Minireview: Roles of fibroblast growth factors 19 and 21 in metabolic regulation and chronic diseases

Molecular Endocrinology

Volumn 29, Issue 10, 2015, Pages 1400-1413

  Zhang, Fangfang ^a,b   Yu, Lechu ^a   Lin, Xiufei ^a,b   Cheng, Peng ^a,b   He, Luqing ^a,b   Li, Xiaokun ^a,b   Lu, Xuemian ^a,b   Tan, Yi ^a,b,c   Yang, Hong ^a   Cai, Lu ^a,b,c   Zhang, Chi ^a,b  

^a THE THIRD AFFILIATED HOSPITAL OF WENZHOU MEDICAL UNIVERSITY   (China)

^b WENZHOU MEDICAL UNIVERSITY   (China)

^c University of Louisville School of Medicine   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BILE ACID; FIBROBLAST GROWTH FACTOR 19; FIBROBLAST GROWTH FACTOR 21; GLUCAGON; GLUCOSE; INSULIN; UNCOUPLING PROTEIN 1; FIBROBLAST GROWTH FACTOR;

ADIPOCYTE; APOPTOSIS; BILE ACID SYNTHESIS; CARDIOVASCULAR DISEASE; CHRONIC DISEASE; DIABETES MELLITUS; ENERGY EXPENDITURE; ENERGY METABOLISM; GLUCONEOGENESIS; GLUCOSE INTOLERANCE; GLUCOSE METABOLISM; GLUCOSE TOLERANCE; GLUCOSE TRANSPORT; GLYCOGEN SYNTHESIS; GLYCOLYSIS; HEMOSTASIS; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; KETOGENESIS; KIDNEY DISEASE; LIPID METABOLISM; LIPOGENESIS; LIPOLYSIS; METABOLIC REGULATION; METABOLIC SYNDROME X; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; WEIGHT REDUCTION; WHITE ADIPOSE TISSUE; METABOLISM;

ADIPOSE TISSUE, WHITE; CHRONIC DISEASE; FIBROBLAST GROWTH FACTORS; HUMANS; METABOLIC SYNDROME X; METABOLISM;

EID: 84943249540     PISSN: 08888809     EISSN: 19449917     Source Type: Journal    
DOI: 10.1210/me.2015-1155     Document Type: Review

References (111)

