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.
A Beenken, M Mohammadi. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 2009; 8(3): 235–253 https://doi.org/10.1038/nrd2792
pmid: 19247306
2
Y Luo, S Ye, X Li, W Lu. Emerging structure-function paradigm of endocrine FGFs in metabolic diseases. Trends Pharmacol Sci 2019; 40(2): 142–153 https://doi.org/10.1016/j.tips.2018.12.002
pmid: 30616873
AE Eriksson, LS Cousens, LH Weaver, BW Matthews. Three-dimensional structure of human basic fibroblast growth factor. Proc Natl Acad Sci USA 1991; 88(8): 3441–3445 https://doi.org/10.1073/pnas.88.8.3441
pmid: 1707542
5
G Chen, Y Liu, R Goetz, L Fu, S Jayaraman, MC Hu, OW Moe, G Liang, X Li, M Mohammadi. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 2018; 553(7689): 461–466 https://doi.org/10.1038/nature25451
pmid: 29342138
6
C Degirolamo, C Sabbà, A Moschetta. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 2016; 15(1): 51–69 https://doi.org/10.1038/nrd.2015.9
pmid: 26567701
7
Y Luo, S Ye, X Chen, F Gong, W Lu, X Li. Rush to the fire: FGF21 extinguishes metabolic stress, metaflammation and tissue damage. Cytokine Growth Factor Rev 2017; 38: 59–65 https://doi.org/10.1016/j.cytogfr.2017.08.001
pmid: 28887067
8
WL McKeehan, F Wang, M Kan. The heparan sulfate-fibroblast growth factor family: diversity of structure and function. Prog Nucleic Acid Res Mol Biol 1998; 59: 135–176 https://doi.org/10.1016/S0079-6603(08)61031-4
pmid: 9427842
N Itoh, DM Ornitz. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem 2011; 149(2): 121–130 https://doi.org/10.1093/jb/mvq121
pmid: 20940169
X Zhang, OA Ibrahimi, SK Olsen, H Umemori, M Mohammadi, DM Ornitz. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 2006; 281(23): 15694–15700 https://doi.org/10.1074/jbc.M601252200
pmid: 16597617
13
HA Armelin. Pituitary extracts and steroid hormones in the control of 3T3 cell growth. Proc Natl Acad Sci USA 1973; 70(9): 2702–2706 https://doi.org/10.1073/pnas.70.9.2702
pmid: 4354860
14
D Gospodarowicz. Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 1974; 249(453): 123–127 https://doi.org/10.1038/249123a0
pmid: 4364816
Y Luo, S Ye, M Kan, WL McKeehan. 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): 21052–21061 https://doi.org/10.1074/jbc.M601559200
17
D Gospodarowicz, CR Ill, PJ Hornsby, GN Gill. Control of bovine adrenal cortical cell proliferation by fibroblast growth factor. Lack of effect of epidermal growth factor. Endocrinology 1977; 100(4): 1080–1089 https://doi.org/10.1210/endo-100-4-1080
pmid: 189990
18
SL Mansour, JM Goddard, MR Capecchi. 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): 13–28
pmid: 8223243
19
C Guo, Y Sun, B Zhou, RM Adam, X Li, WT Pu, BE Morrow, A Moon, X Li. A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. J Clin Invest 2011; 121(4): 1585–1595 https://doi.org/10.1172/JCI44630
pmid: 21364285
M Kan, F Wang, J Xu, JW Crabb, J Hou, WL McKeehan. An essential heparin-binding domain in the fibroblast growth factor receptor kinase. Science 1993; 259(5103): 1918–1921 https://doi.org/10.1126/science.8456318
pmid: 8456318
22
S Ye, Y Luo, W Lu, RB Jones, RJ Linhardt, I Capila, T Toida, M Kan, H Pelletier, WL McKeehan. Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs. Biochemistry 2001; 40(48): 14429–14439 https://doi.org/10.1021/bi011000u
pmid: 11724555
23
R Goetz, M Mohammadi. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol 2013; 14(3): 166–180 https://doi.org/10.1038/nrm3528
pmid: 23403721
24
H Kouhara, YR Hadari, T Spivak-Kroizman, J Schilling, D Bar-Sagi, I Lax, J Schlessinger. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 1997; 89(5): 693–702 https://doi.org/10.1016/S0092-8674(00)80252-4
pmid: 9182757
25
Z Huang, WM Marsiglia, U Basu Roy, N Rahimi, D Ilghari, H Wang, H Chen, W Gai, S Blais, TA Neubert, A Mansukhani, NJ Traaseth, X Li, M Mohammadi. Two FGF receptor kinase molecules act in concert to recruit and transphosphorylate phospholipase Cg. Mol Cell 2016; 61(1): 98–110 https://doi.org/10.1016/j.molcel.2015.11.010
pmid: 26687682
26
K Dorey, E Amaya. FGF signalling: diverse roles during early vertebrate embryogenesis. Development 2010; 137(22): 3731–3742 https://doi.org/10.1242/dev.037689
pmid: 20978071
27
W Lu, Y Luo, M Kan, WL McKeehan. Fibroblast growth factor-10. A second candidate stromal to epithelial cell andromedin in prostate. J Biol Chem 1999; 274(18): 12827–12834 https://doi.org/10.1074/jbc.274.18.12827
pmid: 10212269
28
C Jin, F Wang, X Wu, C Yu, Y Luo, WL McKeehan. Directionally specific paracrine communication mediated by epithelial FGF9 to stromal FGFR3 in two-compartment premalignant prostate tumors. Cancer Res 2004; 64(13): 4555–4562 https://doi.org/10.1158/0008-5472.CAN-03-3752
pmid: 15231666
29
EP Carter, AE Fearon, RP Grose. Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction. Trends Cell Biol 2015; 25(4): 221–233 https://doi.org/10.1016/j.tcb.2014.11.003
pmid: 25467007
30
JD Goldberg, J Zheng, H Castro-Malaspina, AA Jakubowski, G Heller, MR van den Brink, MA Perales. Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants. Bone Marrow Transplant 2013; 48(1): 99–104 https://doi.org/10.1038/bmt.2012.115
pmid: 22750997
31
H Uchi, A Igarashi, K Urabe, T Koga, J Nakayama, R Kawamori, K Tamaki, H Hirakata, T Ohura, M Furue. Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol 2009; 19(5): 461–468
pmid: 19638336
32
S Akita, K Akino, T Imaizumi, A Hirano. Basic fibroblast growth factor accelerates and improves second-degree burn wound healing. Wound Repair Regen 2008; 16(5): 635–641 https://doi.org/10.1111/j.1524-475X.2008.00414.x
pmid: 19128258
33
