FGF21: A novel prospect for the treatment of metabolic diseases

Current Opinion in Investigational Drugs

Volumn 10, Issue 4, 2009, Pages 359-364

  Kharitonenkov, Alexei ^a   Shanafelt, Armen B ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Klotho; Diabetes; FGF receptor; FGF21; Metabolic regulator; Obesity

Indexed keywords

FIBROBLAST GROWTH FACTOR 21;

DRUG DISTRIBUTION; DRUG MECHANISM; HUMAN; METABOLIC REGULATION; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PROTEIN EXPRESSION; REVIEW;

ANIMALS; ANTI-OBESITY AGENTS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; FIBROBLAST GROWTH FACTORS; GENE THERAPY; HUMANS; HYPOGLYCEMIC AGENTS; OBESITY; SIGNAL TRANSDUCTION;

EID: 63849172657     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (40)

1. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J et al: FGF-21 as a novel metabolic regulator. J Clin Invest (2005) 115(6):1627-1635.
2. Kharitonenkov A, Shanafelt AB: Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases. BioDrugs (2008) 22(1):37-44.
3. 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.
4. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster A, Sandusky GE, Sewing S, Treinies I, Zitzer H, Gromada J: 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.
5. Pin CL, Chadi SA, Johnson CL, Kharitonenkov A, Köster A, Weston JY: FGF21 is immediate response gene to stress in pancreatic acinar cells. Gordon Research Conferences - Fibroblast Growth Factors in Development & Disease, Barga, Italy (2008).
6. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A: Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes (2008) 57(5):1246-1253.
7. Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, Mu J, Thompson JR, Berger JP, Wong KK: Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferatoractivated receptor γ and altered metabolic states. Mol Pharmacol (2008) 74(2):403-412.
8. Wang H, Qiang L, Farmer SR: Identification of a domain within peroxisome proliferator-activated receptor 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.
9. 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.
10. Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, Matoulek M, Dostalova I, Humenanska V, Haluzik M: Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (2009):doi:10.1111/j.1365-2265.2008.03502.x.
11. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab (2007) 5(6):426-437.
12. 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.
13. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK et al: Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab (2007) 5(6):415-425.
14. Lundåsen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B, Alexson SE, Rudling M: PPARα is a key regulator of hepatic FGF21. Biochem Biophys Res Commun (2007) 360(2):437-440.
15. Chen WW, Li L, Yang GY, Li K, Qi XY, Zhu W, Tang Y, Liu H, Boden G: Circulating FGF-21 levels in normal subjects and in newly diagnosed patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes (2008) 116(1):65-68.
16. Gälman C, Lundåsen T, Kharitonenkov A, Bina HA, Eriksson M, Hafström I, Dahlin M, Amark P, Angelin B, Rudling M: The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab (2008) 8(2):169-174.
17. Dostálová I, Kaválková P, Haluzíková D, Lacinová Z, Mráz M, Papezová H, Haluzík M: Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa. J Clin Endocrinol Metab (2008) 93(9):3627-3632.
18. Moyers JS, Shiyanova TL, Mehrbod F, Dunbar JD, Noblitt TW, Otto KA, Reifel-Miller A, Kharitonenkov A: Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARγ signaling. J Cell Physiol (2007) 210(1):1-6.
19. Kharitonenkov A, Dunbar JD, Bina HA, Bright S, Moyers JS, Zhang C, Ding L, Micanovic R, Mehrbod SF, Knierman MD, Hale JE, Coskun T, Shanafelt AB: FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J Cell Physiol (2008) 215(1):1-7.
20. Ito S, Kinoshita S, Shiraishi N, Nakagawa S, Sekine S, Fujimori T, Nabeshima YI: Molecular cloning and expression analyses of mouse βKlotho, which encodes a novel Klotho family protein. Mech Dev (2000) 98(1-2):115-119.
21. Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M: βKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA (2007) 104(18):7432-7437.
22. Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M, Asada M, Komi-Kuramochi A, Oka S, Imamura T: βKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol (2008) 22(4):1006-1014.
23. Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M: Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem (2007) 282(37):26687-26695.
24. Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA: Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab (2008) 8(1):77-83.
25. Steiling H, Wüstefeld T, Bugnon P, Brauchle M, Fässler R, Teupser D, Thiery J, Gordon JI, Trautwein C, Werner S: Fibroblast growth factor receptor signalling is crucial for liver homeostasis and regeneration. Oncogene (2003) 22(28):4380-4388.
26. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A: Fibroblast growth factor 21 corrects obesity in mice. Endocrinology (2008) 149(12):6018-6027.
27. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht SN, Hecht R, Li L, Lindberg RA, Chen JL et al: 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.
28. Maratos-Flier E: Molecular insights from the study of ketogenic diets - The role of FGF21 in metabolism. Keystone Symposia on Molecular and Cellular Biology - Type 2 Diabetes and Insulin Resistance, Banff, Canada (2009).
29. Berglund ED, Li CY, Lynes SE, Bina HA, Michael MD, Kharitonenkov A, Wasserman DH: Chronic FGF21 treatment improves insulin sensitivity in ob/ob mice. Abstr American Diabetes Association (2008) 68: Abs 187-OR.
30. Kharitonenkov A: Metabolic actions of FGF-21. Keystone Symposia - Diabetes Mellitus, Insulin Action and Resistance, Breckenridge, CO, USA (2008).
31. Arner P, Pettersson A, Mitchell PJ, Dunbar JD, Kharitonenkov A, Rydén M: FGF21 attenuates lipolysis in human adipocytes - a possible link to improved insulin sensitivity. FEBS Lett (2008) 582(12):1725-1730.
32. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM: Receptor specificity of the fibroblast growth factor family. J Biol Chem (2006) 281(23):15694-15700.
33. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ: The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology (2007) 148(2):774-781.
34. Micanovic R, Raches DW, Dunbar JD, Driver DA, Bina HA, Dickinson CD, Kharitonenkov A: Different roles of N- and C-termini in the functional activity of FGF21. J Cell Phys (2009) 219(2):227-234.
35. Yie J, Hecht R, Patel J, Stevens J, Wang W, Hawkins N, Steavenson S, Smith S, Winters D, Fisher S, Cai L et al: FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett (2009) 583(1):19-24.
36. Leahy JL: Pathogenesis of type 2 diabetes mellitus. Arch Med Res (2005) 36(3):197-209.
37. Lonnqvist F, Arner P, Nordfors L, Schalling M: Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med (1995) 1(9):950-953.
38. Ornitz DM, Itoh N: Fibroblast growth factors. Genome Biol (2001) 2(3):REVIEWS3005.1-REVIEWS3005.12.
39. Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert TA, Zhang F, Linhardt RJ, Yu X et al: Molecular insights into the Klotho-dependent, endocrine mode of action of FGF19 subfamily members. Mol Cell Biol (2007) 27(9):3417-3428.
40. Hsuchou H, Pan W, Kastin AJ: The fasting polypeptide FGF21 can enter brain from blood. Peptides (2007) 28(12):2382-2386.