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Fibroblast growth factor 21 is a hormonal protein that in humans is encoded by the FGF21 gene. This protein is a member of the fibroblast growth factor (FGF) family, and specifically a member of the endocrine subfamily, together with FGF19 (FGF15 in rodents) and FGF23.[1] FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho.[2] Loss of β-Klotho abolishes all effects of FGF21.[3]

FGF21 is a hepatokine – i.e., a hormone secreted by the liver – that, apart from regulating various aspects of glucose, lipid, and energy homeostasis, 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.[4][5][6]

Structure

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It is a single-chain protein typically containing 209 amino acid residues, which is encoded by the mammalian FGF21 gene.[7][8][9]

Function

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FGF21 is beneficially involved in the regulation of lipid, glucose, and energy metabolism.[10] 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.[11][12] 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).[10] In a similar vein, FGF21 promotes glucose uptake in fat ,[13] whereas in liver, it stimulates gluconeogenesis.[14]

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.[15] 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.[16] 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.[10]

FGF family

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Main article: 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.[8] 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.[8][17]

Production and regulation

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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),[18] and by PPAR-γ in the adipose tissue.[19] In Hep G2 cells, FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity.[20] The oxidized form of ketone bodies (acetoacetate) in the culture medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism.[20] HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria.[21]

While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas (where it favors digestive enzyme secretion),[22] circulating levels of FGF21 are derived specifically from the liver in mice.[11]

Skeletal muscle produces FGF21, its expression being regulated by a PI3-kinase/Akt1 signaling mechanism.[23] FGF21 release from the liver is enhanced during exercise, apparently accompanying increased lipolysis and ketogenesis in fat tissue,[24] together with increased hepatic glycogen degradation and enhanced glucose output from the liver.[25] The involvement of FGF21 in mediating thermogenic responses to cold-exposure has been the object of intense studies.[26][27] In general terms, production of FGF21 in non-liver tissues is believed to fulfill mostly autocrine or paracrine functions.[28]

At a systemic level, thyroid hormone can regulate adipose and hepatic FGF21 expression and serum levels in mice.[29] 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,[30] although the latter has been unconfirmed by others.[31] 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.[32] In elderly subjects with T2D resistance training has been reported to significantly lower circulating FGF-21.[33] 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.[34]

FGF21 receptor

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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.[35] 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.[36] FGF21 binds to FGFR through its amino terminus, and to β-klotho though its C-terminus.[37]

FGFRs

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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.[38][39]

β-Klotho

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β-Klotho is a single-pass transmembrane protein containing 1043 amino acid residues whose expression is induced in target cells upon their differentiation.[40] β-Klotho interacts closely with FGFR1c or FGFr4 receptor proteins to enhance their binding affinity for FGF21.[39] Loss of β-Klotho at the receptor site renders such receptors unresponsive to FGF21.[41]

Signalling

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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.[35][42] 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;[42] Other regulatory, intracellular signaling pathways affected by FGF21 in various contexts include cFOS,[14] the Hedgehog pathway,[43] Sirt1-dependent,[44] NF-κB dependent,[45] ATF4 dependent,[46] and BMP2-dependent[47] pathways, among others.

Effects in vitro

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Adipocytes

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FGF21 is one of the most potent insulin sensitizers known.[3] FGF21 stimulates glucose uptake in adipocytes but not in other cell types.[13] This effect is additive to the activity of insulin. FGF21 induces the insulin-sensitizing hormone adiponectin.[48] FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway.[49] FGF21 activates mitochondrial oxidative function in adipocytes by activating PGC-1α.[50][51]

Hepatocytes

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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.[14]

Effects in vivo

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Mice

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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.[13] Treatment of mice with FGF21 results in increased energy expenditure, fat utilization and lipid excretion.[52]

FGF21 enhances gluconeogenesis, fatty acid activation and ketogenesis in the mouse liver under various conditions.[14][53][50] FGF21 treatment improves sensitivity to insulin in normal and high-fat fed wild mice.[54] 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.[55] In the pancreas, FGF21 favors the formation of pancreatic juice through a β-klotho dependent mechanism.[22]

Other animals

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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.[56]

Non-human primates

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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.[57][58]

Clinical significance

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Serum FGF21 levels are significantly increased in obesity and in patients with type 2 diabetes mellitus (T2DM), presumably indicating a state of FGF21-resistance.[59][60]

Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease[61] 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.[62][10] Both high sugar and low protein diets can elevate FGF21 in animals and humans.[3][63] 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.[64]

FGF21 can inhibit mTORC1 in the liver and stimulate adiponectin secretion from fatty tissues, thereby inhibiting aging-associated metabolic syndrome.[50] FGF21 protects against diabetic cardiomyopathy primarily by PGC-1α-induction of beta oxidation.[19] The anti-inflammatory effects if FGF21 may primarily be due to inhibition of NF-κB in macrophages.[19] In mice, FGF21 has been shown to protect against high fat diet-induced inflammation and islet hyperplasia in the pancreas,[65] 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.[66][67][68][60]

From a pharmacological perspective, FGF21 analogs can effectively reduce hyperglycemia in diabetic rodents,[69][70] but not in clinical disease.[71] 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.[72][28] Given these properties, FGF21 and its analogs may prove particularly effective in the treatment of metabolic syndrome.[13][73]

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.[74][75][22] FGF21 appears capable of crossing the blood-brain barrier,[76] 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.[4][5][6][77]


Preclinical studies

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Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.[78]

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.[14]

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,[17] also for eliciting and coordinating the adaptive response to fasting and starvation.[78] FGF21 expression is also induced in white adipose tissue by PPAR-gamma, which may indicate it also regulates metabolism in the fed state.[79] FGF21 is induced in both rodents and humans consuming a low protein diet.[80][81] FGF21 expression is also induced by diets with reduced levels of the essential dietary amino acids methionine,[82][83] isoleucine,[84] or threonine,[85] or with reduced levels of branched-chain amino acids.[86] 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.[87]

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.[3]

In rats, steatosis induced by cafeteria diet was accompanied by high serum FGF21, whereas oral taurine supplementation prevented both steatosis and high FGF21 levels.[88]

Fructose ingestion also induced FGF21 in humans, where it causes a rise in FGF21 levels in serum;[32] likewise in mice, where serum FGF21 increases and induction of FGF21 in the liver can be confirmed.[89] A dramatic increase in circulating FGF21 in humans is induced by the consumption of alcohol.[90] Acutely, the rise in FGF21 in response to alcohol consumption inhibits further drinking.[91] Chronically, the rise in FGF21 expression in the liver may protect against liver damage.[2]

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.[51]

FGF21 mimetics

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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),[92][93][94] and Amgen (mimAb1).[95] 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).[96]

FGF21 antagonists

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At least two peptide compounds showing antagonist properties of FGF21 action have been described, their eventual clinical utility being uncertain.[97][98]

Clinical trials

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LY2405319 (Lilly)

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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).[99]

LLF580 (Novartis)

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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.[100]

AKR-001 (Akero)

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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.[101]

BMS-986036 (Bristol-Myers Squibb)

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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.[71]

PF-05231023 (Pfizer)

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xSubcutaneous 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.[71]

