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The FGF metabolic axis

  • Xiaokun LiEmail author
Open Access
Review
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Abstract

Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term “FGF Metabolic Axis,” which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.

Keywords

FGF19 FGF21 FGF23 FGFR metabolism endocrine Klotho 

Notes

Acknowledgements

I would like to acknowledge the long-term contributions of many members of my Wenzhou FGF team to the FGF field research as I cited in the text that made the idea of “The FGF Metabolic Axis” possible. I thank Dr. Yongde Luo for the expert assistance on the conceptual and practical aspects of the manuscript and Dr. Jin-San Zhang and Dr. Jian Xiao for their assistance. I apologize to those whose works have not been cited here due to the limited discussion scope on this evolving field. This work is supported by the National Key R&D Program of China (No. 2017YFA0506000, Xiaokun Li).

References

  1. 1.
    Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 2009; 8(3): 235–253CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Luo Y, Ye S, Li X, Lu W. Emerging structure-function paradigm of endocrine FGFs in metabolic diseases. Trends Pharmacol Sci 2019; 40(2): 142–153CrossRefPubMedGoogle Scholar
  3. 3.
    Li X, Wang C, Xiao J, McKeehan WL, Wang F. Fibroblast growth factors, old kids on the new block. Semin Cell Dev Biol 2016; 53: 155–167CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Eriksson AE, Cousens LS, Weaver LH, Matthews BW. Three-dimensional structure of human basic fibroblast growth factor. Proc Natl Acad Sci USA 1991; 88(8): 3441–3445CrossRefPubMedGoogle Scholar
  5. 5.
    Chen G, Liu Y, Goetz R, Fu L, Jayaraman S, Hu MC, Moe OW, Liang G, Li X, Mohammadi M. αKlotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 2018; 553(7689): 461–466CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Degirolamo C, Sabbà C, Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 2016; 15(1): 51–69CrossRefPubMedGoogle Scholar
  7. 7.
    Luo Y, Ye S, Chen X, Gong F, Lu W, Li X. Rush to the fire: FGF21 extinguishes metabolic stress, metaflammation and tissue damage. Cytokine Growth Factor Rev 2017; 38: 59–65CrossRefPubMedGoogle Scholar
  8. 8.
    McKeehan WL, Wang F, Kan M. The heparan sulfate-fibroblast growth factor family: diversity of structure and function. Prog Nucleic Acid Res Mol Biol 1998; 59: 135–176CrossRefPubMedGoogle Scholar
  9. 9.
    Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20(11): 563–569CrossRefPubMedGoogle Scholar
  10. 10.
    Itoh N, Ornitz DM. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem 2011; 149(2): 121–130CrossRefPubMedGoogle Scholar
  11. 11.
    Luo Y, Lu W, Li X. Unraveling endocrine FGF signaling complex to combat metabolic diseases. Trends Biochem Sci 2018; 43(8): 563–566CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 2006; 281(23): 15694–15700CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Armelin HA. Pituitary extracts and steroid hormones in the control of 3T3 cell growth. Proc Natl Acad Sci USA 1973; 70(9): 2702–2706CrossRefPubMedGoogle Scholar
  14. 14.
    Gospodarowicz D. Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 1974; 249(453): 123–127CrossRefPubMedGoogle Scholar
  15. 15.
    Burgess WH, Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 1989; 58(1): 575–606CrossRefPubMedGoogle Scholar
  16. 16.
    Luo Y, Ye S, Kan M, McKeehan WL. Control of fibroblast growth factor (FGF) 7- and FGF1-induced mitogenesis and downstream signaling by distinct heparin octasaccharide motifs. J Biol Chem 2006; 281(30): 21052–21061CrossRefPubMedGoogle Scholar
  17. 17.
    Gospodarowicz D, Ill CR, Hornsby PJ, Gill GN. Control of bovine adrenal cortical cell proliferation by fibroblast growth factor. Lack of effect of epidermal growth factor. Endocrinology 1977; 100(4): 1080–1089CrossRefPubMedGoogle Scholar
  18. 18.
    Mansour SL, Goddard JM, Capecchi MR. Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. Development 1993; 117(1): 13–28PubMedGoogle Scholar
  19. 19.
    Guo C, Sun Y, Zhou B, Adam RM, Li X, Pu WT, Morrow BE, Moon A, Li X. A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. J Clin Invest 2011; 121(4): 1585–1595CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ornitz DM, Marie PJ. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev 2015; 29(14): 1463–1486CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kan M, Wang F, Xu J, Crabb JW, Hou J, McKeehan WL. An essential heparin-binding domain in the fibroblast growth factor receptor kinase. Science 1993; 259(5103): 1918–1921CrossRefPubMedGoogle Scholar
  22. 22.
    Ye S, Luo Y, Lu W, Jones RB, Linhardt RJ, Capila I, Toida T, Kan M, Pelletier H, McKeehan WL. Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs. Biochemistry 2001; 40(48): 14429–14439CrossRefPubMedGoogle Scholar
  23. 23.
    Goetz R, Mohammadi M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol 2013; 14(3): 166–180CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 1997; 89(5): 693–702CrossRefPubMedGoogle Scholar
  25. 25.
    Huang Z, Marsiglia WM, Basu Roy U, Rahimi N, Ilghari D, Wang H, Chen H, Gai W, Blais S, Neubert TA, Mansukhani A, Traaseth NJ, Li X, Mohammadi M. Two FGF receptor kinase molecules act in concert to recruit and transphosphorylate phospholipase Cγ. Mol Cell 2016; 61(1): 98–110CrossRefPubMedGoogle Scholar
  26. 26.
    Dorey K, Amaya E. FGF signalling: diverse roles during early vertebrate embryogenesis. Development 2010; 137(22): 3731–3742CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lu W, Luo Y, Kan M, McKeehan WL. Fibroblast growth factor-10. A second candidate stromal to epithelial cell andromedin in prostate. J Biol Chem 1999; 274(18): 12827–12834CrossRefPubMedGoogle Scholar
  28. 28.
