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Abstract

Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis. Excitement surrounding this relatively recently identified hormone is based on the documented metabolic beneficial effects of FGF21, which include weight loss and improved glycemia. The biology of FGF21 is intrinsically complicated owing to its diverse metabolic functions in multiple target organs and its ability to act as an autocrine, paracrine, and endocrine factor. In the liver, FGF21 plays an important role in the regulation of fatty acid oxidation both in the fasted state and in mice consuming a high-fat, low-carbohydrate ketogenic diet. FGF21 also regulates fatty acid metabolism in mice consuming a diet that promotes hepatic lipotoxicity. In white adipose tissue (WAT), FGF21 regulates aspects of glucose metabolism, and in susceptible WAT depots, it can cause browning. This peptide is highly expressed in the pancreas, where it appears to play an anti-inflammatory role in experimental pancreatitis. It also has an anti-inflammatory role in cardiac muscle. Although typically not expressed in skeletal muscle, FGF21 is induced in situations of muscle stress, particularly mitochondrial myopathies. FGF21 has been proposed as a novel therapeutic for metabolic complications such as diabetes and fatty liver disease. This review aims to interpret and delineate the ever-expanding complexity of FGF21 physiology.

Keyword(s): adiposedietfatliverobesityβ-klotho
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2016-02-10
2024-04-13
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Literature Cited

  1. Maratos-Flier E. 1. 2016 Appetite regulation and thermogenesis. Endocrinology: Adult and Pediatric 1 J Jamson 457–78 Philadelphia, PA: Elsevier/Saunders [Google Scholar]
  2. Oulion S, Bertrand S, Escriva H. 2.  2012. Evolution of the FGF gene family. Int. J. Evol. Biol. 2012:298147 [Google Scholar]
  3. Itoh N, Ornitz DM. 3.  2008. Functional evolutionary history of the mouse Fgf gene family. Dev. Dyn. 237:18–27 [Google Scholar]
  4. Tanaka T, Ngwa JS, van Rooij FJ, Zillikens MC, Wojczynski MK. 4.  et al. 2013. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am. J. Clin. Nutr. 97:1395–402 [Google Scholar]
  5. Chu AY, Workalemahu T, Paynter NP, Rose LM, Giulianini F. 5.  et al. 2013. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum. Mol. Genet. 22:1895–902 [Google Scholar]
  6. Nishimura T, Nakatake Y, Konishi M, Itoh N. 6.  2000. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim. Biophys. Acta1492203–6
  7. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R. 7.  et al. 2005. FGF-21 as a novel metabolic regulator. J. Clin. Investig. 115:1627–35 [Google Scholar]
  8. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC. 8.  et al. 2008. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149:6018–27 [Google Scholar]
  9. Xu J, Stanislaus S, Chinookoswong N, Lau YY, Hager T. 9.  et al. 2009. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin resistant mouse models—association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 297:E1105–14 [Google Scholar]
  10. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK. 10.  et al. 2007. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148:774–81 [Google Scholar]
  11. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. 11.  2007. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5:426–37 [Google Scholar]
  12. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L. 12.  et al. 2007. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 5:415–25 [Google Scholar]
  13. Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. 13.  2009. Fibroblast growth factor 21–deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 150:4931–40 [Google Scholar]
  14. Kharitonenkov A, Dunbar JD, Bina HA, Bright S, Moyers JS. 14.  et al. 2008. FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J. Cell Physiol. 215:1–7 [Google Scholar]
  15. Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R. 15.  et al. 2007. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282:26687–95 [Google Scholar]
  16. Yie J, Wang W, Deng L, Tam LT, Stevens J. 16.  et al. 2012. Understanding the physical interactions in the FGF21/FGFR/β-Klotho complex: structural requirements and implications in FGF21 signaling. Chem. Biol. Drug Des. 79:398–410 [Google Scholar]
