGF21 suppresses sweet and alcohol intake: FGF21-deficient mice increased consumption of high-sucrose diet and sucrose, glucose, or fructose solutions; FGF21 overexpression or treatment reduced high-sucrose, sucrose, saccharin, and sucralose intake. The sweet-intake effect was impaired by deleting the FGF21 co-receptor Klb from the hypothalamic paraventricular nucleus (PVN), and FGF21 did not affect nonsweet maltodextrin. Talukdar et al. also showed transgenic FGF21 overexpression reduced sucrose, saccharin, and alcohol intake, with saccharin inhibition reproduced in monkeys treated with an FGF21 analog.
  • FGF21 increases protein intake and is required for adaptive protein preference: systemic FGF21 treatment in a 3-macronutrient choice test significantly increased protein intake and decreased carbohydrate intake without altering fat or total food intake; when fat or carbohydrate was fixed, FGF21 increased consumption of the protein-rich diet, but this effect was lost in mice lacking brain Klb. Central FGF21 administration shifted preference away from low-protein and toward high-protein mixed diets, and protein restriction-induced protein appetite was lost in mice lacking either FGF21 or brain Klb.
  • Human genetic variants in the FGF21 locus have been associated with protein, carbohydrate, and fat intake, and variants in the co-receptor Klb have been associated primarily with alcohol intake.

Methods

  • Narrative review; no new experimental data are reported.
  • Synthesizes human genetic association studies, rodent feeding and macronutrient-preference studies, and mechanistic studies of FGF21/Klb signaling.
  • Main analysis is qualitative synthesis of cited literature, including 3-food choice tests, diet-pair preference tests, nutritional geometry, genetic knockout/overexpression, central FGF21 administration, and brain-specific Klb deletion.

Limitations

  • Stated: the site of FGF21 action in the brain remains uncertain; despite strong Klb expression in the suprachiasmatic nucleus (SCN), no studies directly tested the functional role of FGF21 signaling exclusively in the SCN, and PVN involvement is implicated but not definitive.
  • Stated: mechanisms through which alcohol, carbohydrate, and protein signals interact to regulate FGF21 expression/secretion are unclear; whether overlapping or distinct brain areas mediate alcohol, sweet, and protein preference is unknown; and whether FGF21 effects on macronutrient preference translate to humans remains to be tested.
  • Evident: as a narrative review, it does not use a systematic search or meta-analysis, and its conclusions rely heavily on rodent models and cited studies rather than primary data; the text also notes there are no clear definitions for “normal,” “low,” or “extremely low” dietary protein.

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

Integrity signals

Registry

Crossref · 10.1210/endocr/bqaa019

Cites

193 of 193 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 254 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    FGF21 mediates a unique physiological niche, coordinating adaptive shifts in macronutrient preference that serve to maintain protein intake in the face of dietary protein restriction.

    “FGF21 therefore mediates a unique physiological niche, coordinating adaptive shifts in macronutrient preference that serve to maintain protein intake in the face of dietary protein restriction.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Mice that lack either FGF21 or FGF21 signaling in the brain fail to exhibit the adaptive increase in protein intake in response to dietary protein restriction.

    “mice that lack either FGF21 or FGF21 signaling in the brain fail to exhibit this homeostatic response”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Hill, 2019, FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism, Cell Rep. source

      Not checked in the free run.

  • Premisecitation

    Sodium depletion causes a robust and highly specific motivation to consume sodium, such that salt solutions that are negative/aversive in the replete state become preferred/rewarding in sodium-depleted animals.

    “Sodium depletion causes a robust and highly specific motivation to consume sodium, such that salt solutions that are negative/aversive in the replete state become preferred/rewarding in sodium-depleted animals”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [18] Krause, 2007, Richter and sodium appetite: from adrenalectomy to molecular biology, Appetite. source

      Not checked in the free run.

