Biology:FGF21

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the FGF21 gene.[1] Together with FGF19 (FGF15 in rodents) and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth factor (FGF) family.[2] FGF21 is a potent, extracellularly acting metabolic regulator, whose action was discovered through in vitro phenotypic screening and diet manipulation studies in rodents.,[3][4][5] unlike canonical growth-stimulating FGFs known to stimulate mitosis, differentiation and angiogenesis in their target tissues,[6] FGF21 exerts its action by activating FGF21 receptors located in the cell membrane of target cells.[7] Each FGF21 receptor is composed of a transmembrane FGF receptor protein (either FGFR1, FGFR2 or FGFR3), and its complexing co-receptor β-Klotho.[8][9] Loss of β-Klotho abolishes all effects of FGF21 in vitro and in vivo.[10][11][12] In addition to its action as a hormone, FGF21 may be able to act in an autocrine fashion (typically in fat cells),[13][14] or possibly also in a paracrine manner in the pancreas.[15][16]

Apart from directly regulating energy metabolism in various tissues, FGF21 also regulates simple sugar intake and preferences for sweet foods via signaling through FGF21 receptors in the paraventricular nucleus of the hypothalamus and correlates with reduced dopamine neurotransmission within the nucleus accumbens.[17][18][19] Attempts are under way to develop metabolic medicines using various FGF21 analogs, mimetics or sensitizers of the FGF21 pathway.[20][21]

Structure

It is a single-chain protein containing 209 amino acid residues, which is encoded by the mammalian FGF21 gene.[22][23][24]

Function

FGF21 is beneficially involved in the regulation of lipid, glucose, and energy metabolism.[25] It can be synthesized in several organs and tissues, but it is mainly or solely exported into the circulation by the liver, in amounts typically responding to stress or dietary factors such as caloric or protein intake.[26][27] Depending on the relation between production and target sites, FGF21 can operate in an autocrine, paracrine or endocrine mode. Differences in tissue-specific FGF21 expression and organ responses to the hormone appear to occur under different nutritional or physiological situations. For example, expression of FGF21 is selectively increased in the liver by fasting, by overfeeding in the pancreas, by exercise in muscle, and by cold exposure in brown adipose tissue (BAT).[25] In a similar vein, FGF21 promotes glucose uptake in fat ,[3] whereas in liver, it stimulates gluconeogenesis.[28]

Although a unifying view on the physiological value of FGF21 for the survival of mammals may still be lacking, evidence indicates that, under dietary protein restriction, FGF21 plays a homeostatic role leading to extend lifespan and improve metabolic health; proof of concept for this view has been recently provided in experiments with mice.[29] Conforming to this conjecture, long-term low-protein diets increase FGF21 activation in the brain, leading individuals to behaviorally compensate by preferring foods lower in fat and carbohydrates and higher in protein.[30] Again, generally speaking, conditions that require the mobilization of energy stores induce hepatic and BAT-derived FGF21, while conditions that promote energy storage induce WAT and pancreatic FGF21.[25]

FGF family

Main page: Biology:Fibroblast growth factor

The FGF superfamily comprehends nearly two dozen cell signalling proteins involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion.[23] Most of the members of the non-endocrine FGF family typically reside in the extracellular matrix of the relevant tissue, bound to heparinoid moieties, from which FGF molecules are eventually released by tissue remodeling triggers (such as injury) to act as growth factors on target cells located nearby. Contrarily, endocrine FGFs (FGF19, FGF21, FGF23), don't bind heparinoid elements, and are released in soluble form to the extracellular space of their producing cells, often to act on distant target cells.[23][31]

Production and regulation

FGF21 regulation diagram
Mechanism for FGF21-mediated regulation of metabolism

Expression of the FGF21 gene is primarily up regulated by PPAR-α in the liver (typically by fasting),[32] and by PPAR-γ in the adipose tissue.[33] In Hep G2 cells, FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity.[34] The oxidized form of ketone bodies (acetoacetate) in the culture medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism.[34] HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria.[35]