1. Itoh N, Ohta H. Pathophysiological roles of FGF signaling in the heart. Front Physiol. 2013;4:247.
2. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235-253.
3. Potthoff MJ, Kliewer SA, Mangelsdorf DJ. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 2012;26(4):312-324.
4. Kurosu H, Kuro-O M. Endocrine fibroblast growth factors as regulators of metabolic homeostasis. Biofactors. 2009;35(1):52-60.
5. Fukumoto S. Actions and mode of actions of FGF19 subfamily members. Endocr J. 2008;55(1):23-31.
6. Goetz R, Beenken A, Ibrahimi OA, et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol. 2007;27(9): 3417-3428.
7. Kurosu H, Choi M, Ogawa Y, et al. 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.
8. Kharitonenkov A, Dunbar JD, Bina HA, et al. FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J Cell Physiol. 2008;215(1):1-7.
9. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006; 444(7120):770-774.
10. Cicione C, Degirolamo C, Moschetta A. Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver. Hepatology. 2012;56(6):2404-2411.
11. Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta. 1999;1444(1): 148-151.
12. McWhirter JR, Goulding M, Weiner JA, Chun J, Murre C. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1. Development. 1997;124(17):3221-3232.
13. Gimeno L, Brûlet P, Martínez S. Study of Fgf15 gene expression in developing mouse brain. Gene Expr Patterns. 2003;3(4):473-481.
14. Kir S, Kliewer SA, Mangelsdorf DJ. Roles of FGF19 in liver metabolism. Cold Spring Harb Symp Quant Biol. 2011;76:139-144.
15. Chiang JY. Bile acids: regulation of synthesis. J Lipid Res. 2009; 50(10):1955-1966.
16. Pandak WM, Heuman DM, Hylemon PB, Chiang JY, Vlahcevic ZR. Failure of intravenous infusion of taurocholate to down-regulate cholesterol 7 α-hydroxylase in rats with biliary fistulas. Gastroenterology. 1995;108(2):533-544.
17. Zhang J, Li HT, Fang QC, Jia WP. Role of fibroblast growth factor 19 in maintaining nutrient homeostasis and disease. Biomed Environ Sci. 2014;27(5):319-324.
18. Nicholes K, Guillet S, Tomlinson E, et al. 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.
19. Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta. 2000;1492(1):203-206.
20. Kharitonenkov A, Shanafelt AB. FGF21: a novel prospect for the treatment of metabolic diseases. Curr Opin Investig Drugs. 2009; 10(4):359-364.
21. Fon Tacer K, Bookout AL, Ding X, et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol. 2010;24(10):2050-2064.
22. Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115(6):1627-1635.
23. Kharitonenkov A, Wroblewski VJ, Koester A, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology. 2007;148(2):774-781.
24. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARγ and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5(6):426-437.
25. Inagaki T, Dutchak P, Zhao G, et al. Endocrine regulation of the fasting response by PPARγ-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5(6):415-425.
26. Dutchak PA, Katafuchi T, Bookout AL, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell. 2012;148(3):556-567.
27. Moyers JS, Shiyanova TL, Mehrbod F, et al. Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARγ signaling. J Cell Physiol. 2007;210(1):1-6.
28. Bae KH, Kim JG, Park KG. Transcriptional regulation of fibroblast growth factor 21 expression. Endocrinol Metab (Seoul). 2014;29(2):105-111.
29. Potthoff MJ, Inagaki T, Satapati S, et al. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA. 2009; 106(26):10853-10858.
30. Chau MD, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPKSIRT1-PGC-1α pathway. Proc Natl Acad Sci USA. 2010;107(28): 12553-12558.
31. Ye D, Wang Y, Li H, et al. Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice. Hepatology. 2014; 60(3):977-989.
32. Cheng X, Vispute SG, Liu J, Cheng C, Kharitonenkov A, Klaassen CD. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR). Toxicol Appl Pharmacol. 2014; 278(1):65-71.
33. Johnson CL, Weston JY, Chadi SA, et al. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology. 2009;137(5):1795-1804.
34. Schaap FG, Kremer AE, Lamers WH, Jansen PL, Gaemers IC. Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. Biochimie. 2013;95(4):692-699.
35. Jiang X, Zhang C, Xin Y, et al. Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial-and endoplasmic reticulum stress-dependent pathways in the mouse model. Toxicol Lett. 2013;219(1):65-76.
36. Ji K, Zheng J, Lv J, et al. Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1α pathway. Free Radic Biol Med. 2015;84:161-170.
37. Ribas F, Villarroya J, Hondares E, Giralt M, Villarroya F. FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling. Biochem J. 2014; 463(2):191-199.
38. Yu Y, Bai F, Liu Y, et al. Fibroblast growth factor (FGF21) protects mouse liver against D-galactose-induced oxidative stress and apoptosis via activating Nrf2 and PI3K/Akt pathways. Mol Cell Biochem. 2015;403(1-2):287-299.
39. Planavila A, Redondo-Angulo I, Ribas F, et al. Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc Res. 2015;106(1):19-31.
40. Potthoff MJ, Boney-Montoya J, Choi M, et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell Metab. 2011;13(6):729-738.