    Jin C, Wang F, Wu X, Yu C, Luo Y, McKeehan WL. Directionally specific paracrine communication mediated by epithelial FGF9 to stromal FGFR3 in two-compartment premalignant prostate tumors. Cancer Res 2004; 64(13): 4555–4562CrossRefPubMedGoogle Scholar
  29. 29.
    Carter EP, Fearon AE, Grose RP. Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction. Trends Cell Biol 2015; 25(4): 221–233CrossRefPubMedGoogle Scholar
  30. 30.
    Goldberg JD, Zheng J, Castro-Malaspina H, Jakubowski AA, Heller G, van den Brink MR, Perales MA. Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants. Bone Marrow Transplant 2013; 48(1): 99–104CrossRefPubMedGoogle Scholar
  31. 31.
    Uchi H, Igarashi A, Urabe K, Koga T, Nakayama J, Kawamori R, Tamaki K, Hirakata H, Ohura T, Furue M. Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol 2009; 19(5): 461–468PubMedGoogle Scholar
  32. 32.
    Akita S, Akino K, Imaizumi T, Hirano A. Basic fibroblast growth factor accelerates and improves second-degree burn wound healing. Wound Repair Regen 2008; 16(5): 635–641CrossRefPubMedGoogle Scholar
  33. 33.
    Fu X, Shen Z, Chen Y, Xie J, Guo Z, Zhang M, Sheng Z. Randomised placebo-controlled trial of use of topical recombinant bovine basic fibroblast growth factor for second-degree burns. Lancet 1998; 352(9141): 1661–1664CrossRefPubMedGoogle Scholar
  34. 34.
    Maddaluno L, Urwyler C, Werner S. Fibroblast growth factors: key players in regeneration and tissue repair. Development 2017; 144(22): 4047–4060CrossRefPubMedGoogle Scholar
  35. 35.
    Zhao YZ, Zhang M, Wong HL, Tian XQ, Zheng L, Yu XC, Tian FR, Mao KL, Fan ZL, Chen PP, Li XK, Lu CT. Prevent diabetic cardiomyopathy in diabetic rats by combined therapy of aFGFloaded nanoparticles and ultrasound-targeted microbubble destruction technique. J Control Release 2016; 223: 11–21CrossRefPubMedGoogle Scholar
  36. 36.
    Liang G, Song L, Chen Z, Qian Y, Xie J, Zhao L, Lin Q, Zhu G, Tan Y, Li X, Mohammadi M, Huang Z. Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism. Kidney Int 2018; 93(1): 95–109CrossRefPubMedGoogle Scholar
  37. 37.
    Li R, Li Y,Wu Y, Zhao Y, Chen H, Yuan Y, Xu K, Zhang H, Lu Y, Wang J, Li X, Jia X, Xiao J. Heparin-poloxamer thermosensitive hydrogel loaded with bFGF and NGF enhances peripheral nerve regeneration in diabetic rats. Biomaterials 2018; 168: 24–37CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wu J, Zhu J, He C, Xiao Z, Ye J, Li Y, Chen A, Zhang H, Li X, Lin L, Zhao Y, Zheng J, Xiao J. Comparative study of heparinpoloxamer hydrogel modified bFGF and aFGF for in vivo wound healing efficiency. ACS Appl Mater Interfaces 2016; 8(29): 18710–18721CrossRefPubMedGoogle Scholar
  39. 39.
    Wu J, Ye J, Zhu J, Xiao Z, He C, Shi H, Wang Y, Lin C, Zhang H, Zhao Y, Fu X, Chen H, Li X, Li L, Zheng J, Xiao J. Heparin-based coacervate of FGF2 improves dermal regeneration by asserting a synergistic role with cell proliferation and endogenous facilitated VEGF for cutaneous wound healing. Biomacromolecules 2016; 17(6): 2168–2177CrossRefPubMedGoogle Scholar
  40. 40.
    Wang Q, He Y, Zhao Y, Xie H, Lin Q, He Z, Wang X, Li J, Zhang H, Wang C, Gong F, Li X, Xu H, Ye Q, Xiao J. A thermosensitive heparin-poloxamer hydrogel bridges aFGF to treat spinal cord injury. ACS Appl Mater Interfaces 2017; 9(8): 6725–6745CrossRefPubMedGoogle Scholar
  41. 41.
    Katoh M. Therapeutics targeting FGF signaling network in human diseases. Trends Pharmacol Sci 2016; 37(12): 1081–1096CrossRefPubMedGoogle Scholar
  42. 42.
    Liang G, Liu Z,Wu J, Cai Y, Li X. Anticancer molecules targeting fibroblast growth factor receptors. Trends Pharmacol Sci 2012; 33(10): 531–541CrossRefPubMedGoogle Scholar
  43. 43.
    Cuevas P, Carceller F, Ortega S, Zazo M, Nieto I, Giménez-Gallego G. Hypotensive activity of fibroblast growth factor. Science 1991; 254(5035): 1208–1210CrossRefPubMedGoogle Scholar
  44. 44.
    Konishi M, Mikami T, Yamasaki M, Miyake A, Itoh N. Fibroblast growth factor-16 is a growth factor for embryonic brown adipocytes. J Biol Chem 2000; 275(16): 12119–12122CrossRefPubMedGoogle Scholar
  45. 45.
    Rulifson IC, Collins P, Miao L, Nojima D, Lee KJ, Hardy M, Gupte J, Hensley K, Samayoa K, Cam C, Rottman JB, Ollmann M, Richards WG, Li Y. In vitro and in vivo analyses reveal profound effects of fibroblast growth factor 16 as a metabolic regulator. J Biol Chem 2017; 292(5): 1951–1969CrossRefPubMedGoogle Scholar
  46. 46.
