title: Fibroblast Growth Factor Signaling in Metabolic Regulation.
abstract: The prevalence of obesity is a growing health problem. Obesity is strongly associated with several comorbidities, such as non-alcoholic fatty liver disease, certain cancers, insulin resistance, and type 2 diabetes, which all reduce life expectancy and life quality. Several drugs have been put forward in order to treat these diseases, but many of them have detrimental side effects. The unexpected role of the family of fibroblast growth factors in the regulation of energy metabolism provides new approaches to the treatment of metabolic diseases and offers a valuable tool to gain more insight into metabolic regulation. The known beneficial effects of FGF19 and FGF21 on metabolism, together with recently discovered similar effects of FGF1 suggest that FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. To facilitate the development of new therapies with improved targeting and minimal side effects, a better understanding of the molecular mechanism of action of FGFs is needed. In this review, we will discuss what is currently known about the physiological roles of FGF signaling in tissues important for metabolic homeostasis. In addition, we will discuss current concepts regarding their pharmacological properties and effector tissues in the context of metabolic disease. Also, the recent progress in the development of FGF variants will be reviewed. Our goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease and to provide starting points for the development of FGF-based therapies against metabolic conditions.
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Vera J M
authors.initials: VJ
authors.lastname: Nies
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies , La Jolla, CA , USA.
authors.forename: Gencer
authors.initials: G
authors.lastname: Sancar
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Weilin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: van Zutphen
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Dicky
authors.initials: D
authors.lastname: Struik
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies , La Jolla, CA , USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies , La Jolla, CA , USA.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies , La Jolla, CA , USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies , La Jolla, CA , USA.
authors.forename: Michael Robert
authors.initials: MR
authors.lastname: Downes
keywords: FGF signaling; FGF1; FGF19; FGF21; fibroblast growth factors; metabolic syndrome; therapeutic potential
references.citation: Endocrinology. 2012 Sep;153(9):4238-45
references.pmid: 22778214
references.citation: Circulation. 1998 Feb 24;97(7):645-50
references.pmid: 9495299
references.citation: Gene. 2001 Jun 27;271(2):171-82
references.pmid: 11418238
references.citation: Diabetes. 2010 Jul;59(7):1817-24
references.pmid: 20357365
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14158-63
references.pmid: 20660733
references.citation: J Biol Chem. 2007 Sep 14;282(37):27277-84
references.pmid: 17627937
references.citation: PLoS One. 2012;7(3):e33870
references.pmid: 22442730
references.citation: FEBS Lett. 2009 Jan 5;583(1):19-24
references.pmid: 19059246
references.citation: Mech Dev. 2000 Nov;98(1-2):115-9
references.pmid: 11044614
references.citation: Brain Res Bull. 1992 Sep-Oct;29(3-4):525-8
references.pmid: 1382816
references.citation: Nature. 2000 Dec 14;408(6814):864-8
references.pmid: 11130726
references.citation: Diabetes Metab Res Rev. 2011 Mar;27(3):286-97
references.pmid: 21309058
references.citation: Endocrinology. 2013 Sep;154(9):3099-109
references.pmid: 23766126
references.citation: J Biol Chem. 2011 Oct 7;286(40):34533-41
references.pmid: 21846717
references.citation: Nat Med. 2013 Sep;19(9):1147-52
references.pmid: 23933984