X Fu, Z Shen, Y Chen, J Xie, Z Guo, M Zhang, Z Sheng. Randomised placebo-controlled trial of use of topical recombinant bovine basic fibroblast growth factor for second-degree burns. Lancet 1998; 352(9141): 1661–1664 https://doi.org/10.1016/S0140-6736(98)01260-4
pmid: 9853438
34
L Maddaluno, C Urwyler, S Werner. Fibroblast growth factors: key players in regeneration and tissue repair. Development 2017; 144(22): 4047–4060 https://doi.org/10.1242/dev.152587
pmid: 29138288
35
YZ Zhao, M Zhang, HL Wong, XQ Tian, L Zheng, XC Yu, FR Tian, KL Mao, ZL Fan, PP Chen, XK Li, CT Lu. Prevent diabetic cardiomyopathy in diabetic rats by combined therapy of aFGF-loaded nanoparticles and ultrasound-targeted microbubble destruction technique. J Control Release 2016; 223: 11–21 https://doi.org/10.1016/j.jconrel.2015.12.030
pmid: 26712588
36
G Liang, L Song, Z Chen, Y Qian, J Xie, L Zhao, Q Lin, G Zhu, Y Tan, X Li, M Mohammadi, Z Huang. Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism. Kidney Int 2018; 93(1): 95–109 https://doi.org/10.1016/j.kint.2017.05.013
pmid: 28750927
37
R Li, Y Li, Y Wu, Y Zhao, H Chen, Y Yuan, K Xu, H Zhang, Y Lu, J Wang, X Li, X Jia, J Xiao. Heparin-poloxamer thermosensitive hydrogel loaded with bFGF and NGF enhances peripheral nerve regeneration in diabetic rats. Biomaterials 2018; 168: 24–37 https://doi.org/10.1016/j.biomaterials.2018.03.044
pmid: 29609091
38
J Wu, J Zhu, C He, Z Xiao, J Ye, Y Li, A Chen, H Zhang, X Li, L Lin, Y Zhao, J Zheng, J Xiao. Comparative study of heparin-poloxamer hydrogel modified bFGF and aFGF for in vivo wound healing efficiency. ACS Appl Mater Interfaces 2016; 8(29): 18710–18721 https://doi.org/10.1021/acsami.6b06047
pmid: 27384134
39
J Wu, J Ye, J Zhu, Z Xiao, C He, H Shi, Y Wang, C Lin, H Zhang, Y Zhao, X Fu, H Chen, X Li, L Li, J Zheng, J Xiao. 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): 2168–2177 https://doi.org/10.1021/acs.biomac.6b00398
pmid: 27196997
40
Q Wang, Y He, Y Zhao, H Xie, Q Lin, Z He, X Wang, J Li, H Zhang, C Wang, F Gong, X Li, H Xu, Q Ye, J Xiao. A thermosensitive heparin-poloxamer hydrogel bridges aFGF to treat spinal cord injury. ACS Appl Mater Interfaces 2017; 9(8): 6725–6745 https://doi.org/10.1021/acsami.6b13155
pmid: 28181797
G Liang, Z Liu, J Wu, Y Cai, X Li. Anticancer molecules targeting fibroblast growth factor receptors. Trends Pharmacol Sci 2012; 33(10): 531–541 https://doi.org/10.1016/j.tips.2012.07.001
pmid: 22884522
43
P Cuevas, F Carceller, S Ortega, M Zazo, I Nieto, G Giménez-Gallego. Hypotensive activity of fibroblast growth factor. Science 1991; 254(5035): 1208–1210 https://doi.org/10.1126/science.1957172
pmid: 1957172
44
M Konishi, T Mikami, M Yamasaki, A Miyake, N Itoh. Fibroblast growth factor-16 is a growth factor for embryonic brown adipocytes. J Biol Chem 2000; 275(16): 12119–12122 https://doi.org/10.1074/jbc.275.16.12119
pmid: 10766846
45
IC Rulifson, P Collins, L Miao, D Nojima, KJ Lee, M Hardy, J Gupte, K Hensley, K Samayoa, C Cam, JB Rottman, M Ollmann, WG Richards, Y Li. In vitro and in vivo analyses reveal profound effects of fibroblast growth factor 16 as a metabolic regulator. J Biol Chem 2017; 292(5): 1951–1969 https://doi.org/10.1074/jbc.M116.751404
pmid: 28011645
46
JW Jonker, JM Suh, AR Atkins, M Ahmadian, P Li, J Whyte, M He, H Juguilon, YQ Yin, CT Phillips, RT Yu, JM Olefsky, RR Henry, M Downes, RMA Evans. A PPARg-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 2012; 485(7398): 391–394 https://doi.org/10.1038/nature10998
pmid: 22522926
47
Z Huang, Y Tan, J Gu, Y Liu, L Song, J Niu, L Zhao, L Srinivasan, Q Lin, J Deng, Y Li, DJ Conklin, TA Neubert, L Cai, X Li, M Mohammadi. Uncoupling the mitogenic and metabolic functions of FGF1 by tuning FGF1-FGF receptor dimer stability. Cell Reports 2017; 20(7): 1717–1728 https://doi.org/10.1016/j.celrep.2017.06.063
pmid: 28813681
48
MK Badman, P Pissios, AR Kennedy, G Koukos, JS Flier, E Maratos-Flier. 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): 426–437 https://doi.org/10.1016/j.cmet.2007.05.002
pmid: 17550778
49
T Inagaki, M Choi, A Moschetta, L Peng, CL Cummins, JG McDonald, G Luo, SA Jones, B Goodwin, JA Richardson, RD Gerard, JJ Repa, DJ Mangelsdorf, SA Kliewer. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2(4): 217–225 https://doi.org/10.1016/j.cmet.2005.09.001
pmid: 16213224
50
T Inagaki, P Dutchak, G Zhao, X Ding, L Gautron, V Parameswara, Y Li, R Goetz, M Mohammadi, V Esser, JK Elmquist, RD Gerard, SC Burgess, RE Hammer, DJ Mangelsdorf, SA Kliewer. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5(6): 415–425 https://doi.org/10.1016/j.cmet.2007.05.003
pmid: 17550777
51
A Kharitonenkov, TL Shiyanova, A Koester, AM Ford, R Micanovic, EJ Galbreath, GE Sandusky, LJ Hammond, JS Moyers, RA Owens, J Gromada, JT Brozinick, ED Hawkins, VJ Wroblewski, DS Li, F Mehrbod, SR Jaskunas, AB Shanafelt. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115(6): 1627–1635 https://doi.org/10.1172/JCI23606
pmid: 15902306
52
R Goetz, M Ohnishi, X Ding, H Kurosu, L Wang, J Akiyoshi, J Ma, W Gai, Y Sidis, N Pitteloud, OM Kuro, MS Razzaque, M Mohammadi. Klotho co-receptors inhibit signaling by paracrine FGF8 subfamily ligands. Mol Cell Biol 32(10):1944–1954 https://doi.org/10.1128/MCB.06603-11
pmid: 22451487
53
Y Luo, C Yang, W Lu, R Xie, C Jin, P Huang, F Wang, WL McKeehan. 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): 30069–30078 https://doi.org/10.1074/jbc.M110.148288
54
M Itoh, JC Nacher, K Kuma, S Goto, M Kanehisa. Evolutionary history and functional implications of protein domains and their combinations in eukaryotes. Genome Biol 2007; 8(6): R121 https://doi.org/10.1186/gb-2007-8-6-r121
pmid: 17588271