  17. Micanovic R, Raches DW, Dunbar JD, Driver DA, Bina HA. 17.  et al. 2009. Different roles of N- and C-termini in the functional activity of FGF21. J. Cell. Physiol. 219:227–34 [Google Scholar]
  18. Yie J, Hecht R, Patel J, Stevens J, Wang W. 18.  et al. 2009. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett. 583:19–24 [Google Scholar]
  19. Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC. 19.  et al. 2012. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 16:387–93 [Google Scholar]
  20. Adams AC, Cheng CC, Coskun T, Kharitonenkov A. 20.  2012. FGF21 requires βklotho to act in vivo. PLOS ONE 7:e49977 [Google Scholar]
  21. Fisher FM, Estall JL, Adams AC, Antonellis PJ, Bina HA. 21.  et al. 2011. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. Endocrinology 152:2996–3004 [Google Scholar]
  22. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M. 22.  et al. 2009. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58:250–59 [Google Scholar]
  23. Johnson CL, Weston JY, Chadi SA, Fazio EN, Huff MW. 23.  et al. 2009. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 137:1795–804 [Google Scholar]
  24. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A. 24.  et al. 2006. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal–regulated kinase 1/2 and Akt signaling pathways. Diabetes 55:2470–78 [Google Scholar]
  25. Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L. 25.  et al. 2013. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19:1147–52 [Google Scholar]
  26. Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR. 26.  et al. 2014. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 63:4064–75 [Google Scholar]
  27. Kaess BM, Barnes TA, Stark K, Charchar FJ, Waterworth D. 27.  et al. 2010. FGF21 signalling pathway and metabolic traits—genetic association analysis. Eur. J. Hum. Genet. 18:1344–48 [Google Scholar]
  28. Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D. 28.  et al. 2011. A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea. Gastroenterology 140:1934–42 [Google Scholar]
  29. Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y. 29.  et al. 2008. βKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol. Endocrinol. 22:1006–14 [Google Scholar]
  30. Ming AY, Yoo E, Vorontsov EN, Altamentova SM, Kilkenny DM, Rocheleau JV. 30.  2012. Dynamics and distribution of Klothoβ (KLB) and fibroblast growth factor receptor-1 (FGFR1) in living cells reveal the fibroblast growth factor-21 (FGF21)-induced receptor complex. J. Biol. Chem. 287:19997–20006 [Google Scholar]
  31. Adams AC, Yang C, Coskun T, Cheng CC, Gimeno RE. 31.  et al. 2012. The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue. Mol. Metab. 2:31–37 [Google Scholar]
  32. Lin BC, Wang M, Blackmore C, Desnoyers LR. 32.  2007. Liver-specific activities of FGF19 require Klotho β. J. Biol. Chem. 282:27277–84 [Google Scholar]
  33. Poh W, Wong W, Ong H, Aung MO, Lim SG. 33.  et al. 2012. Klotho-β overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma. Mol. Cancer 11:14 [Google Scholar]
  34. Hagel M, Miduturu C, Sheets M, Rubin N, Weng W. 34.  et al. 2015. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 5:424–37 [Google Scholar]
  35. Wu AL, Kolumam G, Stawicki S, Chen Y, Li J. 35.  et al. 2011. Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci. Transl. Med. 3:113ra26 [Google Scholar]
  36. Moyers JS, Shiyanova TL, Mehrbod F, Dunbar JD, Noblitt TW. 36.  et al. 2007. Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARγ signaling. J. Cell. Physiol. 210:1–6 [Google Scholar]
  37. Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A. 37.  2011. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J. Biol. Chem. 286:34533–41 [Google Scholar]
  38. Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M. 38.  et al. 2010. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139:456–63 [Google Scholar]
  39. Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y. 39.  et al. 2008. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator–activated receptor γ and altered metabolic states. Mol. Pharmacol. 74:403–12 [Google Scholar]
  40. Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A. 40.  et al. 2010. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 59:2781–89 [Google Scholar]