While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas (where it favors digestive enzyme secretion),[16] circulating levels of FGF21 are derived specifically from the liver in mice.[26]

Skeletal muscle produces FGF21, its expression being regulated by a PI3-kinase/Akt1 signaling mechanism.[36] FGF21 release from the liver is enhanced during exercise, apparently accompanying increased lipolysis and ketogenesis in fat tissue,[37] together with increased hepatic glycogen degradation and enhanced glucose output from the liver.[38] The involvement of FGF21 in mediating thermogenic responses to cold-exposure has been the object of intense studies.[39][40] In general terms, production of FGF21 in non-liver tissues is believed to fulfill mostly autocrine or paracrine functions.[41]

At a systemic level, thyroid hormone can regulate adipose and hepatic FGF21 expression and serum levels in mice.[42] Studies in humans revealed a correlation between circulating levels of FGF21 and body mass index (BMI), but contrary to what occurs in rodents, neither fasting nor ketogenic diets have been found to modify such levels,[43] although the latter has been unconfirmed by others.[44] Conversely, the ingestion of fructose has been found to rapidly and sharply increase serum FGF21 levels for up to 4 hours, returning to normal by hour 5.[45] In elderly subjects with T2D resistance training has been reported to significantly lower circulating FGF-21.[46] Also in humans, Liver X receptor (LXR) represses FGF21 via an LXR response element located from -37 to -22 bp on the human FGF21 promoter.[47]

FGF21 receptor

Similar to those of other endocrine FGFs, FGF21 receptor is a heterodimer, composed of an FGF receptor protein (FGFR) and a (β-) klotho co-receptor.[7] Klotho co-receptors of three types have been described (α, β and γ), all of which are sequentially related to β-glucuronidase, although being devoid of enzymic capacity.[48] FGF21 binds to FGFR through its amino terminus, and to β-klotho though its C-terminus.[49]

FGFRs

Many molecular species of FGFR have been identified, all arising from the splicing of four primary FGFR genes, to produce proteins of over 800 amino acid residues. Each FGFR species consists of an extracellular ligand domain composed of three immunoglobulin-like domains, a single transmembrane helix domain, and an intracellular domain having tyrosine kinase activity, which becomes activated upon the functional integration of the FGF21/FGFR/β-Klotho complex. FGF21 can bind to receptor species FGFR1-4.[50][51]

β-Klotho

β-Klotho is a single-pass transmembrane protein containing 1043 amino acid residues whose expression is induced in target cells upon their differentiation.[52] β-Klotho interacts closely with FGFR1c or FGFr4 receptor proteins to enhance their binding affinity for FGF21.[51] Loss of β-Klotho at the receptor site renders such receptors unresponsive to FGF21.[53]

Signalling

In common with all FGF receptors, FGF21R protein embodies a tyrosine kinase capacity, which is activated upon the binding of FGF21, with the simultaneous trigger of receptor dimer generation. Crossed phosphorylation of adjacent receptor dimer chains ensues, which in turns activates their phosphorylating capacities of other intracellular protein substrates, thus sparking a pleiotropic, intracellular signaling cascade.[7][54] Such cascade signaling may result, for example, in the subsequent activation of the AMPK-SIRT1-PGC-1 alpha pathway for the regulation of glucose, lipid, and energy homeostasis;[54] Other regulatory, intracellular signaling pathways affected by FGF21 in various contexts include cFOS,[28] the Hedgehog pathway,[55] Sirt1-dependent,[56] NF-κB dependent,[57] ATF4 dependent,[58] and BMP2-dependent[59] pathways, among others.