55
H Kurosu, M Choi, Y Ogawa, AS Dickson, R Goetz, AV Eliseenkova, M Mohammadi, KP Rosenblatt, SA Kliewer, M Kuro-o. 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): 26687–26695 https://doi.org/10.1074/jbc.M704165200
pmid: 17623664
56
K Fon Tacer, AL Bookout, X Ding, H Kurosu, GB John, L Wang, R Goetz, M Mohammadi, M Kuro-o, DJ Mangelsdorf, SA Kliewer. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010; 24(10): 2050–2064 https://doi.org/10.1210/me.2010-0142
pmid: 20667984
57
H Wang, L Qiang, SR Farmer. 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): 188–200 https://doi.org/10.1128/MCB.00992-07
pmid: 17954559
Y Wang, LA Solt, TP Burris. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor α. J Biol Chem 2010; 285(21): 15668–15673 https://doi.org/10.1074/jbc.M110.102160
pmid: 20332535
60
T Uebanso, Y Taketani, H Yamamoto, K Amo, S Tanaka, H Arai, Y Takei, M Masuda, H Yamanaka-Okumura, E Takeda. Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet. J Nutr Biochem 2012; 23(7): 785–790 https://doi.org/10.1016/j.jnutbio.2011.03.023
pmid: 21889884
61
R Masuyama, I Stockmans, S Torrekens, R Van Looveren, C Maes, P Carmeliet, R Bouillon, G Carmeliet. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest 2006; 116(12): 3150–3159 https://doi.org/10.1172/JCI29463
pmid: 17099775
62
OI Kolek, ER Hines, MD Jones, LK LeSueur, MA Lipko, PR Kiela, JF Collins, MR Haussler, FK Ghishan. 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–G1042 https://doi.org/10.1152/ajpgi.00243.2005
pmid: 16020653
63
Y Zhang, T Lei, JF Huang, SB Wang, LL Zhou, ZQ Yang, XD Chen. 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): 41–47 https://doi.org/10.1016/j.mce.2011.05.003
pmid: 21664250
64
TF Liu, JJ Tang, PS Li, Y Shen, JG Li, HH Miao, BL Li, BL Song. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab 2012; 16(2): 213–225 https://doi.org/10.1016/j.cmet.2012.06.014
pmid: 22863805
65
ES Muise, B Azzolina, DW Kuo, M El-Sherbeini, Y Tan, X Yuan, J Mu, JR Thompson, JP Berger, KK Wong. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor γ and altered metabolic states. Mol Pharmacol 2008; 74(2): 403–412 https://doi.org/10.1124/mol.108.044826
pmid: 18467542
66
AL De Sousa-Coelho, PF Marrero, D Haro. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J 2012; 443(1): 165–171 https://doi.org/10.1042/BJ20111748
pmid: 22233381
67
C Yang, C Jin, X Li, F Wang, WL McKeehan, Y Luo. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS One 2012; 7(3): e33870 https://doi.org/10.1371/journal.pone.0033870
pmid: 22442730
68
S Lee, J Choi, J Mohanty, LP Sousa, F Tome, E Pardon, J Steyaert, MA Lemmon, I Lax, J Schlessinger. Structures of b-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling. Nature 2018; 553(7689): 501–505 https://doi.org/10.1038/nature25010
pmid: 29342135
SA Harrison, ME Rinella, MF Abdelmalek, JF Trotter, AH Paredes, HL Arnold, M Kugelmas, MR Bashir, MJ Jaros, L Ling, SJ Rossi, AM DePaoli, R Loomba. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018; 391(10126): 1174–1185 https://doi.org/10.1016/S0140-6736(18)30474-4
pmid: 29519502
71
GM Hirschfield, O Chazouillères, JP Drenth, D Thorburn, SA Harrison, CS Landis, MJ Mayo, AJ Muir, JF Trotter, DJ Leeming, MA Karsdal, MJ Jaros, L Ling, KH Kim, SJ Rossi, RM Somaratne, AM DePaoli, U Beuers. 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): 483–493 https://doi.org/10.1016/j.jhep.2018.10.035
pmid: 30414864
72
SA Harrison, SJ Rossi, AH Paredes, JF Trotter, MR Bashir, CD Guy, R Banerjee, MJ Jaros, S Owers, BA Baxter, L Ling, AM DePaoli. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology 2019 Feb 25. [Epub ahead of print] doi:10.1002/hep.30590
pmid: 30805949
73
A Sanyal, ED Charles, BA Neuschwander-Tetri, R Loomba, SA Harrison, MF Abdelmalek, EJ Lawitz, D Halegoua-DeMarzio, S Kundu, S Noviello, Y Luo, R Christian. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 2018; 392(10165): 2705–2717 https://doi.org/10.1016/S0140-6736(18)31785-9
pmid: 30554783
74
S Talukdar, Y Zhou, D Li, M Rossulek, J Dong, V Somayaji, Y Weng, R Clark, A Lanba, BM Owen, MB Brenner, JK Trimmer, KE Gropp, JR Chabot, DM Erion, TP Rolph, B Goodwin, RA Calle. 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): 427–440 https://doi.org/10.1016/j.cmet.2016.02.001
pmid: 26959184
75
TO Carpenter, EA Imel, MD Ruppe, TJ Weber, MA Klausner, MM Wooddell, T Kawakami, T Ito, X Zhang, J Humphrey, KL Insogna, M Peacock. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest 2014; 124(4): 1587–1597 https://doi.org/10.1172/JCI72829
pmid: 24569459
76
C Yu, F Wang, M Kan, C Jin, RB Jones, M Weinstein, CX Deng, WL McKeehan. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem 2000; 275(20): 15482–15489 https://doi.org/10.1074/jbc.275.20.15482
pmid: 10809780
77
L Fu, LM John, SH Adams, XX Yu, E Tomlinson, M Renz, PM Williams, R Soriano, R Corpuz, B Moffat, R Vandlen, L Simmons, J Foster, JP Stephan, SP Tsai, TA Stewart. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 2004; 145(6): 2594–2603 https://doi.org/10.1210/en.2003-1671
pmid: 14976145
78
E Tomlinson, L Fu, L John, B Hultgren, X Huang, M Renz, JP Stephan, SP Tsai, L Powell-Braxton, D French, TA Stewart. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 2002; 143(5): 1741–1747 https://doi.org/10.1210/endo.143.5.8850
pmid: 11956156
79
AC Adams, C Yang, T Coskun, CC Cheng, RE Gimeno, Y Luo, A Kharitonenkov. The breadth of FGF21’s metabolic actions are governed by FGFR1 in adipose tissue. Mol Metab 2013; 2(1): 31–37 https://doi.org/10.1016/j.molmet.2012.08.007
pmid: 24024127
80