41. Schaap FG. Role of fibroblast growth factor 19 in the control of glucose homeostasis. Curr Opin Clin Nutr Metab Care. 2012; 15(4):386-391.
42. Li H, Zhang J, Jia W. Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology. Front Med. 2013;7(1):25-30.
43. Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr. 2010; 91(1):254S-257S.
44. Tomlinson E, Fu L, John L, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143(5):1741-1747.
45. Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145(6):2594-2603.
46. Huang X, Yang C, Luo Y, Jin C, Wang F, McKeehan WL. FGFR4 prevents hyperlipidemia and insulin resistance but underlies highfat diet induced fatty liver. Diabetes. 2007;56(10):2501-2510.
47. Kir S, Beddow SA, Samuel VT, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science. 2011;331(6024):1621-1624.
48. Wu X, Ge H, Lemon B, et al. Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice. Proc Natl Acad Sci USA. 2009;106(34):14379-14384.
49. Ryan KK, Kohli R, Gutierrez-Aguilar R, Gaitonde SG, Woods SC, Seeley RJ. Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology. 2013;154(1):9-15.
50. Morton GJ, Matsen ME, Bracy DP, et al. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest. 2013;123(11):4799-4808.
51. Li K, Li L, Yang M, Liu H, Boden G, Yang G. The effects of fibroblast growth factor-21 knockdown and over-expression on its signaling pathway and glucose-lipid metabolism in vitro. Mol Cell Endocrinol. 2012;348(1):21-26.
52. Wente W, Efanov AM, Brenner M, et al. Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes. 2006;55(9):2470-2478.
53. Kharitonenkov A, Shanafelt AB. Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases. BioDrugs. 2008;22(1): 37-44.
54. Lee MS, Choi SE, Ha ES, et al. Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-κB. Metabolism. 2012;61(8):1142-1151.
55. Kim HW, Lee JE, Cha JJ, et al. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology. 2013;154(9):3366-3376.
56. Lin Z, Tian H, Lam KS, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013;17(5):779-789.
57. Holland WL, Adams AC, Brozinick JT, et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 2013;17(5):790-797.
58. Liang Q, Zhong L, Zhang J, et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes. 2014;63(12):4064-4075.
59. Lin Z, Pan X, Wu F, et al. 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.
60. Hotta Y, Nakamura H, Konishi M, et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology. 2009;150(10):4625-4633.
61. Miyata M, Sakaida Y, Matsuzawa H, Yoshinari K, Yamazoe Y. Fibroblast growth factor 19 treatment ameliorates disruption of hepatic lipid metabolism in farnesoid X receptor (Fxr)-null mice. Biol Pharm Bull. 2011;34(12):1885-1889.
62. Bhatnagar S, Damron HA, Hillgartner FB. Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis. J Biol Chem. 2009;284(15):10023-10033.
63. Wu X, Ge H, Baribault H, et al. Dual actions of fibroblast growth factor 19 on lipid metabolism. J Lipid Res. 2013;54(2):325-332.
64. Mai K, Andres J, Biedasek K, et al. Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. Diabetes. 2009;58(7):1532-1538.
65. Yilmaz Y, Eren F, Yonal O, et al. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest. 2010;40(10):887-892.
66. Zhang X, Yeung DC, Karpisek M, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008;57(5):1246-1253.
67. Cuevas-Ramos D, Almeda-Valdes P, Aguilar-Salinas CA, Cuevas-Ramos G, Cuevas-Sosa AA, Gomez-Perez FJ. The role of fibroblast growth factor 21 (FGF21) on energy balance, glucose and lipid metabolism. Curr Diabetes Rev. 2009;5(4):216-220.
68. Chechi K, Carpentier AC, Richard D. Understanding the brown adipocyte as a contributor to energy homeostasis. Trends Endocrinol Metab. 2013;24(8):408-420.
69. Nguyen AD, Lee NJ, Wee NK, et al. Uncoupling protein-1 is protective of bone mass under mild cold stress conditions. Bone. 2015;pii: S8756-3282(15)00218-5.
70. Fisher FM, Kleiner S, Douris N, et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26(3):271-281.
71. Samms RJ, Smith DP, Cheng CC, et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 2015;11(7): 991-999.
72. Véniant MM, Sivits G, Helmering J, et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab. 2015;21(5):731-738.
73. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766-781.
74. Xu Y, Wang L, He J, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310(9):948-959.
75. Coccheri S. Approaches to prevention of cardiovascular complications and events in diabetes mellitus. Drugs. 2007;67(7):997-1026.
76. Zhang C, Shao M, Yang H, et al. Attenuation of hyperlipidemiaand 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.
77. Gallego-Escuredo JM, Gomez-Ambrosi J, Catalan V, et al. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int J Obes (Lond). 2015 Jan;39(1):121-129.
78. Wojcik M, Janus D, Dolezal-Oltarzewska K, et al. A decrease in fasting FGF19 levels is associated with the development of nonalcoholic fatty liver disease in obese adolescents. J Pediatr Endocrinol Metab. 2012;25(11-12):1089-1093.
79. Schreuder TC, Marsman HA, Lenicek M, et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298(3):G440-G445.
