The FGF metabolic axis

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.

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    Not in our library10.1038/s41395-018-0042-7

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):446-456.

    Not in our library10.1093/toxsci/kfs011

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):1859-1864.

    Not in our library10.2337/dc12-2255

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):247ra100.

    Not in our library10.1126/scitranslmed.3009098

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):1228-1235.

    Not in our library10.1002/hep.22771

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):990-996.

    Not in our library10.1038/nm.4363

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):2295-2307.

    Not in our library10.1016/s0002-9440(10)61177-7

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):914-929.

    Not in our library10.1002/hep.28257

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):1037-1050.

    Not in our library10.1002/hep4.1209

90. 90.

    BonDurant LD, Potthoff MJ. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu Rev Nutr. 2018;38(1):173-196.

    Not in our library10.1146/annurev-nutr-071816-064800

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):2993-3000.

    Not in our library10.1210/jc.2013-1250

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-E1228.

    Not in our library10.1210/jc.2012-1132

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):887-892.

    Not in our library10.1111/j.1365-2362.2010.02338.x

94. 94.

    Kliewer SA, Mangelsdorf DJ. A dozen years of discovery: insights into the physiology and pharmacology of FGF21. Cell Metab. 2019;29(2):246-253.

    Not in our library10.1016/j.cmet.2019.01.004

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):3913-3922.

    Not in our library10.1172/jci74915

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):14-21.

    Not in our library10.1016/j.molmet.2016.11.008

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):335-343.

    Not in our library10.1016/j.cmet.2015.12.003

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):344-349.

    Not in our library10.1016/j.cmet.2015.12.008

99. 99.

    Fisher FM, Chui PC, Nasser IA, Popov Y, Cunniff JC, Lundasen T, Kharitonenkov A, Schuppan D, Flier JS, 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.e6.

    Not in our library10.1053/j.gastro.2014.07.044

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):934-942.

     Not in our library10.1002/mc.20241

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):1242-1252.

     Not in our library10.1016/j.bbadis.2015.02.012

102. 102.
     Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury · 2017

     No notice
103. 103.

     Ye D Y, Li H, Jia W, Man K, Lo C 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):977-989.

     Not in our library10.1002/hep.27060

104. 104.
     Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet · 2018

     Not checked
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):4754-4769.

     Not in our library10.1210/en.2016-1710

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 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):162ra153.

     Not in our library10.1126/scitranslmed.3004690

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):333-340.

     Not in our library10.1016/j.cmet.2013.08.005

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):779-789.

     Not in our library10.1016/j.cmet.2013.04.005

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.e4.

     Not in our library10.1016/j.cmet.2017.08.003

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):302-309.

     Not in our library10.1016/j.cmet.2013.12.017

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):12983-12990.

     Not in our library10.1074/jbc.m110.215889

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):630.

     Not in our library10.1038/s41598-018-37198-y

113. 113.
     The starvation hormone, fibroblast growth factor-21, extends lifespan in mice · 2012

     No notice
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):1026-1031.

     Not in our library10.1073/pnas.1514511113

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):205-214.

     Not in our library10.1016/j.molmet.2013.05.005

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):472-480.

     Not in our library10.1016/j.cmet.2016.12.004

117. 117.
     Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas. · 2016

     Not checked
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-E928.

     Not in our library10.1152/ajpendo.00559.2013

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):1795-1804.

     Not in our library10.1053/j.gastro.2009.07.064

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):3496-3509.

     Not in our library10.1172/jci94337

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.e6.

     Not in our library10.1016/j.cmet.2017.04.009

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.e4.

     Not in our library10.1016/j.cmet.2018.04.001

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):327-336.

     Not in our library10.1016/j.celrep.2018.03.070

124. 124.

     Schumann G, Liu C, O’Reilly P, Gao H, Song P, Xu B, Ruggeri B, Amin N, Jia T, Preis S, Segura L 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 G 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):14372-14377.

     Not in our library10.1073/pnas.1611243113

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):1407-1414.

     Not in our library10.1016/j.celrep.2018.07.023

126. 126.

     Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, Gabrielli LA, Sitges M, Giralt M, van B M, Villarroya F. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun. 2013;4(1):2019.

     Not in our library10.1038/ncomms3019

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):122737.

     Not in our library10.1172/jci.insight.122737

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):2229-2241.

     Not in our library10.1194/jlr.m044784

129. 129.

     Lin Z, Pan F, 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):1861-1871.

     Not in our library10.1161/circulationaha.115.015308

130. 130.
     Endocrine Protection of Ischemic Myocardium by FGF21 from the Liver and Adipose Tissue · 2013

     No notice
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):227.

     Not in our library10.1038/s41419-018-0307-5

132. 132.

     Zhang Chi, Huang Zhifeng, Gu Junlian, Yan Xiaoqing, Lu Xuemian, Zhou Shanshan, Wang Shudong, Shao Minglong, Zhang Fangfang, Cheng Peng, Feng Wenke, Tan Yi, Li Xiaokun. 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.