    Jonker JW, Suh JM, Atkins AR, Ahmadian M, Li P, Whyte J, He M, Juguilon H, Yin YQ, Phillips CT, Yu RT, Olefsky JM, Henry RR, Downes M, Evans RMA. A PPARg-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 2012; 485(7398): 391–394CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Huang Z, Tan Y, Gu J, Liu Y, Song L, Niu J, Zhao L, Srinivasan L, Lin Q, Deng J, Li Y, Conklin DJ, Neubert TA, Cai L, Li X, Mohammadi M. Uncoupling the mitogenic and metabolic functions of FGF1 by tuning FGF1-FGF receptor dimer stability. Cell Reports 2017; 20(7): 1717–1728CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007; 5(6): 426–437CrossRefPubMedGoogle Scholar
  49. 49.
    Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2(4): 217–225CrossRefPubMedGoogle Scholar
  50. 50.
    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5(6): 415–425CrossRefPubMedGoogle Scholar
  51. 51.
    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115(6): 1627–1635CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Goetz R, Ohnishi M, Ding X, Kurosu H, Wang L, Akiyoshi J, Ma J, Gai W, Sidis Y, Pitteloud N, Kuro OM, Razzaque MS, Mohammadi M. Klotho co-receptors inhibit signaling by paracrine FGF8 subfamily ligands. Mol Cell Biol 32(10):1944–1954Google Scholar
  53. 53.
    Luo Y, Yang C, Lu W, Xie R, Jin C, Huang P,Wang F, McKeehan WL. Metabolic regulator βKlotho interacts with fibroblast growth factor receptor 4 (FGFR4) to induce apoptosis and inhibit tumor cell proliferation. J Biol Chem 2010; 285(39): 30069–30078CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Itoh M, Nacher JC, Kuma K, Goto S, Kanehisa M. Evolutionary history and functional implications of protein domains and their combinations in eukaryotes. Genome Biol 2007; 8(6): R121CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282(37): 26687–26695CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, Goetz R, Mohammadi M, Kuro-o M, Mangelsdorf DJ, Kliewer SA. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010; 24(10): 2050–2064CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor γ regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol 2008; 28(1): 188–200CrossRefPubMedGoogle Scholar
  58. 58.
    Iizuka K, Takeda J, Horikawa Y. Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes. FEBS Lett 2009; 583(17): 2882–2886CrossRefPubMedGoogle Scholar
  59. 59.
    Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor α. J Biol Chem 2010; 285(21): 15668–15673CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Uebanso T, Taketani Y, Yamamoto H, Amo K, Tanaka S, Arai H, Takei Y, Masuda M, Yamanaka-Okumura H, Takeda E. Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet. J Nutr Biochem 2012; 23(7): 785–790CrossRefPubMedGoogle Scholar
  61. 61.
    Masuyama R, Stockmans I, Torrekens S, Van Looveren R, Maes C, Carmeliet P, Bouillon R, Carmeliet G. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest 2006; 116(12): 3150–3159CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK. 1α,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 2005; 289(6): G1036–G1042CrossRefPubMedGoogle Scholar
  63. 63.
    Zhang Y, Lei T, Huang JF, Wang SB, Zhou LL, Yang ZQ, Chen XD. The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes. Mol Cell Endocrinol 2011; 342(1-2): 41–47CrossRefPubMedGoogle Scholar
  64. 64.
    Liu TF, Tang JJ, Li PS, Shen Y, Li JG, Miao HH, Li BL, Song BL. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab 2012; 16(2): 213–225CrossRefPubMedGoogle Scholar
  65. 65.
    Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, Mu J, Thompson JR, Berger JP, Wong KK. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferatoractivated receptor γ and altered metabolic states. Mol Pharmacol 2008; 74(2): 403–412CrossRefPubMedGoogle Scholar
  66. 66.
    De Sousa-Coelho AL, Marrero PF, Haro D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J 2012; 443(1): 165–171CrossRefPubMedGoogle Scholar
  67. 67.
    Yang C, Jin C, Li X, Wang F, McKeehan WL, Luo Y. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS One 2012; 7(3): e33870CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Lee S, Choi J, Mohanty J, Sousa LP, Tome F, Pardon E, Steyaert J, Lemmon MA, Lax I, Schlessinger J. Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling. Nature 2018; 553(7689): 501–505CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Luo Y, McKeehan WL. Stressed liver and muscle call on adipocytes with FGF21. Front Endocrinol (Lausanne) 2013; 4: 194CrossRefGoogle Scholar
  70. 70.
    Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, Kugelmas M, Bashir MR, Jaros MJ, Ling L, Rossi SJ, DePaoli AM, Loomba R. NGM282 for treatment of nonalcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018; 391(10126): 1174–1185CrossRefPubMedGoogle Scholar
  71. 71.
    Hirschfield GM, Chazouillères O, Drenth JP, Thorburn D, Harrison SA, Landis CS, Mayo MJ, Muir AJ, Trotter JF, Leeming DJ, Karsdal MA, Jaros MJ, Ling L, Kim KH, Rossi SJ, Somaratne RM, DePaoli AM, Beuers U. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol 2019; 70(3): 483–493CrossRefPubMedGoogle Scholar
  72. 72.
    Harrison SA, Rossi SJ, Paredes AH, Trotter JF, Bashir MR, Guy CD, Banerjee R, Jaros MJ, Owers S, Baxter BA, Ling L, DePaoli AM. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology 2019 Feb 25. [Epub ahead of print] doi:  https://doi.org/10.1002/hep.30590
  73. 73.
    Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, Lawitz EJ, Halegoua-DeMarzio D, Kundu S, Noviello S, Luo Y, Christian R. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, doubleblind, placebo-controlled, phase 2a trial. Lancet 2018; 392(10165): 2705–2717CrossRefPubMedGoogle Scholar
  74. 74.
    Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V,Weng Y, Clark R, Lanba A, Owen BM, Brenner MB, Trimmer JK, Gropp KE, Chabot JR, Erion DM, Rolph TP, Goodwin B, Calle RA. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab 2016; 23(3): 427–440CrossRefPubMedGoogle Scholar
  75. 75.
    Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, Kawakami T, Ito T, Zhang X, Humphrey J, Insogna KL, Peacock M. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest 2014; 124(4): 1587–1597CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Yu C, Wang F, Kan M, Jin C, Jones RB, Weinstein M, Deng CX, McKeehan WL. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem 2000; 275(20): 15482–15489CrossRefPubMedGoogle Scholar
  77. 77.
    Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, Williams PM, Soriano R, Corpuz R, Moffat B, Vandlen R, Simmons L, Foster J, Stephan JP, Tsai SP, Stewart TA. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 2004; 145(6): 2594–2603CrossRefPubMedGoogle Scholar
  78. 78.
    Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, Stewart TA. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 2002; 143(5): 1741–1747CrossRefPubMedGoogle Scholar
  79. 79.
    Adams AC, Yang C, Coskun T, Cheng CC, Gimeno RE, Luo Y, Kharitonenkov A. The breadth of FGF21’s metabolic actions are governed by FGFR1 in adipose tissue. Mol Metab 2013; 2(1): 31–37CrossRefGoogle Scholar
  80. 80.
    Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol 2009; 7(11):1189–1194CrossRefPubMedGoogle Scholar
  81. 81.
    Oduyebo I, Camilleri M, Nelson AD, Khemani D, Nord SL, Busciglio I, Burton D, Rhoten D, Ryks M, Carlson P, Donato L, Lueke A, Kim K, Rossi SJ, Zinsmeister AR. Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial. Am J Gastroenterol 2018; 113(5): 725–734CrossRefPubMedGoogle Scholar
  82. 82.
    Pai R, French D, Ma N, Hotzel K, Plise E, Salphati L, Setchell KD, Ware J, Lauriault V, Schutt L, Hartley D, Dambach D. Antibodymediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys. Toxicol Sci 2012; 126(2): 446–456CrossRefPubMedGoogle Scholar
  83. 83.
    Gerhard GS, Styer AM, Wood GC, Roesch SL, Petrick AT, Gabrielsen J, Strodel WE, Still CD, Argyropoulos G. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care 2013; 36(7): 1859–1864CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, To C, Learned RM, Tian H, DePaoli AM, Ling L. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014; 6(247): 247ra100CrossRefPubMedGoogle Scholar
  85. 85.
    Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 2009; 49(4): 1228–1235CrossRefPubMedGoogle Scholar
  86. 86.
    Benoit B, Meugnier E, Castelli M, Chanon S, Vieille-Marchiset A, Durand C, Bendridi N, Pesenti S, Monternier PA, Durieux AC, Freyssenet D, Rieusset J, Lefai E, Vidal H, Ruzzin J. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med 2017; 23(8): 990–996CrossRefPubMedGoogle Scholar
  87. 87.
    Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan JP, Stinson J, Stewart T, French DM. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002; 160(6): 2295–2307CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology 2016; 63(3): 914–929CrossRefPubMedGoogle Scholar
  89. 89.
    Mayo MJ, Wigg AJ, Leggett BA, Arnold H, Thompson AJ, Weltman M, Carey EJ, Muir AJ, Ling L, Rossi SJ, DePaoli AM. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun 2018; 2(9): 1037–1050CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    BonDurant LD, Potthoff MJ. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu Rev Nutr 2018; 38(1): 173–196CrossRefPubMedGoogle Scholar
  91. 91.
    Giannini C, Feldstein AE, Santoro N, Kim G, Kursawe R, Pierpont B, Caprio S. Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab 2013; 98(7): 2993–3000CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Lin Z, Gong Q, Wu C, Yu J, Lu T, Pan X, Lin S, Li X. Dynamic change of serum FGF21 levels in response to glucose challenge in human. J Clin Endocrinol Metab 2012; 97(7): E1224–E1228CrossRefPubMedGoogle Scholar
  93. 93.
    Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, Ozdogan O, Imeryuz N, Kalayci C, Avsar E. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest 2010; 40(10): 887–892CrossRefPubMedGoogle Scholar
  94. 94.
    Kliewer SA, Mangelsdorf DJ. A dozen years of discovery: insights into the physiology and pharmacology of FGF21. Cell Metab 2019; 29(2): 246–253CrossRefPubMedGoogle Scholar
  95. 95.
    Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, Münzberg H, Hutson SM, Gettys TW, Schwartz MW, Morrison CD. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014; 124(9): 3913–3922CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Fisher FM, Kim M, Doridot L, Cunniff JC, Parker TS, Levine DM, Hellerstein MK, Hudgins LC, Maratos-Flier E, Herman MA. A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Mol Metab 2017; 6(1): 14–21CrossRefPubMedGoogle Scholar
  97. 97.
    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. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab 2016; 23(2): 335–343CrossRefPubMedGoogle Scholar
  98. 98.
    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. FGF21 regulates sweet and alcohol preference. Cell Metab 2016; 23(2): 344–349CrossRefPubMedGoogle Scholar
  99. 99.
    Fisher FM, Chui PC, Nasser IA, Popov Y, Cunniff JC, Lundasen T, Kharitonenkov A, Schuppan D, Flier JS and Maratos-Flier E. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 2014; 147(5): 1073–1083.e6CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Huang X, Yu C, Jin C, Yang C, Xie R, Cao D, Wang F, McKeehan WL. Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Mol Carcinog 2006; 45(12): 934–942CrossRefPubMedGoogle Scholar
  101. 101.