Effects in vitro

Adipocytes

FGF21 is one of the most potent insulin sensitizers known.[10] FGF21 stimulates glucose uptake in adipocytes but not in other cell types.[3] This effect is additive to the activity of insulin. FGF21 induces the insulin-sensitizing hormone adiponectin.[60] FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway.[61] FGF21 activates mitochondrial oxidative function in adipocytes by activating PGC-1α.[62][63]

Hepatocytes

In isolated primary hepatocytes, FGF21 treatment was reported to cause robust responses in the phosphorylation of extracellular signal-regulated kinase (ERK 1/2) and in the expression of PGC-1α nuclear protein.[28]

Effects in vivo

Mice

FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects mice from diet-induced obesity when over expressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents.[3] Treatment of mice with FGF21 results in increased energy expenditure, fat utilization and lipid excretion.[64]

FGF21 enhances gluconeogenesis, fatty acid activation and ketogenesis in the mouse liver under various conditions.[28][65][62] FGF21 treatment improves sensitivity to insulin in normal and high-fat fed wild mice.[66] Whether or not in-vivo responses to FGF21 in the liver and other organs are mediated through its prior action on adipocytes is a subject of debate.[67] In the pancreas, FGF21 favors the formation of pancreatic juice through a β-klotho dependent mechanism.[16]

Whether an overexpression or administration of FGF21 affects female fertility in mice is debated. An early report has shown that an overexpression of FGF21 acts centrally to inhibit the surge in reproductive hormones and therefore cause female infertility.[68] A different study showed no correlation of high FGF21 levels with infertility and demonstrated that estrous cycle can be restored in mice overexpressing FGF21 through a high-fat diet.[69] More recently, a report indicated that a single administration of FGF21 can affect the long term fertility in female mice despite the feeding of a high-fat diet.[70] Further studies are needed to study the effect of FGF21 on female fertility.

Other animals

In late-pregnant cows, FGF21 plasma levels change from undetectable to high upon parturition and the beginning of lactation, apparently reflecting a change to an energy insufficient state during early lactation, where the liver was the major source of FGF21.[71]

Non-human primates

Administration of FGF21 or its analogs to obese non-human primates has been shown to decrease food intake, reduce overweight and improve plasma lipid profile while increasing circulating adiponectin.[72][73]

Clinical significance

Serum FGF21 levels are significantly increased in obesity and in patients with type 2 diabetes mellitus (T2DM), presumably indicating a state of FGF21-resistance.[74][75]

Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease[76] and positively correlate with Body Mass Index in humans, again suggesting obesity as a FGF21-resistant state, although this postulate is still a subject of debate.[77][25] Both high sugar and low protein diets can elevate FGF21 in animals and humans.[10][78] Also, reports awaiting confirmation would indicate that circulating FGF21 levels may have prognostic value for the early detection of injury in patients with liver transplantation.[79]

FGF21 can inhibit mTORC1 in the liver and stimulate adiponectin secretion from fatty tissues, thereby inhibiting aging-associated metabolic syndrome.[62] FGF21 protects against diabetic cardiomyopathy primarily by PGC-1α-induction of beta oxidation.[33] The anti-inflammatory effects of FGF21 may primarily be due to inhibition of NF-κB in macrophages.[33] In mice, FGF21 has been shown to protect against high fat diet-induced inflammation and islet hyperplasia in the pancreas,[80] a finding of possible clinical relevance.

A single-nucleotide polymorphism (SNP) of the FGF21 gene – the FGF21 rs838133 variant (frequency 44.7%) – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice.[81][82][83][75]

From a pharmacological perspective, FGF21 analogs can effectively reduce hyperglycemia in diabetic rodents,[84][85] but not in clinical disease.[86] In obese individuals however (mice, monkeys or human), systemically given FGF21 can increase energy expenditure, trigger body weight reduction, and reduce abnormally high circulating insulin, triglycerides, and LDL-cholesterol levels. In obese mice, FGF21 treatment can also reduce circulating glucose and abnormal fat accumulation in the liver.[87][41] Given these properties, FGF21 and its analogs may prove particularly effective in the treatment of metabolic syndrome.[3][88]

Also, FGF21 administration has been shown to cause the reduction of sugar and alcohol intake, and to have anti-toxic or anti-inflammatory effects in the liver and pancreas.[89][90][16] FGF21 appears capable of crossing the blood-brain barrier,[91] and in fact, some of the effects of FGF21 administration on metabolic variables and on food preferences may be mediated through its action in brain pathways.[92][93][94][95]

Preclinical studies

Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.[96]