JR Walters, AM Tasleem, OS Omer, WG Brydon, T Dew, CW le Roux. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol 2009 7(11):1189–1194 https://doi.org/10.1016/j.cgh.2009.04.024
pmid: 19426836
81
I Oduyebo, M Camilleri, AD Nelson, D Khemani, SL Nord, I Busciglio, D Burton, D Rhoten, M Ryks, P Carlson, L Donato, A Lueke, K Kim, SJ Rossi, AR Zinsmeister. 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): 725–734 https://doi.org/10.1038/s41395-018-0042-7
pmid: 29717197
82
R Pai, D French, N Ma, K Hotzel, E Plise, L Salphati, KD Setchell, J Ware, V Lauriault, L Schutt, D Hartley, D Dambach. Antibody-mediated 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): 446–456 https://doi.org/10.1093/toxsci/kfs011
pmid: 22268002
83
GS Gerhard, AM Styer, GC Wood, SL Roesch, AT Petrick, J Gabrielsen, WE Strodel, CD Still, G Argyropoulos. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care 2013; 36(7): 1859–1864 https://doi.org/10.2337/dc12-2255
pmid: 23801799
84
J Luo, B Ko, M Elliott, M Zhou, DA Lindhout, V Phung, C To, RM Learned, H Tian, AM DePaoli, L Ling. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014; 6(247): 247ra100 https://doi.org/10.1126/scitranslmed.3009098
pmid: 25080475
85
FG Schaap, NA van der Gaag, DJ Gouma, PL Jansen. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 2009; 49(4): 1228–1235 https://doi.org/10.1002/hep.22771
pmid: 19185005
86
B Benoit, E Meugnier, M Castelli, S Chanon, A Vieille-Marchiset, C Durand, N Bendridi, S Pesenti, PA Monternier, AC Durieux, D Freyssenet, J Rieusset, E Lefai, H Vidal, J Ruzzin. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med 2017; 23(8): 990–996 https://doi.org/10.1038/nm.4363
pmid: 28650457
87
K Nicholes, S Guillet, E Tomlinson, K Hillan, B Wright, GD Frantz, TA Pham, L Dillard-Telm, SP Tsai, JP Stephan, J Stinson, T Stewart, DM French. 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): 2295–2307 https://doi.org/10.1016/S0002-9440(10)61177-7
pmid: 12057932
88
M Zhou, RM Learned, SJ Rossi, AM DePaoli, H Tian, L Ling. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology 2016; 63(3): 914–929 https://doi.org/10.1002/hep.28257
pmid: 26418580
89
MJ Mayo, AJ Wigg, BA Leggett, H Arnold, AJ Thompson, M Weltman, EJ Carey, AJ Muir, L Ling, SJ Rossi, AM DePaoli. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun 2018; 2(9): 1037–1050 https://doi.org/10.1002/hep4.1209
pmid: 30202819
C Giannini, AE Feldstein, N Santoro, G Kim, R Kursawe, B Pierpont, S Caprio. 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): 2993–3000 https://doi.org/10.1210/jc.2013-1250
pmid: 23626003
92
Z Lin, Q Gong, C Wu, J Yu, T Lu, X Pan, S Lin, X Li. Dynamic change of serum FGF21 levels in response to glucose challenge in human. J Clin Endocrinol Metab 2012; 97(7): E1224–E1228 https://doi.org/10.1210/jc.2012-1132
pmid: 22539584
93
Y Yilmaz, F Eren, O Yonal, R Kurt, B Aktas, CA Celikel, O Ozdogan, N Imeryuz, C Kalayci, E Avsar. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest 2010; 40(10): 887–892 https://doi.org/10.1111/j.1365-2362.2010.02338.x
pmid: 20624171
94
SA Kliewer, DJ Mangelsdorf. A dozen years of discovery: insights into the physiology and pharmacology of FGF21. Cell Metab 2019; 29(2): 246–253 https://doi.org/10.1016/j.cmet.2019.01.004
pmid: 30726758
95
T Laeger, TM Henagan, DC Albarado, LM Redman, GA Bray, RC Noland, H Münzberg, SM Hutson, TW Gettys, MW Schwartz, CD Morrison. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014; 124(9): 3913–3922 https://doi.org/10.1172/JCI74915
pmid: 25133427
96
FM Fisher, M Kim, L Doridot, JC Cunniff, TS Parker, DM Levine, MK Hellerstein, LC Hudgins, E Maratos-Flier, MA Herman. A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Mol Metab 2017; 6(1): 14–21 https://doi.org/10.1016/j.molmet.2016.11.008
pmid: 28123933
97
S von Holstein-Rathlou, LD BonDurant, L Peltekian, MC Naber, TC Yin, KE Claflin, AI Urizar, AN Madsen, C Ratner, B Holst, K Karstoft, A Vandenbeuch, CB Anderson, MD Cassell, AP Thompson, TP Solomon, K Rahmouni, SC Kinnamon, AA Pieper, MP Gillum, MJ Potthoff. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab 2016; 23(2): 335–343 https://doi.org/10.1016/j.cmet.2015.12.003
pmid: 26724858
98
S Talukdar, BM Owen, P Song, G Hernandez, Y Zhang, Y Zhou, WT Scott, B Paratala, T Turner, A Smith, B Bernardo, CP Müller, H Tang, DJ Mangelsdorf, B Goodwin, SA Kliewer. FGF21 regulates sweet and alcohol preference. Cell Metab 2016; 23(2): 344–349 https://doi.org/10.1016/j.cmet.2015.12.008
pmid: 26724861
99
FM Fisher, PC Chui, IA Nasser, Y Popov, JC Cunniff, T Lundasen, A Kharitonenkov, D Schuppan, JS Flier and E Maratos-Flier. 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.e6 https://doi.org/10.1053/j.gastro.2014.07.044
pmid: 25083607
100
X Huang, C Yu, C Jin, C Yang, R Xie, D Cao, F Wang, WL McKeehan. Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Mol Carcinog 2006; 45(12): 934–942 https://doi.org/10.1002/mc.20241
pmid: 16929488
101
N Tanaka, S Takahashi, Y Zhang, KW Krausz, PB Smith, AD Patterson, FJ Gonzalez. 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): 1242–1252 https://doi.org/10.1016/j.bbadis.2015.02.012
pmid: 25736301
102
BN Desai, G Singhal, M Watanabe, D Stevanovic, T Lundasen, FM Fisher, ML Mather, HG Vardeh, N Douris, AC Adams, IA Nasser, GA FitzGerald, JS Flier, C Skarke, E Maratos-Flier. 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): 1395–1406 https://doi.org/10.1016/j.molmet.2017.08.004
pmid: 29107287
103
D Ye, Y Wang, H Li, W Jia, K Man, CM Lo, Y Wang, KS Lam, A Xu. Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1a-mediated antioxidant capacity in mice. Hepatology 2014; 60(3): 977–989 https://doi.org/10.1002/hep.27060
pmid: 24590984
104