References

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  1. ^ Phan P, Saikia BB, Sonnaila S, Agrawal S, Alraawi Z, Kumar TK, Iyer S (September 2021). "The Saga of Endocrine FGFs". Cells. 10 (9): 2418. doi:10.3390/cells10092418. PMC 8465397. PMID 34572066.
  2. ^ a b BonDurant LD, Potthoff MJ (August 2018). "Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis". Annual Review of Nutrition. 38: 173–196. doi:10.1146/annurev-nutr-071816-064800. PMC 6964258. PMID 29727594.
  3. ^ a b c d Flippo KH, Potthoff MJ (March 2021). "Metabolic Messengers: FGF21". Nature Metabolism. 3 (3): 309–317. doi:10.1038/s42255-021-00354-2. PMC 8620721. PMID 33758421.
  4. ^ a b von Holstein-Rathlou S, BonDurant LD, Peltekian L, Naber MC, Yin TC, Claflin KE, Urizar AI, Madsen AN, Ratner C, Holst B, Karstoft K, Vandenbeuch A, Anderson CB, Cassell MD, Thompson AP, Solomon TP, Rahmouni K, Kinnamon SC, Pieper AA, Gillum MP, Potthoff MJ (February 2016). "FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver". Cell Metabolism. 23 (2): 335–43. doi:10.1016/j.cmet.2015.12.003. PMC 4756759. PMID 26724858.
  5. ^ a b Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA (February 2016). "FGF21 Regulates Sweet and Alcohol Preference". Cell Metabolism. 23 (2): 344–9. doi:10.1016/j.cmet.2015.12.008. PMC 4749404. PMID 26724861.
  6. ^ a b Søberg S, Sandholt CH, Jespersen NZ, Toft U, Madsen AL, von Holstein-Rathlou S, Grevengoed TJ, Christensen KB, Bredie WL, Potthoff MJ, Solomon TP, Scheele C, Linneberg A, Jørgensen T, Pedersen O, Hansen T, Gillum MP, Grarup N (May 2017). "FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans". Cell Metabolism. 25 (5): 1045–1053.e6. doi:10.1016/j.cmet.2017.04.009. PMID 28467924.
  7. ^ Nishimura T, Nakatake Y, Konishi M, Itoh N (June 2000). "Identification of a novel FGF, FGF-21, preferentially expressed in the liver". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1492 (1): 203–206. doi:10.1016/S0167-4781(00)00067-1. PMID 10858549.
  8. ^ a b c "Entrez Gene: FGF21 fibroblast growth factor 21".
  9. ^ "Fgf21 fibroblast growth factor 21 [Mus musculus (house mouse)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-07-15.
  10. ^ a b c d Spann RA, Morrison CD, den Hartigh LJ (2021). "The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model". Frontiers in Endocrinology. 12: 802541. doi:10.3389/fendo.2021.802541. PMC 8761941. PMID 35046901.
  11. ^ a b Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, et al. (December 2014). "Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding". Diabetes. 63 (12): 4057–4063. doi:10.2337/db14-0595. PMC 4238010. PMID 25008183.
  12. ^ Erickson A, Moreau R (June 2016). "The regulation of FGF21 gene expression by metabolic factors and nutrients". Hormone Molecular Biology and Clinical Investigation. 30 (1): /j/hmbci.2017.30.issue–1/hmbci–2016-0016/hmbci-2016-0016.xml. doi:10.1515/hmbci-2016-0016. PMID 27285327. S2CID 34750647.
  13. ^ a b c d Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. (June 2005). "FGF-21 as a novel metabolic regulator". The Journal of Clinical Investigation. 115 (6): 1627–1635. doi:10.1172/JCI23606. PMC 1088017. PMID 15902306.
  14. ^ a b c d e Fisher FM, Estall JL, Adams AC, Antonellis PJ, Bina HA, Flier JS, et al. (August 2011). "Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo". Endocrinology. 152 (8): 2996–3004. doi:10.1210/en.2011-0281. PMC 3138239. PMID 21712364.
  15. ^ Hill CM, Albarado DC, Coco LG, Spann RA, Khan MS, Qualls-Creekmore E, et al. (April 2022). "FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice". Nature Communications. 13 (1): 1897. Bibcode:2022NatCo..13.1897H. doi:10.1038/s41467-022-29499-8. PMC 8991228. PMID 35393401.
  16. ^ Hill CM, Laeger T, Dehner M, Albarado DC, Clarke B, Wanders D, et al. (June 2019). "FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism". Cell Reports. 27 (10): 2934–2947.e3. doi:10.1016/j.celrep.2019.05.022. PMC 6579533. PMID 31167139.