FGF21 stimulates phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2 in the liver. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of PGC-1α, but in mice PGC-1α expression was not necessary for the effect of FGF21 on glucose metabolism.[28]

In mice FGF21 is strongly induced in liver by prolonged fasting via PPAR-alpha and in turn induces the transcriptional coactivator PGC-1α and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. In mice, FGF21 may be necessary for them to display the hibernation-like state of torpor,[31] also for eliciting and coordinating the adaptive response to fasting and starvation.[96] FGF21 expression is also induced in white adipose tissue by PPAR-gamma, which may indicate it also regulates metabolism in the fed state.[97] FGF21 is induced in both rodents and humans consuming a low protein diet.[98][99] FGF21 expression is also induced by diets with reduced levels of the essential dietary amino acids methionine,[100][101] isoleucine,[102] or threonine,[103] or with reduced levels of branched-chain amino acids.[104] Interestingly, methionine restriction can increase circulating FGF21 between 5-fold and 10-fold in mice, while simultaneously boosting energy expenditure, insulin sensitivity and mobilization of fat stores, the latter effects requiring intact FGF21 signaling in the brain.[105]

In mice with acute ablation of thermogenic adipose tissues, FGF21-induced weight loss appears to be at least partially mediated by increased physical activity as well as by a centrally mediated increase in energy expenditure.[10]

In rats, steatosis induced by cafeteria diet was accompanied by high serum FGF21, whereas oral taurine supplementation prevented both steatosis and high FGF21 levels.[106]

Fructose ingestion also induced FGF21 in humans, where it causes a rise in FGF21 levels in serum;[45] likewise in mice, where serum FGF21 increases and induction of FGF21 in the liver can be confirmed.[107] A dramatic increase in circulating FGF21 in humans is induced by the consumption of alcohol.[108] Acutely, the rise in FGF21 in response to alcohol consumption inhibits further drinking.[109] Chronically, the rise in FGF21 expression in the liver may protect against liver damage.[8]

Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an LKB1-AMPK-SIRT1-PGC-1α-dependent mechanism in adipocytes, resulting in increased phosphorylation of AMPK, increased cellular NAD+ levels and activation of SIRT1 and deacetylation of SIRT1 targets PGC-1α and histone 3.[63]

FGF21 mimetics

Three types of compounds to enhance FGF21 have been proposed or developed: 1. modified FGF21 proteins, 2. antibodies to the FGF21 receptor complex, and 3. inhibitors of FGF21 degradation by protease. The list of modified FGF21 proteins that have been developed include LY2405319, LY3025876, LY3084077, BMS986036, BMS986171, PF05231023 and AMG876. Antibody-based FGF21R agonists include BFKB8488A and NGM313. A number of antibodies to the FGF21R complex have been developed and tested to some extent as FGF21 mimetics by Genentech (bFKB1),[110][111][112] and Amgen (mimAb1).[113] Although FGF21 mimetics were initially considered an option to treat T2D, the bulk of evidence prompted a change of expectations towards more realistic views for their possible clinical use in the normalization of lipid metabolism in dislipidemic obese patients, and to prevent and treat non-alcoholic steatohepatitis (NASH).[20]

FGF21 antagonists

At least two peptide compounds showing antagonist properties of FGF21 action have been described, their eventual clinical utility being uncertain.[114][115]

Clinical trials

LY2405319 (Lilly)

In a randomized, placebo-controlled, double-blind proof-of-concept trial, 4 weeks of daily subcutaneous treatment of obese diabetic patients with LY2405319 significantly lowered plasma triglycerides and low-density lipoprotein cholesterol (LDLc), and increased high-density lipoprotein cholesterol (HDLc).[116]

LLF580 (Novartis)

In obese, mildly hypertriglyceridemic adults, LLF580 lowered serum triglycerides by 54%, lowered serum triglycerides by 54%, reduced liver fat by 52% over placebo. Treatment with LLF580 had beneficial effects on serum lipids, liver fat, and biomarkers of liver injury; with mild to moderate gastrointestinal adverse effects.[88]

AKR-001 (Akero)