    • cites [19] Berridge, 1984, Sodium depletion enhances salt palatability in rats, Behav Neurosci. source

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    • cites [20] Robinson, 2013, Instant transformation of learned repulsion into motivational “wanting”, Curr Biol. source

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    • cites [21] Fortin, 2017, Physiological state tunes mesolimbic signaling: lessons from sodium appetite and inspiration from Randall R. Sakai, Physiol Behav. source

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  • Premisecitation

    Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein.

    “Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein”
    • Also stated in: § Nutritional regulation of FGF21: increased by high carbohydrate and low protein · hedged
      “liver FGF21 production seems to be robustly stimulated by an imbalance in macronutrients, particularly settings of high-carbohydrate but low-protein intake”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [137] Iizuka, 2009, Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes, FEBS Lett. source

      Not checked in the free run.

    • cites [138] Dushay, 2015, Fructose ingestion acutely stimulates circulating FGF21 levels in humans, Mol Metab. source

      Not checked in the free run.

    • cites [139] Maekawa, 2017, Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice, J Nutr Biochem. source

      Not checked in the free run.

    • cites [140] Iroz, 2017, A specific ChREBP and PPARα cross-talk is required for the glucose-mediated FGF21 response, Cell Rep. source

      Not checked in the free run.

    • cites [141] Pereira, 2017, A low-protein, high-carbohydrate diet increases browning in perirenal adipose tissue but not in inguinal adipose tissue, Nutrition. source

      Not checked in the free run.

    • cites [142] Fisher, 2017, A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism, Mol Metab. source

      Not checked in the free run.

    • cites [143] Lundsgaard, 2017, Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates, Mol Metab. source

      Not checked in the free run.

    • cites [144] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab. source

      Not checked in the free run.

    • cites [145] Solon-Biet, 2016, Defining the nutritional and metabolic context of FGF21 using the geometric framework, Cell Metab. source

      Not checked in the free run.

    • cites [82] Pezeshki, 2016, Low protein diets produce divergent effects on energy balance, Sci Rep. source

      Not checked in the free run.

  • Premisecitation

    The body readily shifts between metabolic fuels during carbohydrate restriction to maintain energy and blood glucose.

    “the body readily shifts between metabolic fuels during carbohydrate restriction to maintain energy and blood glucose”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Smith, 2018, Metabolic flexibility as an adaptation to energy resources and requirements in health and disease, Endocr Rev. source

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    • cites [37] Goodpaster, 2017, Metabolic flexibility in health and disease, Cell Metab. source

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  • May combine two claims. 41
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    Control mice adaptively shift macronutrient preference and increase protein intake in response to dietary protein restriction.

    “while control mice adaptively shift macronutrient preference and increase protein intake in response to dietary protein restriction”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Hill, 2019, FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous FGF21 treatment reduces the consumption of sweet foods and alcohol while alternatively increasing the consumption of protein.

    “exogenous FGF21 treatment reduces the consumption of sweet foods and alcohol while alternatively increasing the consumption of protein”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [144] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab. source

      Not checked in the free run.

    • cites [179] Talukdar, 2016, FGF21 regulates sweet and alcohol preference, Cell Metab. source

      Not checked in the free run.

    • cites [184] Larson, 2019, Fibroblast growth factor-21 controls dietary protein intake in male mice, Endocrinology. source

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    Premisecitation

    Fluid restriction generates a robust physiological response including metabolic adaptations that promote fluid conservation and behavioral adaptations that promote fluid consumption.

    “Fluid restriction generates a robust physiological response, which includes metabolic adaptations that promote fluid conservation and behavioral adaptations that promote fluid consumption.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [10] Augustine, 2018, Hierarchical neural architecture underlying thirst regulation, Nature. source

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    • cites [11] Zimmerman, 2016, Thirst neurons anticipate the homeostatic consequences of eating and drinking, Nature. source

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    • cites [12] Matsuda, 2017, Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ, Nat Neurosci. source

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    • cites [13] Kinsman, 2017, Hypothalamic signaling in body fluid homeostasis and hypertension, Curr Hypertens Rep. source

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    • cites [14] Cunningham, 1992, The effects of ibotenate lesions of the median preoptic nucleus on experimentally-induced and circadian drinking behavior in rats, Brain Res. source

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    • cites [15] Zimmerman, 2017, Neural circuits underlying thirst and fluid homeostasis, Nat Rev Neurosci. source

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  • May combine two claims.