  17. ^ a b Murata Y, Konishi M, Itoh N (2011). "FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology". Journal of Nutrition and Metabolism. 2011: 981315. doi:10.1155/2011/981315. PMC 3038562. PMID 21331285.
  18. ^ Grabacka M, Pierzchalska M, Dean M, Reiss K (December 2016). "Regulation of Ketone Body Metabolism and the Role of PPARα". International Journal of Molecular Sciences. 17 (12): E2093. doi:10.3390/ijms17122093. PMC 5187893. PMID 27983603.
  19. ^ a b c Zhang Y, Liu D, Long XX, Fang QC, Jia WP, Li HT (December 2021). "The role of FGF21 in the pathogenesis of cardiovascular disease". Chinese Medical Journal. 134 (24): 2931–2943. doi:10.1097/CM9.0000000000001890. PMC 8710326. PMID 34939977.
  20. ^ a b Vilà-Brau A, De Sousa-Coelho AL, Mayordomo C, Haro D, Marrero PF (June 2011). "Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line". The Journal of Biological Chemistry. 286 (23): 20423–20430. doi:10.1074/jbc.M111.235044. PMC 3121469. PMID 21502324.
  21. ^ Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, et al. (December 2010). "SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production". Cell Metabolism. 12 (6): 654–661. doi:10.1016/j.cmet.2010.11.003. PMC 3310379. PMID 21109197.
  22. ^ a b c Coate KC, Hernandez G, Thorne CA, Sun S, Le TD, Vale K, et al. (February 2017). "FGF21 Is an Exocrine Pancreas Secretagogue". Cell Metabolism. 25 (2): 472–480. doi:10.1016/j.cmet.2016.12.004. PMC 5299054. PMID 28089565.
  23. ^ Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K (November 2008). "FGF21 is an Akt-regulated myokine". FEBS Letters. 582 (27): 3805–3810. doi:10.1016/j.febslet.2008.10.021. PMC 2604129. PMID 18948104.
  24. ^ Kim KH, Kim SH, Min YK, Yang HM, Lee JB, Lee MS (2013). "Acute exercise induces FGF21 expression in mice and in healthy humans". PLOS ONE. 8 (5): e63517. Bibcode:2013PLoSO...863517K. doi:10.1371/journal.pone.0063517. PMC 3646740. PMID 23667629.
  25. ^ Hansen JS, Clemmesen JO, Secher NH, Hoene M, Drescher A, Weigert C, et al. (August 2015). "Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans". Molecular Metabolism. 4 (8): 551–560. doi:10.1016/j.molmet.2015.06.001. PMC 4529499. PMID 26266087.
  26. ^ Lee P, Brychta RJ, Linderman J, Smith S, Chen KY, Celi FS (January 2013). "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. doi:10.1210/jc.2012-3107. PMC 3537100. PMID 23150685.
  27. ^ Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. (February 2012). "FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis". Genes & Development. 26 (3): 271–281. doi:10.1101/gad.177857.111. PMC 3278894. PMID 22302939.
  28. ^ a b Fisher FM, Maratos-Flier E (2016). "Understanding the Physiology of FGF21". Annual Review of Physiology. 78: 223–241. doi:10.1146/annurev-physiol-021115-105339. PMID 26654352.
  29. ^ Domouzoglou EM, Fisher FM, Astapova I, Fox EC, Kharitonenkov A, Flier JS, et al. (May 2014). "Fibroblast growth factor 21 and thyroid hormone show mutual regulatory dependency but have independent actions in vivo". Endocrinology. 155 (5): 2031–2040. doi:10.1210/en.2013-1902. PMC 3990851. PMID 24564398.
  30. ^ Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, et al. (August 2010). "Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease". Gastroenterology. 139 (2): 456–463. doi:10.1053/j.gastro.2010.04.054. PMC 4862867. PMID 20451522.
  31. ^ Willis SA, Sargeant JA, Yates T, Takamura T, Takayama H, Gupta V, et al. (May 2020). "Acute Hyperenergetic, High-Fat Feeding Increases Circulating FGF21, LECT2, and Fetuin-A in Healthy Men". The Journal of Nutrition. 150 (5): 1076–1085. doi:10.1093/jn/nxz333. PMID 31919514.
  32. ^ a b Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E (January 2015). "Fructose ingestion acutely stimulates circulating FGF21 levels in humans". Molecular Metabolism. 4 (1): 51–57. doi:10.1016/j.molmet.2014.09.008. PMC 4314524. PMID 25685689.