In T2D patients, AKR-001 treatment produced favorable effects in lipoprotein profile, including triglycerides, non-high-density lipoprotein (non-HDL) cholesterol, HDL-C, and apolipoproteins B and C3.[117]

BMS-986036 (Bristol-Myers Squibb)

Subcutaneous treatment of obese, diabetic patients with BMS-986036 (Pegbelfermin, a recombinant PEGylated FGF21 analog), improved serum lipid profile and adiponectin levels, with no effect on HbA1c.[86]

References

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  2. ↑ "Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease". Cell and Tissue Research 342 (1): 1–11. October 2010. doi:10.1007/s00441-010-1024-2. PMID 20730630. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "FGF-21 as a novel metabolic regulator". The Journal of Clinical Investigation 115 (6): 1627–1635. June 2005. doi:10.1172/JCI23606. PMID 15902306. 
  4. ↑ "Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states". Cell Metabolism 5 (6): 426–437. June 2007. doi:10.1016/j.cmet.2007.05.002. PMID 17550778. 
  5. ↑ "Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21". Cell Metabolism 5 (6): 415–425. June 2007. doi:10.1016/j.cmet.2007.05.003. PMID 17550777. 
  6. ↑ "The FGF family: biology, pathophysiology and therapy". Nature Reviews. Drug Discovery 8 (3): 235–253. March 2009. doi:10.1038/nrd2792. PMID 19247306. 
  7. ↑ 7.0 7.1 7.2 "The FGF21 Receptor Signaling Complex: Klothoβ, FGFR1c, and Other Regulatory Interactions". Vitamins and Hormones 101: 17–58. 2016. doi:10.1016/bs.vh.2016.02.008. PMID 27125737. 
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  25. ↑ 25.0 25.1 25.2 25.3 "The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model". Frontiers in Endocrinology 12: 802541. 2021. doi:10.3389/fendo.2021.802541. PMID 35046901. 
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  32. ↑ "Regulation of Ketone Body Metabolism and the Role of PPARα". International Journal of Molecular Sciences 17 (12): E2093. December 2016. doi:10.3390/ijms17122093. PMID 27983603. 
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  36. ↑ "FGF21 is an Akt-regulated myokine". FEBS Letters 582 (27): 3805–3810. November 2008. doi:10.1016/j.febslet.2008.10.021. PMID 18948104. 
  37. ↑ "Acute exercise induces FGF21 expression in mice and in healthy humans". PLOS ONE 8 (5): e63517. 2013. doi:10.1371/journal.pone.0063517. PMID 23667629. Bibcode: 2013PLoSO...863517K. 
  38. ↑ "Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans". Molecular Metabolism 4 (8): 551–560. August 2015. doi:10.1016/j.molmet.2015.06.001. PMID 26266087. 
  39. ↑ "Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis". The Journal of Clinical Endocrinology and Metabolism 98 (1): E98-102. January 2013. doi:10.1210/jc.2012-3107. PMID 23150685. 
  40. ↑ "FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis". Genes & Development 26 (3): 271–281. February 2012. doi:10.1101/gad.177857.111. PMID 22302939. 
  41. ↑ 41.0 41.1 "Understanding the Physiology of FGF21". Annual Review of Physiology 78: 223–241. 2016. doi:10.1146/annurev-physiol-021115-105339. PMID 26654352. 
  42. ↑ "Fibroblast growth factor 21 and thyroid hormone show mutual regulatory dependency but have independent actions in vivo". Endocrinology 155 (5): 2031–2040. May 2014. doi:10.1210/en.2013-1902. PMID 24564398. 
  43. ↑ "Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease". Gastroenterology 139 (2): 456–463. August 2010. doi:10.1053/j.gastro.2010.04.054. PMID 20451522. 