references.citation: Nature. 2012 May 17;485(7398):391-4
references.pmid: 22522926
references.citation: Dev Dyn. 2004 Feb;229(2):380-92
references.pmid: 14745964
references.citation: FEBS Lett. 2008 Nov 12;582(27):3805-10
references.pmid: 18948104
references.citation: Science. 2011 Mar 25;331(6024):1621-4
references.pmid: 21436455
references.citation: PLoS One. 2012;7(11):e48210
references.pmid: 23133616
references.citation: Cell Metab. 2008 Sep;8(3):224-36
references.pmid: 18762023
references.citation: FASEB J. 2006 Dec;20(14):2615-7
references.pmid: 17068114
references.citation: Am J Pathol. 2002 Jun;160(6):2295-307
references.pmid: 12057932
references.citation: Drug Discov Today. 2014 Jan;19(1):51-62
references.pmid: 23932951
references.citation: Oncogene. 2000 Jul 6;19(29):3309-20
references.pmid: 10918587
references.citation: PLoS One. 2013;8(3):e55632
references.pmid: 23533568
references.citation: J Clin Invest. 2013 Nov;123(11):4799-808
references.pmid: 24084738
references.citation: Sci Rep. 2015 Jul 08;5:11382
references.pmid: 26153793
references.citation: Cell. 2012 Feb 3;148(3):556-67
references.pmid: 22304921
references.citation: Cell Metab. 2012 Sep 5;16(3):387-93
references.pmid: 22958921
references.citation: Nature. 2013 Nov 7;503(7474):59-66
references.pmid: 24201279
references.citation: Cell Rep. 2015 May 19;11(7):991-9
references.pmid: 25956583
references.citation: J Biol Chem. 2008 Jun 27;283(26):18066-75
references.pmid: 18441324
references.citation: Cell Metab. 2013 Sep 3;18(3):333-40
references.pmid: 24011069
references.citation: Cell Metab. 2015 May 5;21(5):731-8
references.pmid: 25955208
references.citation: Science. 2005 Jan 21;307(5708):375-9
references.pmid: 15662002
references.citation: Bioconjug Chem. 2013 Jun 19;24(6):915-25
references.pmid: 23594041
references.citation: Cell Metab. 2013 May 7;17(5):790-7
references.pmid: 23663742
references.citation: Mol Metab. 2013 Dec 27;3(3):221-9
references.pmid: 24749049
references.citation: Arterioscler Thromb Vasc Biol. 2012 May;32(5):1220-7
references.pmid: 22267484
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):233-47
references.pmid: 15863038
references.citation: PLoS One. 2012;7(11):e49977
references.pmid: 23209629
references.citation: J Pharmacol Exp Ther. 2013 Aug;346(2):270-80
references.pmid: 23720456
references.citation: Fluids Barriers CNS. 2013 Nov 01;10(1):32
references.pmid: 24176017
references.citation: Endocrinology. 2012 Jan;153(1):69-80
references.pmid: 22067317
references.citation: J Biol Chem. 1975 Apr 10;250(7):2515-20
references.pmid: 1168187
references.citation: J Biol Chem. 2013 Jun 14;288(24):17859-70
references.pmid: 23640895
references.citation: Genes Dev. 2012 Feb 1;26(3):271-81
references.pmid: 22302939
references.citation: Mol Endocrinol. 2010 Oct;24(10):2050-64
references.pmid: 20667984
references.citation: EBioMedicine. 2015 May 30;2(7):730-43
references.pmid: 26288846
references.citation: J Biol Chem. 2011 Apr 15;286(15):12983-90
references.pmid: 21317437
references.citation: Cell. 1997 May 30;89(5):693-702
references.pmid: 9182757
references.citation: Biochim Biophys Acta. 2001 Mar 19;1518(1-2):152-6
references.pmid: 11267671
references.citation: J Clin Invest. 2014 Feb;124(2):515-27
references.pmid: 24401271
references.citation: Pharm Res. 2000 Jan;17(1):63-9
references.pmid: 10714610
references.citation: Sci Transl Med. 2012 Nov 28;4(162):162ra153
references.pmid: 23197570
references.citation: Hepatology. 2012 Sep;56(3):1034-43
references.pmid: 22467244
references.citation: Nat Med. 2014 Apr;20(4):337-8
references.pmid: 24710375
references.citation: Curr Opin Hematol. 2008 May;15(3):215-20
references.pmid: 18391788
references.citation: Mol Endocrinol. 2015 Feb;29(2):213-23
references.pmid: 25495872
references.citation: PLoS One. 2011 Mar 18;6(3):e17868
references.pmid: 21437243