  33. ^ Shabkhiz F, Khalafi M, Rosenkranz S, Karimi P, Moghadami K (April 2021). "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. doi:10.1080/17461391.2020.1762755. PMID 32345132. S2CID 216645518.
  34. ^ Uebanso T, Taketani Y, Yamamoto H, Amo K, Tanaka S, Arai H, et al. (July 2012). "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. doi:10.1016/j.jnutbio.2011.03.023. PMID 21889884.
  35. ^ a b Kilkenny DM, Rocheleau JV (2016). "The FGF21 Receptor Signaling Complex: Klothoβ, FGFR1c, and Other Regulatory Interactions". Vitamins and Hormones. 101: 17–58. doi:10.1016/bs.vh.2016.02.008. PMID 27125737.
  36. ^ Kuro-O M (January 2019). "The Klotho proteins in health and disease". Nature Reviews. Nephrology. 15 (1): 27–44. doi:10.1038/s41581-018-0078-3. PMID 30455427. S2CID 53872296.
  37. ^ Micanovic R, Raches DW, Dunbar JD, Driver DA, Bina HA, Dickinson CD, Kharitonenkov A (May 2009). "Different roles of N- and C- termini in the functional activity of FGF21". Journal of Cellular Physiology. 219 (2): 227–234. doi:10.1002/jcp.21675. PMID 19117008. S2CID 8351143.
  38. ^ Kaur N, Gare SR, Shen J, Raja R, Fonseka O, Liu W (2022). "Multi-organ FGF21-FGFR1 signaling in metabolic health and disease". Frontiers in Cardiovascular Medicine. 9: 962561. doi:10.3389/fcvm.2022.962561. PMC 9378980. PMID 35983184.
  39. ^ a b Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, et al. (September 2007). "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. doi:10.1074/jbc.M704165200. PMC 2496965. PMID 17623664.
  40. ^ Chihara Y, Rakugi H, Ishikawa K, Ikushima M, Maekawa Y, Ohta J, et al. (August 2006). "Klotho protein promotes adipocyte differentiation". Endocrinology. 147 (8): 3835–3842. doi:10.1210/en.2005-1529. PMID 16709611.
  41. ^ Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, et al. (May 2007). "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. Bibcode:2007PNAS..104.7432O. doi:10.1073/pnas.0701600104. PMC 1855074. PMID 17452648.
  42. ^ a b Gao HM, Wang WF, Zhang Q, Han Y, Wang Q, Ren GP, et al. (August 2011). "[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. PMID 22007513.
  43. ^ Ott F, Körner C, Werner K, Gericke M, Liebscher I, Lobsien D, et al. (May 2022). "Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21". Cells. 11 (10): 1680. doi:10.3390/cells11101680. PMC 9139566. PMID 35626717.
  44. ^ Lu H, Jia C, Wu D, Jin H, Lin Z, Pan J, et al. (September 2021). "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. doi:10.1038/s41419-021-04157-x. PMC 8460788. PMID 34556628.
  45. ^ Yu Y, He J, Li S, Song L, Guo X, Yao W, et al. (September 2016). "Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway". International Immunopharmacology. 38: 144–152. doi:10.1016/j.intimp.2016.05.026. PMID 27276443.
  46. ^ Joe Y, Kim S, Kim HJ, Park J, Chen Y, Park HJ, et al. (May 2018). "FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway". FASEB Journal. 32 (5): 2630–2643. doi:10.1096/fj.201700709RR. PMC 5901375. PMID 29295856.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  47. ^ Ishida K, Haudenschild DR (March 2013). "Interactions between FGF21 and BMP-2 in osteogenesis". Biochemical and Biophysical Research Communications. 432 (4): 677–682. doi:10.1016/j.bbrc.2013.02.019. PMID 23416071.
  48. ^ Nakamura MT, Yudell BE, Loor JJ (January 2014). "Regulation of energy metabolism by long-chain fatty acids". Progress in Lipid Research. 53: 124–144. doi:10.1016/j.plipres.2013.12.001. PMID 24362249.
  49. ^ Moyers JS, Shiyanova TL, Mehrbod F, Dunbar JD, Noblitt TW, Otto KA, et al. (January 2007). "Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling". Journal of Cellular Physiology. 210 (1): 1–6. doi:10.1002/jcp.20847. PMID 17063460. S2CID 42083889.
  50. ^ a b c Yan J, Nie Y, Cao J, Luo M, Yan M, Chen Z, He B (2021). "The Roles and Pharmacological Effects of FGF21 in Preventing Aging-Associated Metabolic Diseases". Frontiers in Cardiovascular Medicine. 8: 655575. doi:10.3389/fcvm.2021.655575. PMC 8044345. PMID 33869312.