    Premisecitation

    Humans can survive and arguably thrive on low-carbohydrate ketogenic diets.

    “Humans can survive and arguably thrive on low-carbohydrate ketogenic diets”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Athinarayanan, 2019, Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial, Front Endocrinol (Lausanne). source

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    • cites [39] Gershuni, 2018, Nutritional ketosis for weight management and reversal of metabolic syndrome, Curr Nutr Rep. source

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  • May combine two claims.

    Interpretationreasoning

    There is little evidence that carbohydrate intake is necessary per se, or that carbohydrate restriction promotes a specific appetite for carbohydrate analogous to sodium appetite or protein appetite.

    “Thus there is little evidence that carbohydrate intake is necessary per se, or that carbohydrate restriction promotes a specific appetite for carbohydrate that is analogous to either sodium appetite (described above) or protein appetite (described below).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Animals sense and adaptively respond to the restriction of energy, and this adaptive response is mediated principally by endocrine hormones that act directly in the brain as signals of energy status.

    “it is now well accepted that animals sense and adaptively respond to the restriction of energy, and that this adaptive response is mediated principally by endocrine hormones that act directly in the brain as signals of energy status.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [3] Müller, 2015, Ghrelin, Mol Metab. source

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    • cites [4] Müller, 2019, Glucagon-like peptide 1 (GLP-1), Mol Metab. source

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    • cites [5] Münzberg, 2015, Structure, production and signaling of leptin, Metabolism. source

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    • cites [9] Boyle, 2018, Amylin - Its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity, Mol Metab. source

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    • cites [22] Kanoski, 2016, GLP-1 and weight loss: unraveling the diverse neural circuitry, Am J Physiol Regul Integr Comp Physiol. source

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    • cites [23] Pan, 2018, Leptin and the maintenance of elevated body weight, Nat Rev Neurosci. source

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    • cites [24] Friedman, 2016, The long road to leptin, J Clin Invest. source

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  • May combine two claims.

    Premisecitation

    Fat and carbohydrates, particularly sweet foods, are robust drivers of food choice and intake, with humans preferring and overconsuming sweet and/or fatty foods due to palatability, pleasure, and reward rather than specific defense of metabolic need.

    “Fat and carbohydrates, particularly sweet foods, are robust drivers of food choice and intake, with humans both preferring and overconsuming diets or foods that are sweet and/or fatty, not due to any specific defense of metabolic need, but instead due to palatability, pleasure, and reward”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Berthoud, 2017, Blaming the brain for obesity: integration of hedonic and homeostatic mechanisms, Gastroenterology. source

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    • cites [8] Liu, 2018, Homeostatic and non-homeostatic controls of feeding behavior: Distinct vs. common neural systems, Physiol Behav. source

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    • cites [50] Rossi, 2018, Overlapping brain circuits for homeostatic and hedonic feeding, Cell Metab. source

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    • cites [51] Cameron, 2017, Brain on fire: incentive salience, hedonic hot spots, dopamine, obesity, and other hunger games, Annu Rev Nutr. source

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  • May combine two claims.

    Premisecitation

    Carbohydrate restriction does not pose a severe metabolic or nutritional threat because fat provides sufficient energy and multiple amino acids serve as gluconeogenic substrates.

    “the restriction of dietary carbohydrate intake does not pose a severe metabolic or nutritional threat, since fat provides sufficient energy and multiple amino acids serve as gluconeogenic substrates”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [33] Wasserman, 1991, Hepatic fuel metabolism during muscular work: role and regulation, Am J Physiol.

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    • cites [34] Dardevet, 2006, Regulation of hepatic metabolism by enteral delivery of nutrients, Nutr Res Rev. source

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    • cites [35] Steinhauser, 2018, The circulating metabolome of human starvation, JCI Insight. source

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  • May combine two claims.