80. Marcelin G, Jo YH, Li X, et al. Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol Metab. 2014;3(1):19-28.
81. Li H, Fang Q, Gao F, et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol. 2010;53(5):934-940.
82. Díaz-Delfín J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F. TNF-α represses β-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology. 2012;153(9):4238-4245.
83. Reinehr T, Woelfle J, Wunsch R, Roth CL. Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis. J Clin Endocrinol Metab. 2012;97(6):2143-2150.
84. Brufau G, Stellaard F, Prado K, et al. Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology. 2010;52(4):1455-1464.
85. Wang D, Zhu W, Li J, An C, Wang Z. Serum concentrations of fibroblast growth factors 19 and 21 in women with gestational diabetes mellitus: association with insulin resistance, adiponectin, and polycystic ovary syndrome history. PLoS One. 2013;8(11): e81190.
86. Barutcuoglu B, Basol G, Cakir Y, et al. Fibroblast growth factor-19 levels in type 2 diabetic patients with metabolic syndrome. Ann Clin Lab Sci. 2011;41(4):390-396.
87. Eto K, Tumenbayar B, Nagashima S, et al. Distinct association of serum FGF21 or adiponectin levels with clinical parameters in patients with type 2 diabetes. Diabetes Res Clin Pract. 2010;89(1): 52-57.
88. Chen C, Cheung BM, Tso AW, et al. High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes: a 5.4-year population-based prospective study in Chinese subjects. Diabetes Care. 2011;34(9):2113-2115.
89. Xiao Y, Xu A, Law LS, et al. Distinct changes in serum fibroblast growth factor 21 levels in different subtypes of diabetes. J Clin Endocrinol Metab. 2012;97(1):E54-E58.
90. Vienberg SG, Brøns C, Nilsson E, Astrup A, Vaag A, Andersen B. Impact of short-term high-fat feeding and insulin-stimulated FGF21 levels in subjects with low birth weight and controls. Eur J Endocrinol. 2012;167(1):49-57.
91. Stein S, Stepan H, Kratzsch J, et al. Serum fibroblast growth factor 21 levels in gestational diabetes mellitus in relation to insulin resistance and dyslipidemia. Metabolism. 2010;59(1):33-37.
92. Hao Y, Zhou J, Zhou M, et al. Serum levels of fibroblast growth factor 19 are inversely associated with coronary artery disease in chinese individuals. PLoS One. 2013;8(8):e72345.
93. Saitsu H, Shiota K, Ishibashi M. Analysis of Fibroblast growth factor 15 cis-elements reveals two conserved enhancers which are closely related to cardiac outflow tract development. Mech Dev. 2006;123(9):665-673.
94. Shen Y, Ma X, Zhou J, et al. Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol. 2013;12:124.
95. Lin Z, Wu Z, Yin X, et al. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One. 2010;5(12):e15534.
96. Chow WS, Xu A, Woo YC, et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013;33(10):2454-2459.
97. Lu Y, Liu JH, Zhang LK, et al. Fibroblast growth factor 21 as a possible endogenous factor inhibits apoptosis in cardiac endothelial cells. Chin Med J (Engl). 2010;123(23):3417-3421.
98. Zhang C, Huang Z, Gu J, et al. 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.
99. Yan X, Chen J, Zhang C, et al. FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. J Cell Mol Med. 2015;19(7):1557-1568.
100. Cong WT, Ling J, Tian HS, et al. Proteomic study on the protective mechanism of fibroblast growth factor 21 to ischemia-reperfusion injury. Can J Physiol Pharmacol. 2013;91(11):973-984.
101. Patel V, Adya R, Chen J, et al. Novel insights into the cardioprotective effects of FGF21 in lean and obese rat hearts. PLoS One. 2014;9(2):e87102.
102. Stein S, Bachmann A, Lössner U, et al. Serum levels of the adipokine FGF21 depend on renal function. Diabetes Care. 2009;32(1): 126-128.
103. Reiche M, Bachmann A, Lössner U, Blüher M, Stumvoll M, Fasshauer M. Fibroblast growth factor 19 serum levels: relation to renal function and metabolic parameters. Horm Metab Res. 2010; 42(3):178-181.
104. Li M, Qureshi AR, Ellis E, Axelsson J. Impaired postprandial fibroblast growth factor (FGF)-19 response in patients with stage 5 chronic kidney diseases is ameliorated following antioxidative therapy. Nephrol Dial Transplant. 2013;28(suppl 4):iv212-iv219.
105. Hindricks J, Ebert T, Bachmann A, et al. Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clin Endocrinol (Oxf). 2014;80(6):918-924.
106. Lin Z, Zhou Z, Liu Y, et al. Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. PLoS One. 2011;6(4):e18398.
107. Kharitonenkov A, Beals JM, Micanovic R, et al. Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319. PLoS One. 2013;8(3):e58575.
108. Hecht R, Li YS, Sun J, et al. Rationale-based engineering of a potent long-acting FGF21 analog for the treatment of type 2 diabetes. PLoS One. 2012;7(11):e49345.
109. Huang J, Ishino T, Chen G, et al. Development of a novel longacting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody. J Pharmacol Exp Ther. 2013;346(2):270-280.
110. Foltz IN, Hu S, King C, et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci Transl Med. 2012;4(162):162ra153.
111. Smith R, Duguay A, Bakker A, et al. FGF21 can be mimicked in vitro and in vivo by a novel anti-FGFR1c/β-Klotho bispecific protein. PLoS One. 2013;8(4):e61432.