  41. Diaz-Delfin J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F. 41.  2012. TNF-α represses β-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology 153:4238–45 [Google Scholar]
  42. So WY, Cheng Q, Chen L, Evans-Molina C, Xu A. 42.  et al. 2013. High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator–activated receptor γ signaling. Diabetes 62:3751–59 [Google Scholar]
  43. Hale C, Chen MM, Stanislaus S, Chinookoswong N, Hager T. 43.  et al. 2012. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology 153:69–80 [Google Scholar]
  44. Samson SL, Sathyanarayana P, Jogi M, Gonzalez EV, Gutierrez A. 44.  et al. 2011. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia 54:3093–100 [Google Scholar]
  45. Adams AC, Coskun T, Cheng CC, O'Farrell LS, Dubois SL, Kharitonenkov A. 45.  2013. Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones. Mol. Metab. 2:205–14 [Google Scholar]
  46. Gallego-Escuredo JM, Gomez-Ambrosi J, Catalan V, Domingo P, Giralt M. 46.  et al. 2015. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int. J. Obes. 39:121–29 [Google Scholar]
  47. Lundasen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B. 47.  et al. 2007. PPARα is a key regulator of hepatic FGF21. Biochem. Biophys. Res. Commun. 360:437–40 [Google Scholar]
  48. De Sousa–Coelho AL, Relat J, Hondares E, Perez-Marti A, Ribas F. 48.  et al. 2013. FGF21 mediates the lipid metabolism response to amino acid starvation. J. Lipid Res. 54:1786–97 [Google Scholar]
  49. Pissios P, Hong S, Kennedy AR, Prasad D, Liu FF, Maratos-Flier E. 49.  2013. Methionine and choline regulate the metabolic phenotype of a ketogenic diet. Mol. Metab. 2:306–13 [Google Scholar]
  50. Lees EK, Krol E, Grant L, Shearer K, Wyse C. 50.  et al. 2014. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging Cell 13:817–27 [Google Scholar]
  51. De Sousa–Coelho AL, Marrero PF, Haro D. 51.  2012. Activating transcription factor 4–dependent induction of FGF21 during amino acid deprivation. Biochem. J. 443:165–71 [Google Scholar]
  52. Shimizu N, Maruyama T, Yoshikawa N, Matsumiya R, Ma Y. 52.  et al. 2015. A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling. Nat. Commun. 6:6693 [Google Scholar]
  53. Fisher FM, Chui PC, Nasser IA, Popov Y, Cunniff JC. 53.  et al. 2014. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 147:1073–83.e6 [Google Scholar]
  54. Tanaka N, Takahashi S, Zhang Y, Krausz KW, Smith PB. 54.  et al. 2015. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochim. Biophys. Acta 1852:1242–52 [Google Scholar]
  55. Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ. 55.  et al. 2014. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63:4057–63 [Google Scholar]
  56. Berglund ED, Li CY, Bina HA, Lynes SE, Michael MD. 56.  et al. 2009. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 150:4084–93 [Google Scholar]
  57. Lin X, Li G, He X, Ma X, Zhang K. 57.  et al. 2014. FGF21 inhibits apolipoprotein(a) expression in HepG2 cells via the FGFR1-ERK1/2-Elk-1 pathway. Mol. Cell. Biochem. 393:33–42 [Google Scholar]
  58. Li Y, Wong K, Giles A, Jiang J, Lee JW. 58.  et al. 2014. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 146:539–49.e7 [Google Scholar]
  59. Potthoff MJ, Inagaki T, Satapati S, Ding X, He T. 59.  et al. 2009. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. PNAS 106:10853–58 [Google Scholar]
  60. Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H. 60.  et al. 2011. Paradoxical regulation of human FGF21 by both fasting and feeding signals: Is FGF21 a nutritional adaptation factor?. PLOS ONE 6:e22976 [Google Scholar]
  61. Iizuka K, Takeda J, Horikawa Y. 61.  2009. Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes. FEBS Lett. 583:2882–86 [Google Scholar]
  62. Sanchez J, Palou A, Pico C. 62.  2009. Response to carbohydrate and fat refeeding in the expression of genes involved in nutrient partitioning and metabolism: striking effects on fibroblast growth factor-21 induction. Endocrinology 150:5341–50 [Google Scholar]
  63. Camporez JP, Jornayvaz FR, Petersen MC, Pesta D, Guigni BA. 63.  et al. 2013. Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. Endocrinology 154:3099–109 [Google Scholar]
  64. Li X, Ge H, Weiszmann J, Hecht R, Li YS. 64.  et al. 2009. Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ob mice. FEBS Lett. 583:3230–34 [Google Scholar]