G Singhal, G Kumar, S Chan, FM Fisher, Y Ma, HG Vardeh, IA Nasser, JS Flier, E Maratos-Flier. Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet. Mol Metab 2018; 13: 56–66 https://doi.org/10.1016/j.molmet.2018.03.002
pmid: 29753678
105
M Ye, W Lu, X Wang, C Wang, JL Abbruzzese, G Liang, X Li, Y Luo. FGF21-FGFR1 coordinates phospholipid homeostasis, lipid droplet function, and ER stress in obesity. Endocrinology 2016; 157(12): 4754–4769 https://doi.org/10.1210/en.2016-1710
pmid: 27690692
106
IN Foltz, S Hu, C King, X Wu, C Yang, W Wang, J Weiszmann, J Stevens, JS Chen, N Nuanmanee, J Gupte, R Komorowski, L Sekirov, T Hager, T Arora, H Ge, H Baribault, F Wang, J Sheng, M Karow, M Wang, Y Luo, W McKeehan, Z Wang, MM Véniant, Y Li. Treating diabetes and obesity with an FGF21-mimetic antibody activating the bKlotho/FGFR1c receptor complex. Sci Transl Med 2012; 4(162): 162ra153 https://doi.org/10.1126/scitranslmed.3004690
pmid: 23197570
107
G Gaich, JY Chien, H Fu, LC Glass, MA Deeg, WL Holland, A Kharitonenkov, T Bumol, HK Schilske, DE Moller. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013; 18(3): 333–340 https://doi.org/10.1016/j.cmet.2013.08.005
pmid: 24011069
108
Z Lin, H Tian, KS Lam, S Lin, RC Hoo, M Konishi, N Itoh, Y Wang, SR Bornstein, A Xu, X Li. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013; 17(5): 779–789 https://doi.org/10.1016/j.cmet.2013.04.005
pmid: 23663741
109
Z Huang, L Zhong, JTH Lee, J Zhang, D Wu, L Geng, Y Wang, CM Wong, A Xu. 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.e4 https://doi.org/10.1016/j.cmet.2017.08.003
pmid: 28844880
110
P Lee, JD Linderman, S Smith, RJ Brychta, J Wang, C Idelson, RM Perron, CD Werner, GQ Phan, US Kammula, E Kebebew, K Pacak, KY Chen, FS Celi. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014; 19(2): 302–309 https://doi.org/10.1016/j.cmet.2013.12.017
pmid: 24506871
111
E Hondares, R Iglesias, A Giralt, FJ Gonzalez, M Giralt, T Mampel, F Villarroya. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011; 286(15): 12983–12990 https://doi.org/10.1074/jbc.M110.215889
pmid: 21317437
112
M Ameka, KR Markan, DA Morgan, LD BonDurant, SO Idiga, MC Naber, Z Zhu, LV Zingman, JL Grobe, K Rahmouni, MJ Potthoff. Liver derived FGF21 maintains core body temperature during acute cold exposure. Sci Rep 2019; 9(1): 630 https://doi.org/10.1038/s41598-018-37198-y
pmid: 30679672
113
Y Zhang, Y Xie, ED Berglund, KC Coate, TT He, T Katafuchi, G Xiao, MJ Potthoff, W Wei, Y Wan, RT Yu, RM Evans, SA Kliewer, DJ Mangelsdorf. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 2012; 1: e00065 https://doi.org/10.7554/eLife.00065
pmid: 23066506
114
YH Youm, TL Horvath, DJ Mangelsdorf, SA Kliewer, VD Dixit. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci USA 2016; 113(4): 1026–1031 https://doi.org/10.1073/pnas.1514511113
pmid: 26755598
115
AC Adams, T Coskun, CC Cheng, LS O′Farrell, SL Dubois, A Kharitonenkov. Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones. Mol Metab 2013; 2(3): 205–214 https://doi.org/10.1016/j.molmet.2013.05.005
pmid: 24049735
116
KC Coate, G Hernandez, CA Thorne, S Sun, TDV Le, K Vale, SA Kliewer, DJ Mangelsdorf. FGF21 is an exocrine pancreas secretagogue. Cell Metab 2017; 25(2): 472–480 https://doi.org/10.1016/j.cmet.2016.12.004
pmid: 28089565
117
G Singhal, FM Fisher, MJ Chee, TG Tan, A El Ouaamari, AC Adams, R Najarian, RN Kulkarni, C Benoist, JS Flier, E Maratos-Flier. Fibroblast growth factor 21 (FGF21) protects against high fat diet induced inflammation and islet hyperplasia in pancreas. PLoS One 2016; 11(2): e0148252 https://doi.org/10.1371/journal.pone.0148252
pmid: 26872145
118
CL Johnson, R Mehmood, SW Laing, CV Stepniak, A Kharitonenkov, CL Pin. 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–E928 https://doi.org/10.1152/ajpendo.00559.2013
pmid: 24549397
119
CL Johnson, JY Weston, SA Chadi, EN Fazio, MW Huff, A Kharitonenkov, A Köester, CL Pin. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 2009; 137(5): 1795–1804 https://doi.org/10.1053/j.gastro.2009.07.064
pmid: 19664632
120
M Kuroda, R Muramatsu, N Maedera, Y Koyama, M Hamaguchi, H Fujimura, M Yoshida, M Konishi, N Itoh, H Mochizuki, T Yamashita. Peripherally derived FGF21 promotes remyelination in the central nervous system. J Clin Invest 2017; 127(9): 3496–3509 https://doi.org/10.1172/JCI94337
pmid: 28825598
121
S Soberg, CH Sandholt, NZ Jespersen, U Toft, AL Madsen, S von Holstein-Rathlou, TJ Grevengoed, KB Christensen, WLP Bredie, MJ Potthoff, TPJ Solomon, C Scheele, A Linneberg, T Jorgensen, O Pedersen, T Hansen, MP Gillum, N Grarup. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab 2017; 25(5): 1045–1053.e6 https://doi.org/10.1016/j.cmet.2017.04.009
pmid: 28467924
122
P Song, C Zechner, G Hernandez, J Canovas, Y Xie, V Sondhi, M Wagner, V Stadlbauer, A Horvath, B Leber, MC Hu, OW Moe, DJ Mangelsdorf, SA Kliewer. The hormone FGF21 stimulates water drinking in response to ketogenic diet and alcohol. Cell Metab 2018; 27(6): 1338–1347.e4 https://doi.org/10.1016/j.cmet.2018.04.001
pmid: 29657029
123
TM Frayling, RN Beaumont, SE Jones, H Yaghootkar, MA Tuke, KS Ruth, F Casanova, B West, J Locke, S Sharp, Y Ji, W Thompson, J Harrison, AS Etheridge, PJ Gallins, D Jima, F Wright, Y Zhou, F Innocenti, CM Lindgren, N Grarup, A Murray, RM Freathy, MN Weedon, J Tyrrell, AR Wood. 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): 327–336 https://doi.org/10.1016/j.celrep.2018.03.070
pmid: 29641994
124