  44. ↑ "Acute Hyperenergetic, High-Fat Feeding Increases Circulating FGF21, LECT2, and Fetuin-A in Healthy Men". The Journal of Nutrition 150 (5): 1076–1085. May 2020. doi:10.1093/jn/nxz333. PMID 31919514. 
  45. ↑ 45.0 45.1 "Fructose ingestion acutely stimulates circulating FGF21 levels in humans". Molecular Metabolism 4 (1): 51–57. January 2015. doi:10.1016/j.molmet.2014.09.008. PMID 25685689. 
  46. ↑ "Resistance training attenuates circulating FGF-21 and myostatin and improves insulin resistance in elderly men with and without type 2 diabetes mellitus: A randomised controlled clinical trial". European Journal of Sport Science 21 (4): 636–645. April 2021. doi:10.1080/17461391.2020.1762755. PMID 32345132. 
  47. ↑ "Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet". The Journal of Nutritional Biochemistry 23 (7): 785–790. July 2012. doi:10.1016/j.jnutbio.2011.03.023. PMID 21889884. 
  48. ↑ "The Klotho proteins in health and disease". Nature Reviews. Nephrology 15 (1): 27–44. January 2019. doi:10.1038/s41581-018-0078-3. PMID 30455427. 
  49. ↑ "Different roles of N- and C- termini in the functional activity of FGF21". Journal of Cellular Physiology 219 (2): 227–234. May 2009. doi:10.1002/jcp.21675. PMID 19117008. 
  50. ↑ "Multi-organ FGF21-FGFR1 signaling in metabolic health and disease". Frontiers in Cardiovascular Medicine 9: 962561. 2022. doi:10.3389/fcvm.2022.962561. PMID 35983184. 
  51. ↑ 51.0 51.1 "Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21". The Journal of Biological Chemistry 282 (37): 26687–26695. September 2007. doi:10.1074/jbc.M704165200. PMID 17623664. 
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  53. ↑ "BetaKlotho is required for metabolic activity of fibroblast growth factor 21". Proceedings of the National Academy of Sciences of the United States of America 104 (18): 7432–7437. May 2007. doi:10.1073/pnas.0701600104. PMID 17452648. Bibcode: 2007PNAS..104.7432O. 
  54. ↑ 54.0 54.1 "[Establishment of a novel cell model targeted on FGF-21 receptor for screening anti-diabetic drug candidates"]. Yao Xue Xue Bao = Acta Pharmaceutica Sinica 46 (8): 904–909. August 2011. PMID 22007513. https://pubmed.ncbi.nlm.nih.gov/22007513. 
  55. ↑ "Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21". Cells 11 (10): 1680. May 2022. doi:10.3390/cells11101680. PMID 35626717. 
  56. ↑ "Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway". Cell Death & Disease 12 (10): 865. September 2021. doi:10.1038/s41419-021-04157-x. PMID 34556628. 
  57. ↑ "Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway". International Immunopharmacology 38: 144–152. September 2016. doi:10.1016/j.intimp.2016.05.026. PMID 27276443. 
  58. ↑ "FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway". FASEB Journal 32 (5): 2630–2643. May 2018. doi:10.1096/fj.201700709RR. PMID 29295856. 
  59. ↑ "Interactions between FGF21 and BMP-2 in osteogenesis". Biochemical and Biophysical Research Communications 432 (4): 677–682. March 2013. doi:10.1016/j.bbrc.2013.02.019. PMID 23416071. 
  60. ↑ "Regulation of energy metabolism by long-chain fatty acids". Progress in Lipid Research 53: 124–144. January 2014. doi:10.1016/j.plipres.2013.12.001. PMID 24362249. 
  61. ↑ "Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling". Journal of Cellular Physiology 210 (1): 1–6. January 2007. doi:10.1002/jcp.20847. PMID 17063460. 
  62. ↑ 62.0 62.1 62.2 "The Roles and Pharmacological Effects of FGF21 in Preventing Aging-Associated Metabolic Diseases". Frontiers in Cardiovascular Medicine 8: 655575. 2021. doi:10.3389/fcvm.2021.655575. PMID 33869312. 