     Not in our library10.1007/s00125-015-3630-8

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.e5.

     Not in our library10.1016/j.cmet.2018.04.002

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):83-92.

     Not in our library10.1038/nm.3014

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):806-818.

     Not in our library10.1016/s1474-4422(11)70155-7

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.e4.

     Not in our library10.1016/j.celrep.2019.02.014

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):2126-2145.

     Not in our library10.15252/embj.201696179

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):e12828.

     Not in our library10.14814/phy2.12828

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):1142-1151.

     Not in our library10.1016/j.metabol.2012.01.012

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):3805-3810.

     Not in our library10.1016/j.febslet.2008.10.021

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):670-677.

     Not in our library10.1016/j.cmet.2014.07.012

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):2470-2481.

     Not in our library10.1210/en.2014-2001

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):4064-4075.

     Not in our library10.2337/db14-0541

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):1153-1156.

     Not in our library10.1038/nm.3250

145. 145.

     Bookout AL, de G M, 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):1147-1152.

     Not in our library10.1038/nm.3249

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;2009:412949.

     Not in our library10.1155/2009/412949

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):4702-4717.

     Not in our library10.1007/s12035-017-0663-7

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;133:122-131.

     Not in our library10.1016/j.pbb.2015.03.020

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):1817-1824.

     Not in our library10.2337/db09-1878

150. 150.
     FGF21 Promotes Metabolic Homeostasis via White Adipose and Leptin in Mice · 2012

     No notice
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):250-259.

     Not in our library10.2337/db08-0392

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):e1707.

     Not in our library10.1038/cddis.2015.80

153. 153.
     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. · 2013

     Not checked
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):3366-3376.

     Not in our library10.1210/en.2012-2276

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):4552-4562.

     Not in our library10.7150/thno.24723

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):111457.

     Not in our library10.1016/j.yexcr.2019.06.002

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;93:695-704.

     Not in our library10.1016/j.biopha.2017.06.100

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;108:355-366.

     Not in our library10.1016/j.biopha.2018.09.078

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):514-521.

     Not in our library10.1089/dna.2013.2290

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;38:144-152.

     Not in our library10.1016/j.intimp.2016.05.026

161. 161.
     Fibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat · 2018

     No notice
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):519-527.

     Not in our library10.1007/s12020-014-0309-8

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):751-759.

     Not in our library10.1007/s10753-018-0729-3

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):385-395.

     Not in our library10.1007/s12020-014-0502-9

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):309-319.

     Not in our library10.1007/s10753-015-0251-9

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):2206-2211.

     Not in our library10.1074/jbc.m207872200

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):561-568.

     Not in our library10.1172/jci200419081

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):6500-6505.

     Not in our library10.1073/pnas.101545198

169. 169.
     FGF23 promotes renal calcium reabsorption through the TRPV5 channel · 2014

     No notice
170. 170.
     FGF23 regulates renal sodium handling and blood pressure · 2014

     No notice
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):4003-4008.

     Not in our library10.1172/jci32409

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):1131-1141.

     Not in our library10.1016/j.kint.2017.11.018

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-F139.

     Not in our library10.1152/ajprenal.00081.2017

174. 174.

     ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345-348.

     Not in our library10.1038/81664

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):977-981.

     Not in our library10.1006/bbrc.2001.5084

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):683-692.

     Not in our library10.1172/jci18399

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):233-236.

     Not in our library10.1002/ajmg.a.30599

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):18370-18377.

     Not in our library10.1074/jbc.m602469200

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):4472-4475.

     Not in our library10.1210/jc.2006-1247

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):4037-4042.

     Not in our library10.1210/jc.2006-0305

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):385-390.

     Not in our library10.1093/hmg/ddi034

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):261-266.

     Not in our library10.1007/s00439-005-0026-8

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):5523-5527.

     Not in our library10.1210/jc.2005-0301

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):269-271.

     Not in our library10.1016/j.gene.2014.03.052

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 J S M, Ojo A, Gadegbeku C, Di M G, 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):4393-4408.

     Not in our library10.1172/jci46122

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):2545-2552.

     Not in our library10.1161/circulationaha.108.844506

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):e0213321.

     Not in our library10.1371/journal.pone.0213321

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;1412:9-17.

     Not in our library10.1016/j.brainres.2011.07.028

Cited by papers we hold 5

• Application of neurotrophic and proangiogenic factors as therapy after peripheral nervous system injury · 2022
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• Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations · 2022
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• Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer · 2021
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• An in situ tissue engineering scaffold with growth factors combining angiogenesis and osteoimmunomodulatory functions for advanced periodontal bone regeneration · 2021
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• FGF Signaling Pathway: A Key Regulator of Stem Cell Pluripotency · 2020
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