    Tanaka N, Takahashi S, Zhang Y, Krausz KW, Smith PB, Patterson AD, Gonzalez FJ. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochim Biophys Acta 2015; 1852(7): 1242–1252CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Desai BN, Singhal G, Watanabe M, Stevanovic D, Lundasen T, Fisher FM, Mather ML, Vardeh HG, Douris N, Adams AC, Nasser IA, FitzGerald GA, Flier JS, Skarke C, Maratos-Flier E. Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury. Mol Metab 2017; 6(11): 1395–1406CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Ye D,Wang Y, Li H, Jia W, Man K, Lo CM,Wang Y, Lam KS, Xu A. Fibroblast growth factor 21 protects against acetaminopheninduced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice. Hepatology 2014; 60(3): 977–989CrossRefPubMedGoogle Scholar
  104. 104.
    Singhal G, Kumar G, Chan S, Fisher FM, Ma Y, Vardeh HG, Nasser IA, Flier JS, Maratos-Flier E. Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet. Mol Metab 2018; 13: 56–66CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Ye M, Lu W, Wang X, Wang C, Abbruzzese JL, Liang G, Li X, Luo Y. FGF21-FGFR1 coordinates phospholipid homeostasis, lipid droplet function, and ER stress in obesity. Endocrinology 2016; 157(12): 4754–4769CrossRefPubMedGoogle Scholar
  106. 106.
    Foltz IN, Hu S, King C, Wu X, Yang C, Wang W, Weiszmann J, Stevens J, Chen JS, Nuanmanee N, Gupte J, Komorowski R, Sekirov L, Hager T, Arora T, Ge H, Baribault H,Wang F, Sheng J, Karow M, Wang M, Luo Y, McKeehan W, Wang Z, Véniant MM, Li Y. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci Transl Med 2012; 4(162): 162ra153CrossRefPubMedGoogle Scholar
  107. 107.
    Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013; 18(3): 333–340CrossRefPubMedGoogle Scholar
  108. 108.
    Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, Itoh N, Wang Y, Bornstein SR, Xu A, Li X. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013; 17(5): 779–789CrossRefPubMedGoogle Scholar
  109. 109.
    Huang Z, Zhong L, Lee JTH, Zhang J, Wu D, Geng L, Wang Y, Wong CM, Xu A. The FGF21–CCL11 axis mediates beiging of white adipose tissues by coupling sympathetic nervous system to type 2 immunity. Cell Metab 2017; 26(3): 493–508.e4CrossRefPubMedGoogle Scholar
  110. 110.
    Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014; 19(2): 302–309CrossRefPubMedGoogle Scholar
  111. 111.
    Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011; 286(15): 12983–12990CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Ameka M, Markan KR, Morgan DA, BonDurant LD, Idiga SO, Naber MC, Zhu Z, Zingman LV, Grobe JL, Rahmouni K, Potthoff MJ. Liver derived FGF21 maintains core body temperature during acute cold exposure. Sci Rep 2019; 9(1): 630CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 2012; 1: e00065CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Youm YH, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci USA 2016; 113(4): 1026–1031CrossRefPubMedGoogle Scholar
  115. 115.
    Adams AC, Coskun T, Cheng CC, O’Farrell LS, Dubois SL, Kharitonenkov A. Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones. Mol Metab 2013; 2(3): 205–214CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Coate KC, Hernandez G, Thorne CA, Sun S, Le TDV, Vale K, Kliewer SA, Mangelsdorf DJ. FGF21 is an exocrine pancreas secretagogue. Cell Metab 2017; 25(2): 472–480CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Singhal G, Fisher FM, Chee MJ, Tan TG, El Ouaamari A, Adams AC, Najarian R, Kulkarni RN, Benoist C, Flier JS, Maratos-Flier E. Fibroblast growth factor 21 (FGF21) protects against high fat diet induced inflammation and islet hyperplasia in pancreas. PLoS One 2016; 11(2): e0148252CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Johnson CL, Mehmood R, Laing SW, Stepniak CV, Kharitonenkov A, Pin CL. Silencing of the fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1. Am J Physiol Endocrinol Metab 2014; 306(8): E916–E928CrossRefPubMedGoogle Scholar
  119. 119.
    Johnson CL, Weston JY, Chadi SA, Fazio EN, Huff MW, Kharitonenkov A, Köester A, Pin CL. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 2009; 137(5): 1795–1804CrossRefPubMedGoogle Scholar
  120. 120.
    Kuroda M, Muramatsu R, Maedera N, Koyama Y, Hamaguchi M, Fujimura H, Yoshida M, Konishi M, Itoh N, Mochizuki H, Yamashita T. Peripherally derived FGF21 promotes remyelination in the central nervous system. J Clin Invest 2017; 127(9): 3496–3509CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Soberg S, Sandholt CH, Jespersen NZ, Toft U, Madsen AL, von Holstein-Rathlou S, Grevengoed TJ, Christensen KB, Bredie WLP, Potthoff MJ, Solomon TPJ, Scheele C, Linneberg A, Jorgensen T, Pedersen O, Hansen T, Gillum MP, Grarup N. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab 2017; 25(5): 1045–1053.e6CrossRefPubMedGoogle Scholar
  122. 122.