  65. Arner P, Pettersson A, Mitchell PJ, Dunbar JD, Kharitonenkov A, Ryden M. 65.  2008. FGF21 attenuates lipolysis in human adipocytes—a possible link to improved insulin sensitivity. FEBS Lett. 582:1725–30 [Google Scholar]
  66. Hotta Y, Nakamura H, Konishi M, Murata Y, Takagi H. 66.  et al. 2009. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology 150:4625–33 [Google Scholar]
  67. Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. 67.  2010. Hepatic FGF21 expression is induced at birth via PPARα in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 11:206–12 [Google Scholar]
  68. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M. 68.  et al. 2011. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J. Biol. Chem. 286:12983–90 [Google Scholar]
  69. Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG. 69.  2011. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol. Med. 17:736–40 [Google Scholar]
  70. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ. 70.  et al. 2012. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26:271–81 [Google Scholar]
  71. Lee P, Brychta RJ, Linderman J, Smith S, Chen KY, Celi FS. 71.  2013. Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J. Clin. Endocrinol. Metab. 98:E98–102 [Google Scholar]
  72. Chau MD, Gao J, Yang Q, Wu Z, Gromada J. 72.  2010. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1α pathway. PNAS 107:12553–58 [Google Scholar]
  73. Emanuelli B, Vienberg SG, Smyth G, Cheng C, Stanford KI. 73.  et al. 2014. Interplay between FGF21 and insulin action in the liver regulates metabolism. J. Clin. Investig. 124:515–27 [Google Scholar]
  74. Samms RJ, Smith DP, Cheng CC, Antonellis PP, Perfield JW 2nd. 74.  et al. 2015. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 11:991–99 [Google Scholar]
  75. Véniant MM, Sivits G, Helmering J, Komorowski. 75.  et al. 2015. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab. 21:731–38 [Google Scholar]
  76. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM. 76.  et al. 2013. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19:83–92 [Google Scholar]
  77. Lee P, Linderman J, Smith S, Brychta RJ, Perron R. 77.  et al. 2013. Fibroblast growth factor 21 (FGF21) and bone: Is there a relationship in humans?. Osteoporos. Int. 24:3053–57 [Google Scholar]
  78. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J. 78.  et al. 2014. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 19:302–9 [Google Scholar]
  79. Hondares E, Gallego-Escuredo JM, Flachs P, Frontini A, Cereijo R. 79.  et al. 2014. Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue. Metabolism 63:312–17 [Google Scholar]
  80. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT. 80.  et al. 2012. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148:556–67 [Google Scholar]
  81. Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y. 81.  et al. 2013. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 17:790–97 [Google Scholar]
  82. Lin Z, Tian H, Lam KS, Lin S, Hoo RC. 82.  et al. 2013. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 17:779–89 [Google Scholar]
  83. Hsuchou H, Pan W, Kastin AJ. 83.  2007. The fasting polypeptide FGF21 can enter brain from blood. Peptides 28:2382–86 [Google Scholar]
  84. Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H, Randeva HS. 84.  2011. Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity. Diabetes 60:2758–62 [Google Scholar]
  85. Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD. 85.  et al. 2010. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 59:1817–24 [Google Scholar]
  86. Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD. 86.  et al. 2013. FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. 19:1153–56 [Google Scholar]
  87. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A. 87.  et al. 2007. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–76 [Google Scholar]
  88. Owen BM, Ding X, Morgan DA, Coate KC, Bookout AL. 88.  et al. 2014. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 20:670–77 [Google Scholar]
  89. Douris N, Stevanovic D, Fisher FM, Cisu TI, Chee MJ. 89.  et al. 2015. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 156:2470–81 [Google Scholar]
  90. Johnson CL, Mehmood R, Laing SW, Stepniak CV, Kharitonenkov A, Pin CL. 90.  2014. 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. 306:E916–28 [Google Scholar]