    Premisecitation

    Studies using the geometric framework generally observe either a very weak or nonexistent regulation of fat intake, and fat acts to dilute protein and carbohydrate and thus increase intake.

    “the studies using the geometric framework generally observe either a very weak or nonexistent regulation of fat intake, and as a result, fat acts to dilute protein and carbohydrate and thus increase intake”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Sørensen, 2008, Protein-leverage in mice: the geometry of macronutrient balancing and consequences for fat deposition, Obesity (Silver Spring). source

      Not checked in the free run.

    • cites [30] Simpson, 1997, Geometric analysis of macronutrient selection in the rat, Appetite. source

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    • cites [41] Raubenheimer, 1997, Integrative models of nutrient balancing: application to insects and vertebrates, Nutr Res Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular FGF21 signaling is mediated by a receptor complex including FGFR1c and beta-Klotho (Klb), with Klb providing cellular specificity and FGFR driving intracellular signaling.

    “Cellular FGF21 signaling is mediated by a receptor complex that includes a classic FGF receptor (FGFR1c) and a co-receptor known as beta-Klotho (Klb), with Klb functioning as the primary binding/targeting factor providing cellular specificity and FGFR functioning as the catalytic subunit that drives intracellular signaling”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Lee, 2018, Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling, Nature. source

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    • cites [113] Ding, 2012, βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism, Cell Metab. source

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  • May combine two claims.

    Premisecitation

    Nutritional geometry studies strongly argue that a number of species defend protein intake, eat to a protein target, and prioritize protein over fat or carbohydrate intake.

    “These data strongly argue that a number of species defend protein intake, eat to a protein target, and prioritize protein over fat or carbohydrate intake”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [29] Sørensen, 2008, Protein-leverage in mice: the geometry of macronutrient balancing and consequences for fat deposition, Obesity (Silver Spring). source

      Not checked in the free run.

    • cites [30] Simpson, 1997, Geometric analysis of macronutrient selection in the rat, Appetite. source

      Not checked in the free run.

    • cites [41] Raubenheimer, 1997, Integrative models of nutrient balancing: application to insects and vertebrates, Nutr Res Rev. source

      Not checked in the free run.

    • cites [104] Kyriazakis, 1991, The ability of pigs to control their protein intake when fed in three different ways, Physiol Behav. source

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  • May combine two claims.

    Premisereasoning

    Protein is prioritized and regulated to a specific target, so small changes in the proportion of dietary protein can induce large changes in total food and energy intake (protein leveraging).

    “The observation that protein is prioritized and regulated to a specific target suggests that small changes in the proportion of dietary protein can induce large changes in total food and energy intake, a concept termed protein leveraging”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [29] Sørensen, 2008, Protein-leverage in mice: the geometry of macronutrient balancing and consequences for fat deposition, Obesity (Silver Spring). source

      Not checked in the free run.

    • cites [30] Simpson, 1997, Geometric analysis of macronutrient selection in the rat, Appetite. source

      Not checked in the free run.

    • cites [32] Raubenheimer, 2019, protein leverage: theoretical foundations and ten points of clarification, Obesity (Silver Spring). source

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    • cites [56] Gosby, 2014, Protein leverage and energy intake, Obes Rev. source

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    • cites [105] Simpson, 2005, Obesity: the protein leverage hypothesis, Obes Rev. source

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    • cites [106] Solon-Biet, 2014, The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice, Cell Metab. source

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    • cites [107] Solon-Biet, 2015, Macronutrient balance, reproductive function, and lifespan in aging mice, Proc Natl Acad Sci U S A. source

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    • cites [108] Gosby, 2011, Testing protein leverage in lean humans: a randomised controlled experimental study, PLoS One. source

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  • May combine two claims.

    Interpretationreasoning

    Dietary protein content influences feeding behavior, body weight, and metabolism, and protein intake is regulated and defended in a manner at least analogous to energy intake.

    “Collectively, these data provide a convincing argument, not only that dietary protein content influences feeding behavior, body weight, and metabolism, but more particularly that protein intake is regulated and defended in a manner at least analogous to energy intake.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FGF21 reduces body weight, glucose levels, and lipid concentrations in models of obesity.