G Schumann, C Liu, P O’Reilly, H Gao, P Song, B Xu, B Ruggeri, N Amin, T Jia, S Preis, M Segura Lepe, S Akira, C Barbieri, S Baumeister, S Cauchi, TK Clarke, S Enroth, K Fischer, J Hällfors, SE Harris, S Hieber, E Hofer, JJ Hottenga, Å Johansson, PK Joshi, N Kaartinen, J Laitinen, R Lemaitre, A Loukola, J Luan, LP Lyytikäinen, M Mangino, A Manichaikul, H Mbarek, Y Milaneschi, A Moayyeri, K Mukamal, C Nelson, J Nettleton, E Partinen, R Rawal, A Robino, L Rose, C Sala, T Satoh, R Schmidt, K Schraut, R Scott, AV Smith, JM Starr, A Teumer, S Trompet, AG Uitterlinden, C Venturini, AC Vergnaud, N Verweij, V Vitart, D Vuckovic, J Wedenoja, L Yengo, B Yu, W Zhang, JH Zhao, DI Boomsma, J Chambers, DI Chasman, T Daniela, E de Geus, I Deary, JG Eriksson, T Esko, V Eulenburg, OH Franco, P Froguel, C Gieger, HJ Grabe, V Gudnason, U Gyllensten, TB Harris, AL Hartikainen, AC Heath, L Hocking, A Hofman, C Huth, MR Jarvelin, JW Jukema, J Kaprio, JS Kooner, Z Kutalik, J Lahti, C Langenberg, T Lehtimäki, Y Liu, PA Madden, N Martin, A Morrison, B Penninx, N Pirastu, B Psaty, O Raitakari, P Ridker, R Rose, JI Rotter, NJ Samani, H Schmidt, TD Spector, D Stott, D Strachan, I Tzoulaki, P van der Harst, CM van Duijn, P Marques-Vidal, P Vollenweider, NJ Wareham, JB Whitfield, J Wilson, B Wolffenbuttel, G Bakalkin, E Evangelou, Y Liu, KM Rice, S Desrivières, SA Kliewer, DJ Mangelsdorf, CP Müller, D Levy, P Elliott. KLB is associated with alcohol drinking, and its gene product b-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci USA 2016; 113(50): 14372–14377 https://doi.org/10.1073/pnas.1611243113
pmid: 27911795
125
LM Restelli, B Oettinghaus, M Halliday, C Agca, M Licci, L Sironi, C Savoia, J Hench, M Tolnay, A Neutzner, A Schmidt, A Eckert, G Mallucci, L Scorrano, S Frank. Neuronal mitochondrial dysfunction activates the integrated stress response to induce fibroblast growth factor 21. Cell Reports 2018; 24(6): 1407–1414 https://doi.org/10.1016/j.celrep.2018.07.023
pmid: 30089252
126
A Planavila, I Redondo, E Hondares, M Vinciguerra, C Munts, R Iglesias, LA Gabrielli, M Sitges, M Giralt, M van Bilsen, F Villarroya. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 2013; 4(1): 2019 https://doi.org/10.1038/ncomms3019
pmid: 23771152
127
T Morville, RE Sahl, SA Trammell, JS Svenningsen, MP Gillum, JW Helge, C Clemmensen. Divergent effects of resistance and endurance exercise on plasma bile acids, FGF19, and FGF21 in humans. JCI Insight 2018; 3(15): 122737 https://doi.org/10.1172/jci.insight.122737
pmid: 30089729
128
MK Brahma, RC Adam, NM Pollak, D Jaeger, KA Zierler, N Pöcher, R Schreiber, M Romauch, T Moustafa, S Eder, T Ruelicke, K Preiss-Landl, A Lass, R Zechner, G Haemmerle. Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis. J Lipid Res 2014; 55(11): 2229–2241 https://doi.org/10.1194/jlr.M044784
pmid: 25176985
129
Z Lin, X Pan, F Wu, D Ye, Y Zhang, Y Wang, L Jin, Q Lian, Y Huang, H Ding, C Triggle, K Wang, X Li, A Xu. 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): 1861–1871 https://doi.org/10.1161/CIRCULATIONAHA.115.015308
pmid: 25794851
130
SQ Liu, D Roberts, A Kharitonenkov, B Zhang, SM Hanson, YC Li, LQ Zhang, YH Wu. Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci Rep 2013; 3(1): 2767 https://doi.org/10.1038/srep02767
pmid: 24067542
131
H Yang, A Feng, S Lin, L Yu, X Lin, X Yan, X Lu, C Zhang. Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death Dis 2018; 9(2): 227 https://doi.org/10.1038/s41419-018-0307-5
pmid: 29445083
132
C Zhang, Z Huang, J Gu, X Yan, X Lu, S Zhou, S Wang, M Shao, F Zhang, P Cheng, W Feng, Y Tan, X Li. 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): 1937–1948 https://doi.org/10.1007/s00125-015-3630-8
pmid: 26040473
133
X Pan, Y Shao, F Wu, Y Wang, R Xiong, J Zheng, H Tian, B Wang, Y Wang, Y Zhang, Z Han, A Qu, H Xu, A Lu, T Yang, X Li, A Xu, J Du, Z. LinFGF21 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.e5 https://doi.org/10.1016/j.cmet.2018.04.002
pmid: 29706566
134
KH Kim, YT Jeong, H Oh, SH Kim, JM Cho, YN Kim, SS Kim, DH Kim, KY Hur, HK Kim, T Ko, J Han, HL Kim, J Kim, SH Back, M Komatsu, H Chen, DC Chan, M Konishi, N Itoh, CS Choi, MS Lee. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 2013; 19(1): 83–92 https://doi.org/10.1038/nm.3014
pmid: 23202295
135
A Suomalainen, JM Elo, KH Pietiläinen, AH Hakonen, K Sevastianova, M Korpela, P Isohanni, SK Marjavaara, T Tyni, S Kiuru-Enari, H Pihko, N Darin, K Õunap, LA Kluijtmans, A Paetau, J Buzkova, LA Bindoff, J Annunen-Rasila, J Uusimaa, A Rissanen, H Yki-Järvinen, M Hirano, M Tulinius, J Smeitink, H Tyynismaa. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011; 10(9): 806–818 https://doi.org/10.1016/S1474-4422(11)70155-7
pmid: 21820356
136
L Geng, B Liao, L Jin, Z Huang, CR Triggle, H Ding, J Zhang, Y Huang, Z Lin, A Xu. Exercise alleviates obesity-induced metabolic dysfunction via enhancing FGF21 sensitivity in adipose tissues. Cell Rep 2019; 26(10): 2738–2752.e4 https://doi.org/10.1016/j.celrep.2019.02.014
pmid: 30840894
137
RO Pereira, SM Tadinada, FM Zasadny, KJ Oliveira, KMP Pires, A Olvera, J Jeffers, R Souvenir, R Mcglauflin, A Seei, T Funari, H Sesaki, MJ Potthoff, CM Adams, EJ Anderson, ED Abel. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 2017; 36(14): 2126–2145 https://doi.org/10.15252/embj.201696179
pmid: 28607005
138
Y Tanimura, W Aoi, Y Takanami, Y Kawai, K Mizushima, Y Naito, T Yoshikawa. Acute exercise increases fibroblast growth factor 21 in metabolic organs and circulation. Physiol Rep 2016; 4(12): e12828 https://doi.org/10.14814/phy2.12828
pmid: 27335433
139
MS Lee, SE Choi, ES Ha, SY An, TH Kim, SJ Han, HJ Kim, DJ Kim, Y Kang, KW Lee. 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): 1142–1151 https://doi.org/10.1016/j.metabol.2012.01.012
pmid: 22398021