    Song P, Zechner C, Hernandez G, Canovas J, Xie Y, Sondhi V, Wagner M, Stadlbauer V, Horvath A, Leber B, Hu MC, Moe OW, Mangelsdorf DJ, Kliewer SA. The hormone FGF21 stimulates water drinking in response to ketogenic diet and alcohol. Cell Metab 2018; 27(6): 1338–1347.e4CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    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. 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 2018; 23(2): 327–336CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Schumann G, Liu C, O’Reilly P, Gao H, Song P, Xu B, Ruggeri B, Amin N, Jia T, Preis S, Segura Lepe M, Akira S, Barbieri C, Baumeister S, Cauchi S, Clarke TK, Enroth S, Fischer K, Hällfors J, Harris SE, Hieber S, Hofer E, Hottenga JJ, Johansson Å, Joshi PK, Kaartinen N, Laitinen J, Lemaitre R, Loukola A, Luan J, Lyytikäinen LP, Mangino M, Manichaikul A, Mbarek H, Milaneschi Y, Moayyeri A, Mukamal K, Nelson C, Nettleton J, Partinen E, Rawal R, Robino A, Rose L, Sala C, Satoh T, Schmidt R, Schraut K, Scott R, Smith AV, Starr JM, Teumer A, Trompet S, Uitterlinden AG, Venturini C, Vergnaud AC, Verweij N, Vitart V, Vuckovic D, Wedenoja J, Yengo L, Yu B, Zhang W, Zhao JH, Boomsma DI, Chambers J, Chasman DI, Daniela T, de Geus E, Deary I, Eriksson JG, Esko T, Eulenburg V, Franco OH, Froguel P, Gieger C, Grabe HJ, Gudnason V, Gyllensten U, Harris TB, Hartikainen AL, Heath AC, Hocking L, Hofman A, Huth C, Jarvelin MR, Jukema JW, Kaprio J, Kooner JS, Kutalik Z, Lahti J, Langenberg C, Lehtimäki T, Liu Y, Madden PA, Martin N, Morrison A, Penninx B, Pirastu N, Psaty B, Raitakari O, Ridker P, Rose R, Rotter JI, Samani NJ, Schmidt H, Spector TD, Stott D, Strachan D, Tzoulaki I, van der Harst P, van Duijn CM, Marques-Vidal P, Vollenweider P, Wareham NJ, Whitfield JB, Wilson J, Wolffenbuttel B, Bakalkin G, Evangelou E, Liu Y, Rice KM, Desrivières S, Kliewer SA, Mangelsdorf DJ, Müller CP, Levy D, Elliott P. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci USA 2016; 113(50): 14372–14377CrossRefPubMedGoogle Scholar
  125. 125.
    Restelli LM, Oettinghaus B, Halliday M, Agca C, Licci M, Sironi L, Savoia C, Hench J, Tolnay M, Neutzner A, Schmidt A, Eckert A, Mallucci G, Scorrano L, Frank S. Neuronal mitochondrial dysfunction activates the integrated stress response to induce fibroblast growth factor 21. Cell Reports 2018; 24(6): 1407–1414CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, Gabrielli LA, Sitges M, Giralt M, van Bilsen M, Villarroya F. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 2013; 4(1): 2019CrossRefPubMedGoogle Scholar
  127. 127.
    Morville T, Sahl RE, Trammell SA, Svenningsen JS, Gillum MP, Helge JW, Clemmensen C. Divergent effects of resistance and endurance exercise on plasma bile acids, FGF19, and FGF21 in humans. JCI Insight 2018; 3(15): 122737CrossRefPubMedGoogle Scholar
  128. 128.
    Brahma MK, Adam RC, Pollak NM, Jaeger D, Zierler KA, Pöcher N, Schreiber R, Romauch M, Moustafa T, Eder S, Ruelicke T, Preiss-Landl K, Lass A, Zechner R, Haemmerle G. Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis. J Lipid Res 2014; 55(11): 2229–2241CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Lin Z, Pan X, Wu F, Ye D, Zhang Y, Wang Y, Jin L, Lian Q, Huang Y, Ding H, Triggle C, Wang K, Li X, Xu A. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation 2015; 131(21): 1861–1871CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Liu SQ, Roberts D, Kharitonenkov A, Zhang B, Hanson SM, Li YC, Zhang LQ, Wu YH. Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci Rep 2013; 3(1): 2767CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Yang H, Feng A, Lin S, Yu L, Lin X, Yan X, Lu X, Zhang C. Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death Dis 2018; 9(2): 227CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Zhang C, Huang Z, Gu J, Yan X, Lu X, Zhou S, Wang S, Shao M, Zhang F, Cheng P, Feng W, Tan Y, Li X. Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway. Diabetologia 2015; 58 (8): 1937–1948Google Scholar
  133. 133.
    Pan X, Shao Y, Wu F, Wang Y, Xiong R, Zheng J, Tian H, Wang B, Wang Y, Zhang Y, Han Z, Qu A, Xu H, Lu A, Yang T, Li X, Xu A, Du J, Lin Z. FGF21 prevents angiotensin II–induced hypertension and vascular dysfunction by activation of ACE2/angiotensin-(1–7) axis in mice. Cell Metab 2018; 27(6): 1323–1337.e5CrossRefPubMedGoogle Scholar
  134. 134.
    Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim DH, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 2013; 19(1): 83–92CrossRefPubMedGoogle Scholar
  135. 135.
    Suomalainen A, Elo JM, Pietiläinen KH, Hakonen AH, Sevastianova K, Korpela M, Isohanni P, Marjavaara SK, Tyni T, Kiuru-Enari S, Pihko H, Darin N, Õunap K, Kluijtmans LA, Paetau A, Buzkova J, Bindoff LA, Annunen-Rasila J, Uusimaa J, Rissanen A, Yki-Järvinen H, Hirano M, Tulinius M, Smeitink J, Tyynismaa H. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011; 10(9): 806–818CrossRefPubMedGoogle Scholar
  136. 136.
    Geng L, Liao B, Jin L, Huang Z, Triggle CR, Ding H, Zhang J, Huang Y, Lin Z, Xu A. Exercise alleviates obesity-induced metabolic dysfunction via enhancing FGF21 sensitivity in adipose tissues. Cell Rep 2019; 26(10): 2738–2752.e4CrossRefPubMedGoogle Scholar
  137. 137.