    “FGF21’s ability to reduce body weight, glucose levels, and lipid concentrations in models of obesity generated substantial initial interest”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [114] Kharitonenkov, 2005, FGF-21 as a novel metabolic regulator, J Clin Invest. source

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    • cites [115] Kharitonenkov, 2007, The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21, Endocrinology. source

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    • cites [116] Coskun, 2008, Fibroblast growth factor 21 corrects obesity in mice, Endocrinology. source

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

    Premisecitation

    FGF21 is a member of the endocrine FGFs along with FGF15/19 and FGF23, which circulate in appreciable amounts in the bloodstream and act as true endocrine hormones.

    “FGF21 is a member of a small subgroup of FGFs, along with FGF15/19 and FGF23, known as the “endocrine” FGFs that circulate in appreciable amounts within the bloodstream and act as true endocrine hormones”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Itoh, 2015, Endocrine FGFs: evolution, physiology, pathophysiology, and pharmacotherapy, Front Endocrinol (Lausanne). source

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    • cites [111] Angelin, 2012, Circulating fibroblast growth factors as metabolic regulators–a critical appraisal, Cell Metab. source

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  • May combine two claims.

    Interpretationreasoning

    Protein restriction triggers a specific appetite for protein, although it is currently unclear whether this appetite is innate or a learned response.

    “These data collectively suggest that protein restriction triggers a specific appetite for protein, although it is currently unclear whether this appetite is innate (like sodium appetite) or instead a learned response”
    Quote in the paperSubstantial claim

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

    Premisecitation

    More recent work suggests that FGF21 is more appropriately a signal of metabolic or cellular stress.

    “more recent work has led to the suggestion that FGF21 is more appropriately a signal of metabolic or cellular stress”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Maratos-Flier, 2017, Fatty liver and FGF21 physiology, Exp Cell Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Protein intake is the primary driver of circulating FGF21 levels, but maximal FGF21 occurs in mice consuming diets that were both low in protein and high in carbohydrate.

    “their data suggest that protein intake is the primary driver of circulating FGF21 levels, but that maximal FGF21 occurs in mice consuming diets that were both low in protein and high in carbohydrate”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Solon-Biet, 2016, Defining the nutritional and metabolic context of FGF21 using the geometric framework, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both acute carbohydrate ingestion and long-term exposure to high-carbohydrate diets significantly increase liver FGF21 mRNA expression and circulating FGF21 levels.

    “Both acute carbohydrate ingestion and long-term exposure to high-carbohydrate diets significantly increase liver FGF21 mRNA expression and circulating FGF21 levels”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [137] Iizuka, 2009, Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes, FEBS Lett. source

      Not checked in the free run.

    • cites [138] Dushay, 2015, Fructose ingestion acutely stimulates circulating FGF21 levels in humans, Mol Metab. source

      Not checked in the free run.

    • cites [139] Maekawa, 2017, Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice, J Nutr Biochem. source

      Not checked in the free run.

    • cites [140] Iroz, 2017, A specific ChREBP and PPARα cross-talk is required for the glucose-mediated FGF21 response, Cell Rep. source

      Not checked in the free run.

    • cites [141] Pereira, 2017, A low-protein, high-carbohydrate diet increases browning in perirenal adipose tissue but not in inguinal adipose tissue, Nutrition. source

      Not checked in the free run.

    • cites [142] Fisher, 2017, A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism, Mol Metab. source

      Not checked in the free run.

    • cites [143] Lundsgaard, 2017, Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates, Mol Metab. source

      Not checked in the free run.

    • cites [144] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab. source

      Not checked in the free run.

    • cites [145] Solon-Biet, 2016, Defining the nutritional and metabolic context of FGF21 using the geometric framework, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alcohol consumption robustly increases FGF21, largely by the liver.