BM Owen, X Ding, DA Morgan, KC Coate, AL Bookout, K Rahmouni, SA Kliewer, DJ Mangelsdorf. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 2014; 20(4): 670–677 https://doi.org/10.1016/j.cmet.2014.07.012
pmid: 25130400
142
N Douris, DM Stevanovic, FM Fisher, TI Cisu, MJ Chee, NL Nguyen, E Zarebidaki, AC Adams, A Kharitonenkov, JS Flier, TJ Bartness, E Maratos-Flier. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 2015; 156(7): 2470–2481 https://doi.org/10.1210/en.2014-2001
pmid: 25924103
143
Q Liang, L Zhong, J Zhang, Y Wang, SR Bornstein, CR Triggle, H Ding, KS Lam, A Xu. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 2014; 63(12): 4064–4075 https://doi.org/10.2337/db14-0541
pmid: 25024372
144
BM Owen, AL Bookout, X Ding, VY Lin, SD Atkin, L Gautron, SA Kliewer, DJ Mangelsdorf. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 2013; 19(9): 1153–1156 https://doi.org/10.1038/nm.3250
pmid: 23933983
145
AL Bookout, MH de Groot, BM Owen, S Lee, L Gautron, HL Lawrence, X Ding, JK Elmquist, JS Takahashi, DJ Mangelsdorf, SA Kliewer. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013; 19(9): 1147–1152 https://doi.org/10.1038/nm.3249
pmid: 23933984
146
N Ishida. Role of PPARa in the control of torpor through FGF21-NPY pathway: from circadian clock to seasonal change in mammals. PPAR Res 2009; 2009: 412949 https://doi.org/10.1155/2009/412949
pmid: 19536348
147
Q Wang, J Yuan, Z Yu, L Lin, Y Jiang, Z Cao, P Zhuang, MJ Whalen, B Song, XJ Wang, X Li, EH Lo, Y Xu, X Wang. FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol 2018; 55(6): 4702–4717 https://doi.org/10.1007/s12035-017-0663-7
pmid: 28712011
148
Y Yu, F Bai, W Wang, Y Liu, Q Yuan, S Qu, T Zhang, G Tian, S Li, D Li, G Ren. 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: 122–131 https://doi.org/10.1016/j.pbb.2015.03.020
pmid: 25871519
149
DA Sarruf, JP Thaler, GJ Morton, J German, JD Fischer, K Ogimoto, MW Schwartz. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 2010; 59(7): 1817–1824 https://doi.org/10.2337/db09-1878
pmid: 20357365
150
MM Véniant, C Hale, J Helmering, MM Chen, S Stanislaus, J Busby, S Vonderfecht, J Xu, DJ Lloyd. FGF21 promotes metabolic homeostasis via white adipose and leptin in mice. PLoS One 2012; 7(7): e40164 https://doi.org/10.1371/journal.pone.0040164
pmid: 22792234
151
J Xu, DJ Lloyd, C Hale, S Stanislaus, M Chen, G Sivits, S Vonderfecht, R Hecht, YS Li, RA Lindberg, JL Chen, DY Jung, Z Zhang, HJ Ko, JK Kim, MM Véniant. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58(1): 250–259 https://doi.org/10.2337/db08-0392
pmid: 18840786
152
WY So, Q Cheng, A Xu, KS Lam, PS Leung. Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice. Cell Death Dis 2015; 6(3): e1707 https://doi.org/10.1038/cddis.2015.80
pmid: 25811804
153
C Zhang, M Shao, H Yang, L Chen, L Yu, W Cong, H Tian, F Zhang, P Cheng, L Jin, Y Tan, X Li, L Cai, X Lu. 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): e82275 https://doi.org/10.1371/journal.pone.0082275
pmid: 24349242
154
HW Kim, JE Lee, JJ Cha, YY Hyun, JE Kim, MH Lee, HK Song, DH Nam, JY Han, SY Han, KH Han, YS Kang, DR Cha. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology 2013; 154(9): 3366–3376 https://doi.org/10.1210/en.2012-2276
pmid: 23825123
155
TT Tang, YY Li, JJ Li, K Wang, Y Han, WY Dong, ZF Zhu, N Xia, SF Nie, M Zhang, ZP Zeng, BJ Lv, J Jiao, H Liu, ZS Xian, XP Yang, Y Hu, YH Liao, Q Wang, X Tu, Z Mallat, Y Huang, GP Shi, X Cheng. Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction. Theranostics 20184552–4562 https://doi.org/10.7150/thno.24723
pmid: 30214638
S Li, X Guo, T Zhang, N Wang, J Li, P Xu, S Zhang, G Ren, D Li. Fibroblast growth factor 21 ameliorates high glucose-induced fibrogenesis in mesangial cells through inhibiting STAT5 signaling pathway. Biomed Pharmacother 2017; 93: 695–704 https://doi.org/10.1016/j.biopha.2017.06.100
pmid: 28692941
158
S Li, N Wang, X Guo, J Li, T Zhang, G Ren, D Li. Fibroblast growth factor 21 regulates glucose metabolism in part by reducing renal glucose reabsorption. Biomed Pharmacother 2018; 108: 355–366 https://doi.org/10.1016/j.biopha.2018.09.078
pmid: 30227329
159
XL Lin, XL He, JF Zeng, H Zhang, Y Zhao, JK Tan, Z Wang. FGF21 increases cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARg-LXRa pathway in THP1 macrophage-derived foam cells. DNA Cell Biol 2014; 33(8): 514–521 https://doi.org/10.1089/dna.2013.2290
pmid: 24735204
160
Y Yu, J He, S Li, L Song, X Guo, W Yao, D Zou, X Gao, Y Liu, F Bai, G Ren, D Li. Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-kB signaling pathway. Int Immunopharmacol 2016; 38: 144–152 https://doi.org/10.1016/j.intimp.2016.05.026
pmid: 27276443
161
H Li, G Wu, Q Fang, M Zhang, X Hui, B Sheng, L Wu, Y Bao, P Li, A Xu, W Jia. Fibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat. Nat Commun 2018; 9(1): 272 https://doi.org/10.1038/s41467-017-02677-9
pmid: 29348470
162
SM Li, WF Wang, LH Zhou, L Ma, Y An, WJ Xu, TH Li, YH Yu, DS Li, Y Liu. 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): 519–527 https://doi.org/10.1007/s12020-014-0309-8
pmid: 24895044
163
JY Li, N Wang, MH Khoso, CB Shen, MZ Guo, XX Pang, DS Li, WF Wang. FGF-21 elevated IL-10 production to correct LPS-induced inflammation. Inflammation 2018; 41(3): 751–759 https://doi.org/10.1007/s10753-018-0729-3
pmid: 29427162
164
WF Wang, L Ma, MY Liu, TT Zhao, T Zhang, YB Yang, HX Cao, XH Han, DS Li. A novel function for fibroblast growth factor 21: stimulation of NADPH oxidase-dependent ROS generation. Endocrine 2015; 49(2): 385–395 https://doi.org/10.1007/s12020-014-0502-9
pmid: 25542183
H Saito, K Kusano, M Kinosaki, H Ito, M Hirata, H Segawa, K Miyamoto, N Fukushima. 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): 2206–2211 https://doi.org/10.1074/jbc.M207872200