  51. ^ a b Chau MD, Gao J, Yang Q, Wu Z, Gromada J (July 2010). "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. Bibcode:2010PNAS..10712553C. doi:10.1073/pnas.1006962107. PMC 2906565. PMID 20616029.
  52. ^ Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A (December 2008). "Fibroblast growth factor 21 corrects obesity in mice". Endocrinology. 149 (12): 6018–27. doi:10.1210/en.2008-0816. PMID 18687777.
  53. ^ Domouzoglou EM, Maratos-Flier E (April 2011). "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. doi:10.3945/ajcn.110.001941. PMC 3057552. PMID 21346090.
  54. ^ Camporez JP, Jornayvaz FR, Petersen MC, Pesta D, Guigni BA, Serr J, et al. (September 2013). "Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice". Endocrinology. 154 (9): 3099–3109. doi:10.1210/en.2013-1191. PMC 3749479. PMID 23766126.
  55. ^ Chen W, Hoo RL, Konishi M, Itoh N, Lee PC, Ye HY, et al. (October 2011). "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. doi:10.1074/jbc.M111.285965. PMC 3186378. PMID 21849508.
  56. ^ Schoenberg KM, Giesy SL, Harvatine KJ, Waldron MR, Cheng C, Kharitonenkov A, Boisclair YR (December 2011). "Plasma FGF21 is elevated by the intense lipid mobilization of lactation". Endocrinology. 152 (12): 4652–61. doi:10.1210/en.2011-1425. PMID 21990311.
  57. ^ Thompson WC, Zhou Y, Talukdar S, Musante CJ (August 2016). "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. doi:10.1007/s10928-016-9481-1. PMC 4954843. PMID 27405817.
  58. ^ Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, et al. (March 2016). "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. doi:10.1016/j.cmet.2016.02.001. PMID 26959184.
  59. ^ Cheng X, Zhu B, Jiang F, Fan H (2011). "Serum FGF-21 levels in type 2 diabetic patients". Endocrine Research. 36 (4): 142–8. doi:10.3109/07435800.2011.558550. PMID 21973233. S2CID 24454698.
  60. ^ a b Xie T, Leung PS (2017). "Fibroblast growth factor 21: a regulator of metabolic disease and health span". American Journal of Physiology. Endocrinology and Metabolism. 313 (3): E292–E302. doi:10.1152/ajpendo.00101.2017. PMC 5625087. PMID 28559437.
  61. ^ Yan H, Xia M, Chang X, Xu Q, Bian H, Zeng M, et al. (2011). "Circulating fibroblast growth factor 21 levels are closely associated with hepatic fat content: a cross-sectional study". PLOS ONE. 6 (9): e24895. Bibcode:2011PLoSO...624895Y. doi:10.1371/journal.pone.0024895. PMC 3174975. PMID 21949781.
  62. ^ Kralisch S, Fasshauer M (July 2011). "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. doi:10.1097/MCO.0b013e328346a326. PMID 21505329. S2CID 45095074.
  63. ^ Hill CM, Berthoud HR, Münzberg H, Morrison CD (October 2018). "Homeostatic sensing of dietary protein restriction: A case for FGF21". Frontiers in Neuroendocrinology. 51: 125–131. doi:10.1016/j.yfrne.2018.06.002. PMC 6175661. PMID 29890191.
  64. ^ Ye D, Li H, Wang Y, Jia W, Zhou J, Fan J, et al. (January 2016). "Circulating Fibroblast Growth Factor 21 Is A Sensitive Biomarker for Severe Ischemia/reperfusion Injury in Patients with Liver Transplantation". Scientific Reports. 6: 19776. Bibcode:2016NatSR...619776Y. doi:10.1038/srep19776. PMC 4726235. PMID 26806156.
  65. ^ Singhal G, Fisher FM, Chee MJ, Tan TG, El Ouaamari A, Adams AC, et al. (2016). "Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas". PLOS ONE. 11 (2): e0148252. Bibcode:2016PLoSO..1148252S. doi:10.1371/journal.pone.0148252. PMC 4752212. PMID 26872145.
  66. ^ Frayling TM, Beaumont RN, Jones SE, Yaghootkar H, Tuke MA, Ruth KS, et al. (April 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 Reports. 23 (2): 327–336. doi:10.1016/j.celrep.2018.03.070. PMC 5912948. PMID 29641994.
  67. ^ Greenhill C (July 2017). "Liver: FGF21 - the cause of having a 'sweet tooth'?". Nature Reviews. Endocrinology. 13 (7): 378. doi:10.1038/nrendo.2017.62. PMID 28497814. S2CID 3906326.
  68. ^ Geach T (March 2016). "Neuroendocrinology: FGF21 influences a 'sweet tooth' in mice". Nature Reviews. Endocrinology. 12 (3): 123. doi:10.1038/nrendo.2016.8. PMID 26822924. S2CID 8239766.