    Pereira RO, Tadinada SM, Zasadny FM, Oliveira KJ, Pires KMP, Olvera A, Jeffers J, Souvenir R, Mcglauflin R, Seei A, Funari T, Sesaki H, Potthoff MJ, Adams CM, Anderson EJ, Abel ED. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 2017; 36(14): 2126–2145CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Tanimura Y, Aoi W, Takanami Y, Kawai Y, Mizushima K, Naito Y, Yoshikawa T. Acute exercise increases fibroblast growth factor 21 in metabolic organs and circulation. Physiol Rep 2016; 4(12): e12828CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Lee MS, Choi SE, Ha ES, An SY, Kim TH, Han SJ, Kim HJ, Kim DJ, Kang Y, Lee KW. Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-kB. Metabolism 2012; 61(8): 1142–1151CrossRefPubMedGoogle Scholar
  140. 140.
    Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt-regulated myokine. FEBS Lett 2008; 582(27): 3805–3810CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Owen BM, Ding X, Morgan DA, Coate KC, Bookout AL, Rahmouni K, Kliewer SA, Mangelsdorf DJ. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 2014; 20(4): 670–677CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Douris N, Stevanovic DM, Fisher FM, Cisu TI, Chee MJ, Nguyen NL, Zarebidaki E, Adams AC, Kharitonenkov A, Flier JS, Bartness TJ, Maratos-Flier E. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 2015; 156(7): 2470–2481CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR, Triggle CR, Ding H, Lam KS, Xu A. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 2014; 63(12): 4064–4075CrossRefPubMedGoogle Scholar
  144. 144.
    Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, Kliewer SA, Mangelsdorf DJ. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 2013; 19(9): 1153–1156CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, Ding X, Elmquist JK, Takahashi JS, Mangelsdorf DJ, Kliewer SA. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013; 19(9): 1147–1152CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Ishida N. Role of PPARα in the control of torpor through FGF21-NPY pathway: from circadian clock to seasonal change in mammals. PPAR Res 2009; 2009: 412949CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Wang Q, Yuan J, Yu Z, Lin L, Jiang Y, Cao Z, Zhuang P, Whalen MJ, Song B, Wang XJ, Li X, Lo EH, Xu Y, Wang X. FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol 2018; 55(6): 4702–4717CrossRefPubMedGoogle Scholar
  148. 148.
    Yu Y, Bai F, Wang W, Liu Y, Yuan Q, Qu S, Zhang T, Tian G, Li S, Li D, Ren G. Fibroblast growth factor 21 protects mouse brain against D-galactose induced aging via suppression of oxidative stress response and advanced glycation end products formation. Pharmacol Biochem Behav 2015; 133: 122–131CrossRefPubMedGoogle Scholar
  149. 149.
    Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, Schwartz MW. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 2010; 59(7): 1817–1824CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Véniant MM, Hale C, Helmering J, Chen MM, Stanislaus S, Busby J, Vonderfecht S, Xu J, Lloyd DJ. FGF21 promotes metabolic homeostasis via white adipose and leptin in mice. PLoS One 2012; 7(7): e40164CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Véniant MM. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58(1): 250–259CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    So WY, Cheng Q, Xu A, Lam KS, Leung PS. Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice. Cell Death Dis 2015; 6(3): e1707CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Zhang C, Shao M, Yang H, Chen L, Yu L, Cong W, Tian H, Zhang F, Cheng P, Jin L, Tan Y, Li X, Cai L, Lu X. Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS One 2013; 8(12): e82275CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Kim HW, Lee JE, Cha JJ, Hyun YY, Kim JE, Lee MH, Song HK, Nam DH, Han JY, Han SY, Han KH, Kang YS, Cha DR. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology 2013; 154(9): 3366–3376CrossRefPubMedGoogle Scholar
  155. 155.
    Tang TT, Li YY, Li JJ, Wang K, Han Y, Dong WY, Zhu ZF, Xia N, Nie SF, Zhang M, Zeng ZP, Lv BJ, Jiao J, Liu H, Xian ZS, Yang XP, Hu Y, Liao YH, Wang Q, Tu X, Mallat Z, Huang Y, Shi GP, Cheng X. Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction. Theranostics 2018; 8(16): 4552–4562CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Wang N, Zhao TT, Li SM, Li YH, Wang YJ, Li DS, Wang WF. Fibroblast growth factor 21 ameliorates pancreatic fibrogenesis via regulating polarization of macrophages. Exp Cell Res 2019; 382 (1): 111457CrossRefPubMedGoogle Scholar
  157. 157.
    Li S, Guo X, Zhang T, Wang N, Li J, Xu P, Zhang S, Ren G, Li D. Fibroblast growth factor 21 ameliorates high glucose-induced fibrogenesis in mesangial cells through inhibiting STAT5 signaling pathway. Biomed Pharmacother 2017; 93: 695–704CrossRefPubMedGoogle Scholar
  158. 158.
    Li S, Wang N, Guo X, Li J, Zhang T, Ren G, Li D. Fibroblast growth factor 21 regulates glucose metabolism in part by reducing renal glucose reabsorption. Biomed Pharmacother 2018; 108: 355–366CrossRefPubMedGoogle Scholar
  159. 159.
    Lin XL, He XL, Zeng JF, Zhang H, Zhao Y, Tan JK, Wang Z. FGF21 increases cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells. DNA Cell Biol 2014; 33(8): 514–521CrossRefPubMedGoogle Scholar
  160. 160.
    Yu Y, He J, Li S, Song L, Guo X, Yao W, Zou D, Gao X, Liu Y, Bai F, Ren G, Li D. Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway. Int Immunopharmacol 2016; 38: 144–152CrossRefPubMedGoogle Scholar
  161. 161.
    Li H, Wu G, Fang Q, Zhang M, Hui X, Sheng B, Wu L, Bao Y, Li P, Xu A, Jia W. Fibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat. Nat Commun 2018; 9(1): 272CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Li SM, Wang WF, Zhou LH, Ma L, An Y, Xu WJ, Li TH, Yu YH, Li DS, Liu Y. Fibroblast growth factor 21 expressions in white blood cells and sera of patients with gestational diabetes mellitus during gestation and postpartum. Endocrine 2015; 48(2): 519–527CrossRefPubMedGoogle Scholar
  163. 163.