pmid: 12419819
167
T Shimada, M Kakitani, Y Yamazaki, H Hasegawa, Y Takeuchi, T Fujita, S Fukumoto, K Tomizuka, T Yamashita. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113(4): 561–568 https://doi.org/10.1172/JCI200419081
pmid: 14966565
168
T Shimada, S Mizutani, T Muto, T Yoneya, R Hino, S Takeda, Y Takeuchi, T Fujita, S Fukumoto, T Yamashita. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98(11): 6500–6505 https://doi.org/10.1073/pnas.101545198
pmid: 11344269
169
O Andrukhova, A Smorodchenko, M Egerbacher, C Streicher, U Zeitz, R Goetz, V Shalhoub, M Mohammadi, EE Pohl, B Lanske, RG Erben. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J 2014; 33(3): 229–246 https://doi.org/10.1002/embj.201284188
pmid: 24434184
170
O Andrukhova, S Slavic, A Smorodchenko, U Zeitz, V Shalhoub, B Lanske, EE Pohl, RG Erben. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 2014; 6(6): 744–759 https://doi.org/10.1002/emmm.201303716
pmid: 24797667
171
IZ Ben-Dov, H Galitzer, V Lavi-Moshayoff, R Goetz, M Kuro-o, M Mohammadi, R Sirkis, T Naveh-Many, J Silver. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007; 117(12): 4003–4008 https://doi.org/10.1172/JCI32409
pmid: 17992255
172
L Toro, V Barrientos, P León, M Rojas, M Gonzalez, A González-Ibáñez, S Illanes, K Sugikawa, N Abarzúa, C Bascuñán, K Arcos, C Fuentealba, AM Tong, AA Elorza, ME Pinto, R Alzamora, C Romero, L Michea. Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury. Kidney Int 2018; 93(5): 1131–1141 https://doi.org/10.1016/j.kint.2017.11.018
pmid: 29395333
173
S Rabadi, I Udo, DE Leaf, SS Waikar, M Christov. Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol 2018; 314(1): F132–F139 https://doi.org/10.1152/ajprenal.00081.2017
pmid: 28877877
174
ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26(3): 345–348 https://doi.org/10.1038/81664
pmid: 11062477
175
AE Bowe, R Finnegan, SM Jan de Beur, J Cho, MA Levine, R Kumar, SC Schiavi. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun 2001; 284(4): 977–981 https://doi.org/10.1006/bbrc.2001.5084
pmid: 11409890
176
M Riminucci, MT Collins, NS Fedarko, N Cherman, A Corsi, KE White, S Waguespack, A Gupta, T Hannon, MJ Econs, P Bianco, P Gehron Robey. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003; 112(5): 683–692 https://doi.org/10.1172/JCI18399
pmid: 12952917
177
WH Hoffman, HW Jueppner, BR Deyoung, MS O’dorisio, KS Given. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 2005; 134(3): 233–236 https://doi.org/10.1002/ajmg.a.30599
pmid: 15742370
178
K Kato, C Jeanneau, MA Tarp, A Benet-Pagès, B Lorenz-Depiereux, EP Bennett, U Mandel, TM Strom, H Clausen. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 2006; 281(27): 18370–18377 https://doi.org/10.1074/jbc.M602469200
pmid: 16638743
179
S Ichikawa, EA Imel, AH Sorenson, R Severe, P Knudson, GJ Harris, JL Shaker, MJ Econs. 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): 4472–4475 https://doi.org/10.1210/jc.2006-1247
pmid: 16940445
180
HJ Garringer, C Fisher, TE Larsson, SI Davis, DL Koller, MJ Cullen, MS Draman, N Conlon, A Jain, NS Fedarko, B Dasgupta, KE White. 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): 4037–4042 https://doi.org/10.1210/jc.2006-0305
pmid: 16868048
181
A Benet-Pagès, P Orlik, TM Strom, B Lorenz-Depiereux. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 2005; 14(3): 385–390 https://doi.org/10.1093/hmg/ddi034
pmid: 15590700
182
I Chefetz, R Heller, A Galli-Tsinopoulou, G Richard, B Wollnik, M Indelman, F Koerber, O Topaz, R Bergman, E Sprecher, E Schoenau. A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification. Hum Genet 2005; 118(2): 261–266 https://doi.org/10.1007/s00439-005-0026-8
pmid: 16151858
183
K Araya, S Fukumoto, R Backenroth, Y Takeuchi, K Nakayama, N Ito, N Yoshii, Y Yamazaki, T Yamashita, J Silver, T Igarashi, T Fujita. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 2005; 90(10): 5523–5527 https://doi.org/10.1210/jc.2005-0301
pmid: 16030159
184
F Abbasi, S Ghafouri-Fard, M Javaheri, A Dideban, A Ebrahimi, A Ebrahim-Habibi. A new missense mutation in FGF23 gene in a male with hyperostosis-hyperphosphatemia syndrome (HHS). Gene 2014; 542(2): 269–271 https://doi.org/10.1016/j.gene.2014.03.052
pmid: 24680727
185
C Faul, AP Amaral, B Oskouei, MC Hu, A Sloan, T Isakova, OM Gutiérrez, R Aguillon-Prada, J Lincoln, JM Hare, P Mundel, A Morales, J Scialla, M Fischer, EZ Soliman, J Chen, AS Go, SE Rosas, L Nessel, RR Townsend, HI Feldman, M St John Sutton, A Ojo, C Gadegbeku, GS Di Marco, S Reuter, D Kentrup, K Tiemann, M Brand, JA Hill, OW Moe, M Kuro-O, JW Kusek, MG Keane, M Wolf. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121(11): 4393–4408 https://doi.org/10.1172/JCI46122
pmid: 21985788
186
OM Gutiérrez, JL Januzzi, T Isakova, K Laliberte, K Smith, G Collerone, A Sarwar, U Hoffmann, E Coglianese, R Christenson, TJ Wang, C deFilippi, M Wolf. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119(19): 2545–2552 https://doi.org/10.1161/CIRCULATIONAHA.108.844506
pmid: 19414634
187
ER McGrath, JJ Himali, D Levy, SC Conner, MP Pase, CR Abraham, P Courchesne, CL Satizabal, RS Vasan, AS Beiser, S Seshadri. Circulating fibroblast growth factor 23 levels and incident dementia: The Framingham heart study. PLoS One 2019; 14(3): e0213321 https://doi.org/10.1371/journal.pone.0213321
pmid: 30830941
188
P Liu, L Chen, X Bai, A Karaplis, D Miao, N Gu. Impairment of spatial learning and memory in transgenic mice overexpressing human fibroblast growth factor-23. Brain Res 2011; 1412: 9–17 https://doi.org/10.1016/j.brainres.2011.07.028
pmid: 21824606