  69. ^ Ye X, Qi J, Yu D, Wu Y, Zhu S, Li S, et al. (April 2017). "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. doi:10.1016/j.jdiacomp.2017.01.008. PMID 28143735.
  70. ^ Ye X, Qi J, Wu Q, Yu D, Li S, Wu Y, Li D (June 2016). "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. doi:10.1016/j.ejphar.2016.04.025. PMID 27089817.
  71. ^ a b c Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS, Christian R (January 2019). "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. doi:10.1002/oby.22344. PMC 6587787. PMID 30520566.
  72. ^ Kharitonenkov A, DiMarchi R (November 2015). "FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties". Trends in Endocrinology and Metabolism. 26 (11): 608–617. doi:10.1016/j.tem.2015.09.007. PMID 26490383. S2CID 3696213.
  73. ^ Rader DJ, Maratos-Flier E, Nguyen A, Hom D, Ferriere M, Li Y, et al. (January 2022). "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. doi:10.1210/clinem/dgab624. PMC 8914500. PMID 34431493.
  74. ^ Zhang Y, Pan Y, Xiong R, Zheng J, Li Q, Zhang S, et al. (September 2018). "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. doi:10.1016/j.bbrc.2018.04.157. PMID 29730296. S2CID 19263334.
  75. ^ Zhang D, Wang S, Ospina E, Shabandri O, Lank D, Akakpo JY, et al. (June 2021). "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. doi:10.1002/hep4.1683. PMC 8183176. PMID 34141985.
  76. ^ Hsuchou H, Pan W, Kastin AJ (December 2007). "The fasting polypeptide FGF21 can enter brain from blood". Peptides. 28 (12): 2382–2386. doi:10.1016/j.peptides.2007.10.007. PMC 2151924. PMID 17996984.
  77. ^ Søberg S, Sandholt CH, Jespersen NZ, Toft U, Madsen AL, von Holstein-Rathlou S, et al. (May 2017). "FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans". Cell Metabolism. 25 (5): 1045–1053.e6. doi:10.1016/j.cmet.2017.04.009. PMID 28467924.
  78. ^ a b Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, et al. (June 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 United States of America. 106 (26): 10853–10858. Bibcode:2009PNAS..10610853P. doi:10.1073/pnas.0904187106. PMC 2705613. PMID 19541642.
  79. ^ Kliewer SA, Mangelsdorf DJ (January 2010). "Fibroblast growth factor 21: from pharmacology to physiology". The American Journal of Clinical Nutrition. 91 (1): 254S–257S. doi:10.3945/ajcn.2009.28449B. PMC 2793111. PMID 19906798.
  80. ^ Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, et al. (September 2014). "FGF21 is an endocrine signal of protein restriction". The Journal of Clinical Investigation. 124 (9): 3913–3922. doi:10.1172/JCI74915. PMC 4153701. PMID 25133427.
  81. ^ Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, et al. (July 2016). "Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health". Cell Reports. 16 (2): 520–530. doi:10.1016/j.celrep.2016.05.092. PMC 4947548. PMID 27346343.
  82. ^ Lees EK, Król E, Grant L, Shearer K, Wyse C, Moncur E, et al. (October 2014). "Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21". Aging Cell. 13 (5): 817–827. doi:10.1111/acel.12238. PMC 4331744. PMID 24935677.
  83. ^ Yu D, Yang SE, Miller BR, Wisinski JA, Sherman DS, Brinkman JA, et al. (June 2018). "Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms". FASEB Journal. 32 (6): 3471–3482. doi:10.1096/fj.201701211R. PMC 5956241. PMID 29401631.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  84. ^ Yu D, Richardson NE, Green CL, Spicer AB, Murphy ME, Flores V, et al. (May 2021). "The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine". Cell Metabolism. 33 (5): 905–922.e6. doi:10.1016/j.cmet.2021.03.025. PMC 8102360. PMID 33887198.
  85. ^ Yap YW, Rusu PM, Chan AY, Fam BC, Jungmann A, Solon-Biet SM, et al. (June 2020). "Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution". Nature Communications. 11 (1): 2894. Bibcode:2020NatCo..11.2894Y. doi:10.1038/s41467-020-16568-z. PMC 7283339. PMID 32518324.