    “another nutritional intervention was shown to robustly increase FGF21: alcohol consumption. Ample evidence, in both rodents and humans, demonstrates that ethanol intake increases FGF21 production, largely by the liver”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [123] von Holstein-Rathlou, 2019, Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite, J Physiol. source

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    • cites [164] Desai, 2017, Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury, Mol Metab. source

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    • cites [165] Søberg, 2018, FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest, Mol Metab. source

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    • cites [166] Søberg, 2017, FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans, Cell Metab. source

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    • cites [167] Song, 2018, The hormone FGF21 stimulates water drinking in response to ketogenic diet and alcohol, Cell Metab. source

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    • cites [168] Liu, 2016, Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury, Sci Rep. source

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    • cites [169] Lanng, 2019, Gluco-metabolic effects of oral and intravenous alcohol administration in men, Endocr Connect. source

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  • May combine two claims.

    Premisecitation

    The best evidence currently supports the hypothalamic PVN as a site mediating FGF21 effects on sweet intake, as deletion of Klb from the PVN blocked the effects on sweet intake.

    “The best evidence currently supports the hypothalamic PVN, as the deletion of Klb from the PVN blocked the effects on sweet intake”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF21-dependent effects on intake appeared to be specific for sweet/sugar, as there was no effect on the nonsweet carbohydrate maltodextrin.

    “these FGF21-dependent effects appeared to be specific for sweet/sugar, as there was no effect on the nonsweet carbohydrate maltodextrin”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice that genetically overexpressed or were treated with FGF21 reduced their consumption of a high-sucrose diet and reduced their consumption of sucrose and the noncaloric sweeteners saccharin and sucralose.

    “mice that genetically overexpressed or were treated with FGF21 reduced their consumption of a high-sucrose diet and reduced their consumption of sucrose and the noncaloric sweeteners saccharin and sucralose”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of FGF21 on sweet intake could be reproduced by exogenous FGF21 administration in control mice, but not mice lacking Klb in the brain.

    “This effect on sweet intake could be reproduced by exogenous FGF21 administration in control mice, but not mice lacking Klb in the brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Talukdar, 2016, FGF21 regulates sweet and alcohol preference, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF21-deficient mice increased their consumption of a solid, high-sucrose diet, as well as solutions containing sucrose, glucose, or fructose.

    “FGF21-deficient mice increased their consumption of a solid, high-sucrose diet, as well as solutions containing sucrose, glucose, or fructose”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] von Holstein-Rathlou, 2016, FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PVN oxytocin neurons influence sweet intake, express Klb, and are responsive to FGF21.

    “PVN oxytocin neurons influence sweet intake, express Klb, and are responsive to FGF21”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Matsui, 2018, Neuronal SIRT1 regulates macronutrient-based diet selection through FGF21 and oxytocin signalling in mice, Nat Commun. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    FGF21 acts directly in the brain to suppress both sweet and alcohol consumption and preference.

    “Collectively, these data provide compelling evidence that FGF21 acts directly in the brain to suppress both sweet and alcohol consumption and preference”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [123] von Holstein-Rathlou, 2019, Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite, J Physiol. source

      Not checked in the free run.

    • cites [125] BonDurant, 2018, Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis, Annu Rev Nutr. source

      Not checked in the free run.

    • cites [182] Gillum, 2018, Parsing the potential neuroendocrine actions of FGF21 in primates, Endocrinology. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The increase in FGF21 is directly related to reduced protein intake, as it occurs in settings of both low and high carbohydrate and low and high fat.

    “This increase in FGF21 is directly related to reduced protein intake, as it occurs in settings of both low and high carbohydrate and low and high fat”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [77] Hill, 2019, FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism, Cell Rep. source

      Not checked in the free run.

    • cites [145] Solon-Biet, 2016, Defining the nutritional and metabolic context of FGF21 using the geometric framework, Cell Metab. source

      Not checked in the free run.

    • cites [146] Laeger, 2014, FGF21 is an endocrine signal of protein restriction, J Clin Invest. source

      Not checked in the free run.

    • cites [162] Laeger, 2018, Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes, Diabetologia. source

      Not checked in the free run.