  91. Uonaga T, Toyoda K, Okitsu T, Zhuang X, Yamane S. 91.  et al. 2010. FGF-21 enhances islet engraftment in mouse syngeneic islet transplantation model. Islets 2:247–51 [Google Scholar]
  92. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. 92.  2008. FGF21 is an Akt-regulated myokine. FEBS Lett. 582:3805–10 [Google Scholar]
  93. Hojman P, Pedersen M, Nielsen AR, Krogh-Madsen R, Yfanti C. 93.  et al. 2009. Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 58:2797–801 [Google Scholar]
  94. Kim KH, Kim SH, Min YK, Yang HM, Lee JB, Lee MS. 94.  2013. Acute exercise induces FGF21 expression in mice and in healthy humans. PLOS ONE 8:e63517 [Google Scholar]
  95. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkila S, Wenz T. 95.  et al. 2010. Mitochondrial myopathy induces a starvation-like response. Hum. Mol. Genet. 19:3948–58 [Google Scholar]
  96. Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C. 96.  et al. 2013. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat. Commun. 4:2019 [Google Scholar]
  97. Yan X, Chen J, Zhang C, Zhou S, Zhang Z. 97.  et al. 2015. FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. J. Cell. Mol. Med. 19:1557–68 [Google Scholar]
  98. Chen WW, Li L, Yang GY, Li K, Qi XY. 98.  et al. 2008. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diabetes 116:65–68 [Google Scholar]
  99. Mai K, Andres J, Biedasek K, Weicht J, Bobbert T. 99.  et al. 2009. Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. Diabetes 58:1532–38 [Google Scholar]
  100. Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F. 100.  2009. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator–activated receptor agonists but not ketosis in man. J. Clin. Endocrinol. Metab. 94:3594–601 [Google Scholar]
  101. Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D. 101.  2009. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 32:1542–46 [Google Scholar]
  102. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG. 102.  et al. 2008. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57:1246–53 [Google Scholar]
  103. Li H, Fang Q, Gao F, Fan J, Zhou J. 103.  et al. 2010. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J. Hepatol. 53:934–40 [Google Scholar]
  104. Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B. 104.  et al. 2010. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur. J. Clin. Investig. 40:887–92 [Google Scholar]
  105. Kralisch S, Tonjes A, Krause K, Richter J, Lossner U. 105.  et al. 2013. Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans. J. Endocrinol. 216:135–43 [Google Scholar]
  106. Hanks LJ, Casazza K, Ashraf AP, Wallace S, Gutierrez OM. 106.  2015. Fibroblast growth factor-21, body composition, and insulin resistance in pre-pubertal and early pubertal males and females. Clin. Endocrinol. 82:550–56 [Google Scholar]
  107. Reinehr T, Woelfle J, Wunsch R, Roth CL. 107.  2012. 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. 97:2143–50 [Google Scholar]
  108. Habegger KM, Stemmer K, Cheng C, Muller TD, Heppner KM. 108.  et al. 2013. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62:1453–63 [Google Scholar]
  109. Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E. 109.  2015. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol. Metab. 4:51–57 [Google Scholar]
  110. Davis RL, Liang C, Edema-Hildebrand F, Riley C, Needham M, Sue CM. 110.  2013. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology 81:1819–26 [Google Scholar]
  111. Koene S, de Laat P, van Tienoven DH, Vriens D, Brandt AM. 111.  et al. 2014. Serum FGF21 levels in adult m.3243A > G carriers: clinical implications.. Neurology 83:125–33 [Google Scholar]
  112. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA. 112.  et al. 2013. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18:333–40 [Google Scholar]
  113. Kharitonenkov A, Adams AC. 113.  2014. Inventing new medicines: the FGF21 story. Mol. Metab. 3:221–29 [Google Scholar]
  114. Gimeno RE, Moller DE. 114.  2014. FGF21-based pharmacotherapy—potential utility for metabolic disorders. Trends Endocrinol. Metab. 25:303–11 [Google Scholar]
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  • Article Type: Review Article
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