references.citation: Hum Mol Genet. 2014 Jan 1;23 (1):24-39
references.pmid: 23943793
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7432-7
references.pmid: 17452648
references.citation: Cell Metab. 2010 Mar 3;11(3):206-12
references.pmid: 20197053
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49
references.pmid: 15863030
references.citation: Hum Mol Genet. 2010 Oct 15;19(20):3948-58
references.pmid: 20656789
references.citation: Mol Metab. 2012 Aug 28;2(1):31-7
references.pmid: 24024127
references.citation: J Cell Sci. 1992 Dec;103 ( Pt 4):931-42
references.pmid: 1362571
references.citation: J Cell Physiol. 2007 Jan;210(1):1-6
references.pmid: 17063460
references.citation: Exp Neurol. 1996 Feb;137(2):318-23
references.pmid: 8635547
references.citation: Mol Endocrinol. 2008 Apr;22(4):1006-14
references.pmid: 18187602
references.citation: Diabetes. 2004 Dec;53(12):3097-106
references.pmid: 15561939
references.citation: Sci Transl Med. 2011 Dec 14;3(113):113ra126
references.pmid: 22174314
references.citation: Trends Endocrinol Metab. 2015 Jan;26(1):22-9
references.pmid: 25476453
references.citation: Physiol Behav. 1994 Aug;56(2):211-8
references.pmid: 7524109
references.citation: J Cell Physiol. 2009 May;219(2):227-34
references.pmid: 19117008
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):107-37
references.pmid: 15863029
references.citation: J Mol Biol. 2004 Jun 11;339(4):821-34
references.pmid: 15165853
references.citation: Science. 1990 Sep 28;249(4976):1567-70
references.pmid: 1699274
references.citation: Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E964-76
references.pmid: 17132826
references.citation: Cell Metab. 2014 Oct 7;20(4):670-7
references.pmid: 25130400
references.citation: Genes Dev. 1997 Aug 15;11(16):2040-51
references.pmid: 9284044
references.citation: Nutr Metab (Lond). 2012 Oct 30;9(1):94
references.pmid: 23106963
references.citation: Diabetes. 2009 Jan;58(1):250-9
references.pmid: 18840786
references.citation: Front Endocrinol (Lausanne). 2014 Feb 24;5:18
references.pmid: 24605108
references.citation: J Clin Endocrinol Metab. 2010 May;95(5):2451-7
references.pmid: 20228166
references.citation: Diabetes. 2013 Nov;62(11):3751-9
references.pmid: 23897951
references.citation: Diabetes. 2009 Dec;58(12):2797-801
references.pmid: 19720803
references.citation: Nat Commun. 2015 Apr 28;6:6980
references.pmid: 25916467
references.citation: Endocrinology. 2008 Dec;149(12):6018-27
references.pmid: 18687777
references.citation: PLoS One. 2010 Apr 21;5(4):e10273
references.pmid: 20422052
references.citation: Mol Metab. 2015 Jun 25;4(9):605-9
references.pmid: 26413466
references.citation: Nature. 1992 Aug 20;358(6388):678-81
references.pmid: 1379697
references.citation: Peptides. 2007 Dec;28(12):2382-6
references.pmid: 17996984
references.citation: Front Endocrinol (Lausanne). 2013 Dec 18;4:194
references.pmid: 24385972
references.citation: Diabetes. 2006 Sep;55(9):2470-8
references.pmid: 16936195
references.citation: PLoS One. 2012;7(5):e38022
references.pmid: 22701542
references.citation: Endocrinology. 2009 Sep;150(9):4084-93
references.pmid: 19470704
references.citation: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6267-72
references.pmid: 10339576
references.citation: Nature. 2014 Sep 18;513(7518):436-9
references.pmid: 25043058
references.citation: PLoS One. 2014 Nov 26;9(11):e112109
references.pmid: 25427253
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12553-8
references.pmid: 20616029
references.citation: Obes Res. 1995 Dec;3 Suppl 5:697S-706S
references.pmid: 8653551
references.citation: Cell Tissue Res. 2010 Oct;342(1):1-11
references.pmid: 20730630
references.citation: J Clin Invest. 2004 Feb;113(4):561-8
references.pmid: 14966565
references.citation: PLoS One. 2013 Apr 22;8(4):e61432
references.pmid: 23630589
references.citation: Am J Clin Nutr. 1992 Jan;55(1 Suppl):278S-282S