  63. ↑ 63.0 63.1 "Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway". Proceedings of the National Academy of Sciences of the United States of America 107 (28): 12553–8. July 2010. doi:10.1073/pnas.1006962107. PMID 20616029. Bibcode: 2010PNAS..10712553C. 
  64. ↑ "Fibroblast growth factor 21 corrects obesity in mice". Endocrinology 149 (12): 6018–27. December 2008. doi:10.1210/en.2008-0816. PMID 18687777. 
  65. ↑ "Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis". The American Journal of Clinical Nutrition 93 (4): 901S–9015. April 2011. doi:10.3945/ajcn.110.001941. PMID 21346090. 
  66. ↑ "Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice". Endocrinology 154 (9): 3099–3109. September 2013. doi:10.1210/en.2013-1191. PMID 23766126. 
  67. ↑ "Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes". The Journal of Biological Chemistry 286 (40): 34559–34566. October 2011. doi:10.1074/jbc.M111.285965. PMID 21849508. 
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  69. ↑ Singhal, Garima; Douris, Nicholas; Fish, Alan J.; Zhang, Xinyao; Adams, Andrew C.; Flier, Jeffrey S.; Pissios, Pavlos; Maratos-Flier, Eleftheria (August 2016). "Fibroblast growth factor 21 has no direct role in regulating fertility in female mice" (in en). Molecular Metabolism 5 (8): 690–698. doi:10.1016/j.molmet.2016.05.010. PMID 27656406. 
  70. ↑ Moeckli, Beat; Pham, Thuy-Vy; Slits, Florence; Latrille, Samuel; Peloso, Andrea; Delaune, Vaihere; Oldani, Graziano; Lacotte, Stéphanie et al. (November 2022). "FGF21 negatively affects long-term female fertility in mice" (in en). Heliyon 8 (11): e11490. doi:10.1016/j.heliyon.2022.e11490. PMID 36406708. Bibcode: 2022Heliy...811490M. 
  71. ↑ "Plasma FGF21 is elevated by the intense lipid mobilization of lactation". Endocrinology 152 (12): 4652–61. December 2011. doi:10.1210/en.2011-1425. PMID 21990311. 
  72. ↑ "PF-05231023, a long-acting FGF21 analogue, decreases body weight by reduction of food intake in non-human primates". Journal of Pharmacokinetics and Pharmacodynamics 43 (4): 411–425. August 2016. doi:10.1007/s10928-016-9481-1. PMID 27405817. 
  73. ↑ "A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects". Cell Metabolism 23 (3): 427–440. March 2016. doi:10.1016/j.cmet.2016.02.001. PMID 26959184. 
  74. ↑ "Serum FGF-21 levels in type 2 diabetic patients". Endocrine Research 36 (4): 142–8. 2011. doi:10.3109/07435800.2011.558550. PMID 21973233. 
  75. ↑ 75.0 75.1 "Fibroblast growth factor 21: a regulator of metabolic disease and health span". American Journal of Physiology. Endocrinology and Metabolism 313 (3): E292–E302. 2017. doi:10.1152/ajpendo.00101.2017. PMID 28559437. 
  76. ↑ "Circulating fibroblast growth factor 21 levels are closely associated with hepatic fat content: a cross-sectional study". PLOS ONE 6 (9): e24895. 2011. doi:10.1371/journal.pone.0024895. PMID 21949781. Bibcode: 2011PLoSO...624895Y. 
  77. ↑ "Fibroblast growth factor 21: effects on carbohydrate and lipid metabolism in health and disease". Current Opinion in Clinical Nutrition and Metabolic Care 14 (4): 354–359. July 2011. doi:10.1097/MCO.0b013e328346a326. PMID 21505329. 
  78. ↑ "Homeostatic sensing of dietary protein restriction: A case for FGF21". Frontiers in Neuroendocrinology 51: 125–131. October 2018. doi:10.1016/j.yfrne.2018.06.002. PMID 29890191. 
  79. ↑ "Circulating Fibroblast Growth Factor 21 Is A Sensitive Biomarker for Severe Ischemia/reperfusion Injury in Patients with Liver Transplantation". Scientific Reports 6: 19776. January 2016. doi:10.1038/srep19776. PMID 26806156. Bibcode: 2016NatSR...619776Y. 