    • cites [163] Stemmer, 2015, FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice, Diabetologia. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF21 has been directly linked to metabolic stress and liver steatosis.

    “FGF21 has been directly linked to metabolic stress and liver steatosis”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [132] Dushay, 2010, Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease, Gastroenterology. source

      Not checked in the free run.

    • cites [136] Maratos-Flier, 2017, Fatty liver and FGF21 physiology, Exp Cell Res. source

      Not checked in the free run.

    • cites [170] Yilmaz, 2010, Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease, Eur J Clin Invest. source

      Not checked in the free run.

    • cites [171] Li, 2010, Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride, J Hepatol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although wild-type mice exhibit changes in growth, body composition, food intake, energy expenditure, and glucose metabolism in response to dietary protein restriction, these effects are absent in mice that lack FGF21.

    “Although wild-type mice exhibit changes in growth, body composition, food intake, energy expenditure, and glucose metabolism in response to dietary protein restriction, these effects are absent in mice that lack FGF21”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [77] Hill, 2019, FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism, Cell Rep. source

      Not checked in the free run.

    • cites [146] Laeger, 2014, FGF21 is an endocrine signal of protein restriction, J Clin Invest. source

      Not checked in the free run.

    • cites [148] Maida, 2016, A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution, J Clin Invest. source

      Not checked in the free run.

    • cites [160] Laeger, 2016, Metabolic responses to dietary protein restriction require an increase in FGF21 that is delayed by the absence of GCN2, Cell Rep. source

      Not checked in the free run.

    • cites [183] Hill, 2017, Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints, Sci Rep. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FGF21, via its effects in the brain, acts to suppress the consumption of carbohydrate (particularly sweet) while increasing the consumption of protein.

    “FGF21, via its effects in the brain, acts to suppress the consumption of carbohydrate (particularly sweet) while increasing the consumption of protein.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    FGF21 directly suppresses sweet and alcohol intake but increases protein intake.

    “FGF21 directly suppresses sweet and alcohol intake but increases protein intake”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    Deleting Klb from the brain recapitulates the phenotype, strongly arguing that the metabolic response to protein restriction requires FGF21 acting directly in the brain.

    “we recapitulated this phenotype by deleting Klb from the brain, strongly arguing that the metabolic response to protein restriction requires FGF21 acting directly in the brain”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Hill, 2019, FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the classic 3-macronutrient choice test, systemic FGF21 treatment significantly increased protein intake and decreased carbohydrate intake, without altering fat or total food intake.

    “systemic FGF21 treatment significantly increased protein intake and decreased carbohydrate intake, without altering fat or total food intake”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Larson, 2019, Fibroblast growth factor-21 controls dietary protein intake in male mice, Endocrinology. source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Protein restriction induces a unique and selective appetite for protein, but this adaptive, physiological shift in macronutrient preference was lost in mice lacking either FGF21 or Klb in the brain.

    “protein restriction induces a unique and selective appetite for protein, but that this adaptive, physiological shift in macronutrient preference was lost in mice lacking either FGF21 or Klb in the brain”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Hill, 2019, FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The effects of FGF21 are not simply the result of pharmacological treatment, as physiological shifts in macronutrient preference during dietary protein restriction depend on FGF21 and its ability to signal in the brain.

    “these effects of FGF21 are not simply the result of pharmacological treatment, as physiological shifts in macronutrient preference during dietary protein restriction depend on FGF21 and its ability to signal in the brain”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The effects of FGF21 on feeding behavior are highly consistent with the nutritional regulation of FGF21, as FGF21 is increased by high carbohydrate/alcohol intake and by low protein intake.

    “These effects on feeding behavior are also highly consistent with the nutritional regulation of FGF21, as FGF21 is increased by high carbohydrate/alcohol intake and by low protein intake.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    FGF21 mediates adaptive changes in both metabolism and behavior in response to excess consumption of carbohydrate and alcohol, and/or reductions in protein intake.

    “it does not act to regulate food intake generally but instead to mediate adaptive changes in both metabolism and behavior in response to excess consumption of carbohydrate and alcohol, and/or reductions in the intake of protein intake.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The brain appears to be a primary mediator of FGF21's actions, although FGF21 may act on multiple tissues.