references.pmid: 1370249
references.citation: Nat Commun. 2013;4:2019
references.pmid: 23771152
references.citation: Front Physiol. 2013 Sep 06;4:247
references.pmid: 24046748
references.citation: Cell Rep. 2015 Nov 24;13(8):1521-7
references.pmid: 26586424
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14379-84
references.pmid: 19706524
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3143-8
references.pmid: 22315431
references.citation: Neurosci Biobehav Rev. 1990 Fall;14(3):263-71
references.pmid: 2234606
references.citation: Am J Physiol. 1989 Jan;256(1 Pt 2):R217-23
references.pmid: 2912214
references.citation: Front Endocrinol (Lausanne). 2011 Nov 29;2:86
references.pmid: 22649390
references.citation: PLoS One. 2013 Sep 06;8(9):e73011
references.pmid: 24039848
references.citation: Nat Rev Drug Discov. 2009 Mar;8(3):235-53
references.pmid: 19247306
references.citation: Diabetes. 2014 Dec;63(12):4057-63
references.pmid: 25008183
references.citation: Cell Metab. 2012 Dec 5;16(6):693-705
references.pmid: 23217254
references.citation: Biophys J. 2012 Dec 5;103(11):2379-88
references.pmid: 23283237
references.citation: PLoS One. 2012;7(5):e38438
references.pmid: 22675463
references.citation: Eur J Neurosci. 2001 Jun;13(12):2299-308
references.pmid: 11454034
references.citation: J Biol Chem. 2010 Feb 19;285(8):5165-70
references.pmid: 20018895
references.citation: Metabolism. 2012 Aug;61(8):1142-51
references.pmid: 22398021
references.citation: Cell Metab. 2005 Oct;2(4):217-25
references.pmid: 16213224
references.citation: Trends Endocrinol Metab. 2014 Jun;25(6):303-11
references.pmid: 24709036
references.citation: Endocrinology. 2013 Jan;154(1):9-15
references.pmid: 23183168
references.citation: Dev Dyn. 2003 Apr;226(4):663-74
references.pmid: 12666204
references.citation: Diabetes. 2002 Dec;51 Suppl 3:S405-13
references.pmid: 12475783
references.citation: Endocrinology. 2002 May;143(5):1741-7
references.pmid: 11956156
references.citation: Diabetes. 2007 Oct;56(10):2501-10
references.pmid: 17664243
references.citation: Endocrinology. 2004 Jun;145(6):2594-603
references.pmid: 14976145
references.citation: Mol Biol Cell. 1997 Dec;8(12 ):2449-61
references.pmid: 9398667
references.citation: Diabetes. 2009 Jul;58(7):1532-8
references.pmid: 19401423
references.citation: J Clin Invest. 2005 Jun;115(6):1627-35
references.pmid: 15902306
references.citation: Genes Dev. 2003 Jul 1;17 (13):1581-91
references.pmid: 12815072
references.citation: PLoS One. 2013;8(2):e57927
references.pmid: 23469107
references.citation: Cancer Sci. 2008 Jul;99(7):1319-25
references.pmid: 18452557
references.citation: Cell Metab. 2007 Jun;5(6):415-25
references.pmid: 17550777
references.citation: Gastroenterology. 2014 Feb;146(2):539-49.e7
references.pmid: 24184811
references.citation: PLoS One. 2013;8(3):e58575
references.pmid: 23536797
references.citation: J Biol Chem. 2006 Jun 9;281(23):15694-700
references.pmid: 16597617
references.citation: Curr Diab Rep. 2009 Jun;9(3):208-14
references.pmid: 19490822
references.citation: Nat Med. 2015 Feb;21(2):159-65
references.pmid: 25559344
references.citation: PLoS One. 2012;7(11):e49345
references.pmid: 23209571
references.citation: Cell Metab. 2013 May 7;17(5):779-89
references.pmid: 23663741
references.citation: Brain Res Bull. 1991 Sep-Oct;27(3-4):327-32
references.pmid: 1720341
references.citation: Lancet Neurol. 2011 Sep;10(9):806-18
references.pmid: 21820356
references.citation: Mol Med. 2011;17 (7-8):736-40
references.pmid: 21373720
references.citation: FEBS Lett. 2010 Mar 5;584(5):1054-8
references.pmid: 20138876
references.citation: Mol Cell Biol. 2007 May;27(9):3417-28
references.pmid: 17339340
references.citation: Endocrinology. 2011 Aug;152(8):2996-3004
references.pmid: 21712364
references.citation: J Biol Chem. 2000 May 19;275(20):15482-9
references.pmid: 10809780