  80. ↑ "Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas". PLOS ONE 11 (2): e0148252. 2016. doi:10.1371/journal.pone.0148252. PMID 26872145. Bibcode: 2016PLoSO..1148252S. 
  81. ↑ "A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure". Cell Reports 23 (2): 327–336. April 2018. doi:10.1016/j.celrep.2018.03.070. PMID 29641994. 
  82. ↑ "Liver: FGF21 - the cause of having a 'sweet tooth'?". Nature Reviews. Endocrinology 13 (7): 378. July 2017. doi:10.1038/nrendo.2017.62. PMID 28497814. 
  83. ↑ "Neuroendocrinology: FGF21 influences a 'sweet tooth' in mice". Nature Reviews. Endocrinology 12 (3): 123. March 2016. doi:10.1038/nrendo.2016.8. PMID 26822924. 
  84. ↑ "Pharmacological efficacy of FGF21 analogue, liraglutide and insulin glargine in treatment of type 2 diabetes". Journal of Diabetes and Its Complications 31 (4): 726–734. April 2017. doi:10.1016/j.jdiacomp.2017.01.008. PMID 28143735. 
  85. ↑ "Long-lasting hypoglycemic effect of modified FGF-21 analog with polyethylene glycol in type 1 diabetic mice and its systematic toxicity". European Journal of Pharmacology 781: 198–208. June 2016. doi:10.1016/j.ejphar.2016.04.025. PMID 27089817. 
  86. ↑ 86.0 86.1 "Pegbelfermin (BMS-986036), PEGylated FGF21, in Patients with Obesity and Type 2 Diabetes: Results from a Randomized Phase 2 Study". Obesity 27 (1): 41–49. January 2019. doi:10.1002/oby.22344. PMID 30520566. 
  87. ↑ "FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties". Trends in Endocrinology and Metabolism 26 (11): 608–617. November 2015. doi:10.1016/j.tem.2015.09.007. PMID 26490383. 
  88. ↑ 88.0 88.1 "LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia". The Journal of Clinical Endocrinology and Metabolism 107 (1): e57–e70. January 2022. doi:10.1210/clinem/dgab624. PMID 34431493. 
  89. ↑ "FGF21 mediates the protective effect of fenofibrate against acetaminophen -induced hepatotoxicity via activating autophagy in mice". Biochemical and Biophysical Research Communications 503 (2): 474–481. September 2018. doi:10.1016/j.bbrc.2018.04.157. PMID 29730296. 
  90. ↑ "Fructose Protects Against Acetaminophen-Induced Hepatotoxicity Mainly by Activating the Carbohydrate-Response Element-Binding Protein α-Fibroblast Growth Factor 21 Axis in Mice". Hepatology Communications 5 (6): 992–1008. June 2021. doi:10.1002/hep4.1683. PMID 34141985. 
  91. ↑ "The fasting polypeptide FGF21 can enter brain from blood". Peptides 28 (12): 2382–2386. December 2007. doi:10.1016/j.peptides.2007.10.007. PMID 17996984. 
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  98. ↑ "FGF21 is an endocrine signal of protein restriction". The Journal of Clinical Investigation 124 (9): 3913–3922. September 2014. doi:10.1172/JCI74915. PMID 25133427. 
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  106. ↑ "A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats". Cellular Physiology and Biochemistry 43 (2): 644–659. 2017. doi:10.1159/000480649. PMID 28942443. 
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  115. ↑ "Fundamentals of FGF19 & FGF21 action in vitro and in vivo". PLOS ONE 7 (5): e38438. 2012. doi:10.1371/journal.pone.0038438. PMID 22675463. Bibcode: 2012PLoSO...738438A. 
  116. ↑ "The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes". Cell Metabolism 18 (3): 333–340. September 2013. doi:10.1016/j.cmet.2013.08.005. PMID 24011069. 
  117. ↑ "AKR-001, an Fc-FGF21 Analog, Showed Sustained Pharmacodynamic Effects on Insulin Sensitivity and Lipid Metabolism in Type 2 Diabetes Patients". Cell Reports. Medicine 1 (4): 100057. July 2020. doi:10.1016/j.xcrm.2020.100057. PMID 33205064. 

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