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Fibroblast growth factor 21 is a protein that in mammals is encoded by the FGF21 gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily which includes FGF23 and FGF15/19. FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho.
FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. FGFs act through a family of four FGF receptors. Binding is complicated and requires both interaction of the FGF molecule with an FGF receptor and binding to heparin through an heparin binding domain. Endocrine FGFs lack a heparin binding domain and thus can be released into the circulation.
FGF21 is a hepatokine – i.e., a hormone secreted by the liver – that 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.
A single-nucleotide polymorphism of the FGF21 gene – the FGF21 rs838133 variant – 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.
FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity. The oxidized form of ketone bodies (acetoacetate) in a cultured medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism. HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria.
While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas, circulating levels of FGF21 are derived specifically from the liver in mice. In liver FGF21 expression is regulated by PPARα and levels rise substantially with both fasting and consumption of ketogenic diets.
Liver X receptor (LXR) represses FGF21 in humans via an LXR response element located from -37 to -22 bp on the human FGF21 promoter.
FGF21 stimulates glucose uptake in adipocytes but not in other cell types. This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway. FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents. Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion.
Beta Klotho (KLB) functions as a cofactor essential for FGF21 activity.
In cows plasma FGF21 was nearly undetectable in late pregnancy (LP), peaked at parturition, and then stabilized at lower, chronically elevated concentrations during early lactation (EL). Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL. The liver was the major source of plasma FGF21 in early lactation with little or no contribution by WAT, skeletal muscle, and mammary gland. Meaningful expression of the FGF21 coreceptor β-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland. Expression of β-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT.
Serum FGF-21 levels were significantly increased in patients with type 2 diabetes mellitus (T2DM) which may indicate a role in the pathogenesis of T2DM. Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease and positively correlate with BMI in humans suggesting obesity as a FGF21-resistant state.
A single-nucleotide polymorphism (SNP) of the FGF21 gene – the FGF21 rs838133 variant – 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.
Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.
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.
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. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor, playing a key role in eliciting and coordinating the adaptive starvation response. FGF21 expression is also induced in white adipose tissue by PPAR-gamma, which may indicate it also regulates metabolism in the fed state. FGF21 is induced in both rodents and humans consuming a low protein diet. FGF21 expression is also induced by diets with reduced levels of the essential dietary amino acid methionine or with reduced levels of branched-chain amino acids.
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.
Acutely, the rise in FGF21 in response to alcohol consumption inhibits further drinking. Chronically, the rise in FGF21 expression in the liver may protect against liver damage.
- ↑ 1.0 1.1 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. 1492 (1): 203–6. doi:10.1016/S0167-4781(00)00067-1. PMID 10858549.
- ↑ 2.0 2.1 "Entrez Gene: FGF21 fibroblast growth factor 21".
- ↑ 3.0 3.1 BonDurant LD, Potthoff MJ (May 2018). "Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis". Annu Rev Nutr. doi:10.1146/annurev-nutr-071816-064800. PMID 29727594.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 7.0 7.1 Frayling TM, Beaumont RN, Jones SE, Yaghootkar H, Tuke MA, Ruth KS, Casanova F, West B, Locke J, Sharp S, Ji Y, Thompson W, Harrison J, Etheridge AS, Gallins PJ, Jima D, Wright F, Zhou Y, Innocenti F, Lindgren CM, Grarup N, Murray A, Freathy RM, Weedon MN, Tyrrell J, Wood AR (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. PMID 29641994. Lay summary – Neuroscience News (14 April 2018).
- ↑ 8.0 8.1 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.
- ↑ 9.0 9.1 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.
- ↑ 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): 20423–30. doi:10.1074/jbc.M111.235044. PMC 3121469. PMID 21502324.
- ↑ Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, Li Y, Bunkenborg J, Alt FW, Denu JM, Jacobson MP, Verdin E (December 2010). "SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production". Cell Metabolism. 12 (6): 654–61. doi:10.1016/j.cmet.2010.11.003. PMC 3310379. PMID 21109197.
- ↑ Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, Mohammadi M, Potthoff MJ (December 2014). "Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding". Diabetes. 63 (12): 4057–63. doi:10.2337/db14-0595. PMC 4238010. PMID 25008183.
- ↑ Uebanso T, Taketani Y, Yamamoto H, Amo K, Tanaka S, Arai H, Takei Y, Masuda M, Yamanaka-Okumura H, Takeda E (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): 785–90. doi:10.1016/j.jnutbio.2011.03.023. PMID 21889884.
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- ↑ Lees EK, Król E, Grant L, Shearer K, Wyse C, Moncur E, Bykowska AS, Mody N, Gettys TW, Delibegovic M (October 2014). "Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21". Aging Cell. 13 (5): 817–27. doi:10.1111/acel.12238. PMC 4331744. PMID 24935677.
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- Youm YH, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD (January 2016). "Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution". Proceedings of the National Academy of Sciences of the United States of America. 113 (4): 1026–31. Bibcode:2016PNAS..113.1026Y. doi:10.1073/pnas.1514511113. PMC 4743827. PMID 26755598.
- fibroblast+growth+factor+21 at the US National Library of Medicine Medical Subject Headings (MeSH)
- "FGF21". Information Hyperlinked over Proteins. ihop-net.org. Retrieved August 12, 2008.
- "FGF21". Gene Cards. Weizmann Institute of Science. Retrieved August 12, 2008.
- Got a sweet tooth? Blame your liver Phys.org, 2017
This article incorporates text from the United States National Library of Medicine, which is in the public domain.