    Li JY, Wang N, Khoso MH, Shen CB, Guo MZ, Pang XX, Li DS, Wang WF. FGF-21 elevated IL-10 production to correct LPS-induced inflammation. Inflammation 2018; 41(3): 751–759CrossRefPubMedGoogle Scholar
  164. 164.
    Wang WF, Ma L, Liu MY, Zhao TT, Zhang T, Yang YB, Cao HX, Han XH, Li DS. A novel function for fibroblast growth factor 21: stimulation of NADPH oxidase-dependent ROS generation. Endocrine 2015; 49(2): 385–395CrossRefPubMedGoogle Scholar
  165. 165.
    Li SM, Yu YH, Li L, Wang WF, Li DS. Treatment of CIA mice with FGF21 down-regulates TH17-IL-17 axis. Inflammation 2016; 39(1): 309–319CrossRefPubMedGoogle Scholar
  166. 166.
    Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, Miyamoto K, Fukushima N. Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1α,25-dihydroxyvitamin D3 production. J Biol Chem 2003; 278(4): 2206–2211CrossRefPubMedGoogle Scholar
  167. 167.
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113(4): 561–568CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98(11): 6500–6505CrossRefPubMedGoogle Scholar
  169. 169.
    Andrukhova O, Smorodchenko A, Egerbacher M, Streicher C, Zeitz U, Goetz R, Shalhoub V, Mohammadi M, Pohl EE, Lanske B, Erben RG. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J 2014; 33(3): 229–246PubMedPubMedCentralGoogle Scholar
  170. 170.
    Andrukhova O, Slavic S, Smorodchenko A, Zeitz U, Shalhoub V, Lanske B, Pohl EE, Erben RG. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 2014; 6(6): 744–759CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007; 117(12): 4003–4008PubMedPubMedCentralGoogle Scholar
  172. 172.
    Toro L, Barrientos V, León P, Rojas M, Gonzalez M, González-Ibáñez A, Illanes S, Sugikawa K, Abarzúa N, Bascuñán C, Arcos K, Fuentealba C, Tong AM, Elorza AA, Pinto ME, Alzamora R, Romero C, Michea L. Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury. Kidney Int 2018; 93(5): 1131–1141CrossRefPubMedGoogle Scholar
  173. 173.
    Rabadi S, Udo I, Leaf DE, Waikar SS, Christov M. Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol 2018; 314(1): F132–F139CrossRefPubMedGoogle Scholar
  174. 174.
    ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26(3): 345–348CrossRefGoogle Scholar
  175. 175.
    Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun 2001; 284(4): 977–981CrossRefPubMedGoogle Scholar
  176. 176.
    Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003; 112(5): 683–692CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Hoffman WH, Jueppner HW, Deyoung BR, O’dorisio MS, Given KS. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 2005; 134(3): 233–236CrossRefPubMedGoogle Scholar
  178. 178.
    Kato K, Jeanneau C, Tarp MA, Benet-Pagès A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 2006; 281(27): 18370–18377CrossRefPubMedGoogle Scholar
  179. 179.
    Ichikawa S, Imel EA, Sorenson AH, Severe R, Knudson P, Harris GJ, Shaker JL, Econs MJ. Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene. J Clin Endocrinol Metab 2006; 91(11): 4472–4475CrossRefPubMedGoogle Scholar
  180. 180.
    Garringer HJ, Fisher C, Larsson TE, Davis SI, Koller DL, Cullen MJ, Draman MS, Conlon N, Jain A, Fedarko NS, Dasgupta B, White KE. The role of mutant UDP-N-acetyl-α-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis. J Clin Endocrinol Metab 2006; 91(10): 4037–4042CrossRefPubMedGoogle Scholar
  181. 181.
    Benet-Pagès A, Orlik P, Strom TM, Lorenz-Depiereux B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 2005; 14(3): 385–390CrossRefPubMedGoogle Scholar
  182. 182.
    Chefetz I, Heller R, Galli-Tsinopoulou A, Richard G, Wollnik B, Indelman M, Koerber F, Topaz O, Bergman R, Sprecher E, Schoenau E. A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification. Hum Genet 2005; 118(2): 261–266CrossRefPubMedGoogle Scholar
  183. 183.
    Araya K, Fukumoto S, Backenroth R, Takeuchi Y, Nakayama K, Ito N, Yoshii N, Yamazaki Y, Yamashita T, Silver J, Igarashi T, Fujita T. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 2005; 90(10): 5523–5527CrossRefPubMedGoogle Scholar
  184. 184.
    Abbasi F, Ghafouri-Fard S, Javaheri M, Dideban A, Ebrahimi A, Ebrahim-Habibi A. A new missense mutation in FGF23 gene in a male with hyperostosis-hyperphosphatemia syndrome (HHS). Gene 2014; 542(2): 269–271CrossRefPubMedGoogle Scholar
  185. 185.
    Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121(11): 4393–4408CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Gutiérrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann U, Coglianese E, Christenson R, Wang TJ, deFilippi C, Wolf M. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119(19): 2545–2552CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    McGrath ER, Himali JJ, Levy D, Conner SC, Pase MP, Abraham CR, Courchesne P, Satizabal CL, Vasan RS, Beiser AS, Seshadri S. Circulating fibroblast growth factor 23 levels and incident dementia: The Framingham heart study. PLoS One 2019; 14(3): e0213321CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Liu P, Chen L, Bai X, Karaplis A, Miao D, Gu N. Impairment of spatial learning and memory in transgenic mice overexpressing human fibroblast growth factor-23. Brain Res 2011; 1412: 9–17CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouChina

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