  86. ^ Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, et al. (February 2018). "Restoration of metabolic health by decreased consumption of branched-chain amino acids". The Journal of Physiology. 596 (4): 623–645. doi:10.1113/JP275075. PMC 5813603. PMID 29266268.
  87. ^ Fang H, Stone KP, Forney LA, Wanders D, Gettys TW (2021). "Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine". Frontiers in Endocrinology. 12: 773975. doi:10.3389/fendo.2021.773975. PMC 8669746. PMID 34917032.
  88. ^ Abd Elwahab AH, Ramadan BK, Schaalan MF, Tolba AM (2017). "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. doi:10.1159/000480649. PMID 28942443. S2CID 30807960.
  89. ^ Fisher FM, Kim M, Doridot L, Cunniff JC, Parker TS, Levine DM, et al. (January 2017). "A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism". Molecular Metabolism. 6 (1): 14–21. doi:10.1016/j.molmet.2016.11.008. PMC 5220398. PMID 28123933.
  90. ^ Desai BN, Singhal G, Watanabe M, Stevanovic D, Lundasen T, Fisher FM, et al. (November 2017). "Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury". Molecular Metabolism. 6 (11): 1395–1406. doi:10.1016/j.molmet.2017.08.004. PMC 5681240. PMID 29107287.
  91. ^ Flippo KH, Trammell SA, Gillum MP, Aklan I, Perez MB, Yavuz Y, et al. (February 2022). "FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit". Cell Metabolism. 34 (2): 317–328.e6. doi:10.1016/j.cmet.2021.12.024. PMC 9093612. PMID 35108517.{{cite journal}}: CS1 maint: PMC embargo expired (link)
  92. ^ Kolumam G, Chen MZ, Tong R, Zavala-Solorio J, Kates L, van Bruggen N, et al. (July 2015). "Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex". EBioMedicine. 2 (7): 730–743. doi:10.1016/j.ebiom.2015.05.028. PMC 4534681. PMID 26288846.
  93. ^ Rajan S, Mandikian D, Baruch A, Gelzleichter TR, Stevens D, Sonoda J, et al. (2017). "Preclinical pharmacokinetic characterization of an adipose tissue-targeting monoclonal antibody in obese and non-obese animals". mAbs. 9 (8): 1379–1388. doi:10.1080/19420862.2017.1373923. PMC 5680808. PMID 28895785.
  94. ^ Chen MZ, Chang JC, Zavala-Solorio J, Kates L, Thai M, Ogasawara A, et al. (November 2017). "FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes". Molecular Metabolism. 6 (11): 1454–1467. doi:10.1016/j.molmet.2017.09.003. PMC 5681280. PMID 29107292.
  95. ^ Foltz IN, Hu S, King C, Wu X, Yang C, Wang W, et al. (November 2012). "Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex". Science Translational Medicine. 4 (162): 162ra153. doi:10.1126/scitranslmed.3004690. PMID 23197570. S2CID 206680935.
  96. ^ Talukdar S, Kharitonenkov A (April 2021). "FGF19 and FGF21: In NASH we trust". Molecular Metabolism. 46: 101152. doi:10.1016/j.molmet.2020.101152. PMC 8085573. PMID 33383173.
  97. ^ Pan J, Parlee SD, Brunel FM, Li P, Lu W, Perez-Tilve D, et al. (October 2020). "Optimization of Peptide Inhibitors of β-Klotho as Antagonists of Fibroblast Growth Factors 19 and 21". ACS Pharmacology & Translational Science. 3 (5): 978–986. doi:10.1021/acsptsci.0c00100. PMC 7551714. PMID 33073195.
  98. ^ Adams AC, Coskun T, Rovira AR, Schneider MA, Raches DW, Micanovic R, et al. (2012). "Fundamentals of FGF19 & FGF21 action in vitro and in vivo". PloS One. 7 (5): e38438. doi:10.1371/journal.pone.0038438. PMC 3365001. PMID 22675463.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  99. ^ Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al. (September 2013). "The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes". Cell Metabolism. 18 (3): 333–340. doi:10.1016/j.cmet.2013.08.005. PMID 24011069.
  100. ^ Rader DJ, Maratos-Flier E, Nguyen A, Hom D, Ferriere M, Li Y, et al. (January 2022). "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. doi:10.1210/clinem/dgab624. PMC 8914500. PMID 34431493.
  101. ^ Kaufman A, Abuqayyas L, Denney WS, Tillman EJ, Rolph T (July 2020). "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. doi:10.1016/j.xcrm.2020.100057. PMC 7659583. PMID 33205064.
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