    “Although FGF21 may act on multiple tissues, the brain appears to be a primary mediator.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FGF21 sequence variants are linked with alterations in macronutrient preference and alcohol intake in humans.

    “FGF21 sequence variants are linked with alterations in macronutrient preference and alcohol intake in humans”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [172] Tanaka, 2013, Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake, Am J Clin Nutr. source

      Not checked in the free run.

    • cites [173] Chu, 2013, Novel locus including FGF21 is associated with dietary macronutrient intake, Hum Mol Genet. source

      Not checked in the free run.

    • cites [166] Søberg, 2017, FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans, Cell Metab. source

      Not checked in the free run.

    • cites [174] Frayling, 2018, A common allele in FGF21 associated with sugar intake is associated with body shape, lower total body-fat percentage, and higher blood pressure, Cell Rep. source

      Not checked in the free run.

    • cites [175] Merino, 2019, Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium, Mol Psychiatry. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    FGF21 signaling in the brain is not only sufficient to increase protein intake, but brain FGF21 signaling is absolutely necessary for mice to exhibit physiologically adaptive increases in protein intake in response to protein restriction.

    “Available evidence therefore strongly indicates that FGF21 signaling in the brain is not only sufficient to increase protein intake, but that brain FGF21 signaling is absolutely necessary for mice to exhibit physiologically adaptive increases in protein intake in response to protein restriction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Hill, 2019, FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The ability of FGF21 treatment to shift preference toward protein was lost in mice lacking Klb in the brain, suggesting that FGF21 acts in the brain to produce a protein preference.

    “this ability of FGF21 treatment to shift preference toward protein was lost in mice lacking Klb in the brain, again suggesting that FGF21 acts in the brain to produce a protein preference”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Larson, 2019, Fibroblast growth factor-21 controls dietary protein intake in male mice, Endocrinology. source

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    Foods that are rich in carbohydrate but poor in protein are relatively common in nature.

    “specifically the excessive consumption of foods that are rich in carbohydrate but poor in protein (relatively common in nature)”

  • The paper relies on this without support.

    Diets high in carbohydrate but low in protein do not cause energy restriction.

    “Such diets do not trigger traditional energy balance signals because no energy restriction is occurring”
2 of 2

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?

  • Maximal circulating FGF21 levels increase in response to a combination of low-protein and high-carbohydrate conditions.

    “maximal levels of circulating FGF21 increase in response to a combination of low-protein and high-carbohydrate conditions [152,158,165].”

    From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [165]

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.

  • Study author's name differs from reference 184

    Minor

    The text attributes the cited study to Larsen, while reference 184 lists Larson as its first author.

1 of 1

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Authors
Hill, C. M., Qualls-Creekmore, E., Berthoud, H.-R., Soto, P., Yu, S., McDougal, D. H., Münzberg, H., & Morrison, C. D.
Affiliations
  • Pennington Biomedical Research Center (US)
  • Pennington Biomedical Research Center, Baton Rouge, LA
Corresponding author
Morrison, Christopher D
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2020-02-12
Volume
161
Issue
3
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/endocr/bqaa019
PMC
PMC7053867
OpenAlex
W3005797782
Semantic Scholar
0d2708691ec52eeddea77bf4fc6fcd5cc72106b0
Cited by
99
References
193
Citations by year
2026: 8 · 2025: 15 · 2024: 13 · 2023: 18 · 2022: 21 · 2021: 19 · 2020: 5
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Civil War Book Review (submittedVersion)
Funders
National Institutes of Health (R01DK105032, F32DK115137)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Physiology › Dietary Effects on Health
Keywords
FGF21, macronutrient preference, protein restriction, nutrient homeostasis, food intake regulation, protein-carbohydrate ratio, protein intake
MeSH terms
Nutrients, Animals, Brain, Dietary Carbohydrates, Dietary Proteins, Feeding Behavior, Fibroblast Growth Factors, Homeostasis

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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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