Skip to main content

Advertisement

SpringerLink
Log in

The Role and Potential Therapeutic Implications of the Fibroblast Growth Factors in Energy Balance and Type 2 Diabetes

  • Pathogenesis of Type 2 Diabetes and Insulin Resistance (RM Watanabe, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Obesity and its associated metabolic diseases have reached epidemic proportions worldwide, reducing life expectancy and quality of life. Several drugs have been tested to treat these diseases but many of them have damaging side effects. Consequently, there is an urgent need to develop more effective therapies. Recently, endocrine fibroblast growth factors (FGFs) have become attractive targets in the treatment of metabolic diseases. This review summarizes their most important functions as well as FGF-based therapies for the treatment of obesity and type 2 diabetes (T2D).

Recent Findings

Recent studies demonstrate that circulating levels of FGF19 are reduced in obesity. In fact, exogenous FGF19 administration is associated with a reduction in food intake as well as with improvements in glycaemia. In contrast, FGF21 levels are elevated in subjects with abdominal obesity, insulin resistance and T2D, probably representing a compensatory response. Additionally, elevated levels of circulating FGF23 in individuals with obesity and T2D are reported in most clinical studies. Finally, increased FGF1 levels in obese patients associated with adipogenesis have been described.

Summary

FGFs constitute important molecules in the treatment of metabolic diseases due to their beneficial effects on glucose and lipid metabolism. Among all members, FGF19 and FGF21 have demonstrated the ability to improve glucose, lipid and energy homeostasis, along with FGF1, which was recently discovered to have beneficial effects on metabolic homeostasis. Additionally, FGF23 may also play a role in insulin resistance or energy homeostasis beyond mineral metabolism control. These results highlight the relevant use of FGFs as potential biomarkers for the early diagnosis of metabolic diseases. In this regard, notable progress has been made in the development of FGF-based therapies and different approaches are being tested in different clinical trials. However, further studies are needed to determine their potential therapeutic use in the treatment of obesity and obesity-related comorbidities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Frühbeck G, Toplak H, Woodward E, Yumuk V, Maislos M, Oppert JM. Obesity: the gateway to ill health - an EASO position statement on a rising public health, clinical and scientific challenge in Europe. Obes Facts. 2013;6:117–20.

    Article  PubMed  Google Scholar 

  2. 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. 2013;384:766–81.

    Article  Google Scholar 

  3. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Frühbeck G, Gómez-Ambrosi J. Control of body weight: a physiologic and transgenic perspective. Diabetologia. 2003;46:143–72.

    Article  PubMed  Google Scholar 

  5. •• Bray GA, Frühbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016;387:1947–56. Thorough review describing different strategies to treat obesity

    Article  PubMed  Google Scholar 

  6. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–62.

    Article  CAS  PubMed  Google Scholar 

  7. Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145:2594–603.

    Article  CAS  PubMed  Google Scholar 

  8. Itoh N. Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease. Cell Tissue Res. 2010;342:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8:235–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004;20:563–9.

    Article  CAS  PubMed  Google Scholar 

  11. Ornitz DM. FGFs, heparan sulfate and FGFRs: complex interactions essential for development. BioEssays. 2000;22:108–12.

    Article  CAS  PubMed  Google Scholar 

  12. 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;27:3417–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fukumoto S. Actions and mode of actions of FGF19 subfamily members. Endocr J. 2008;55:23–31.

    Article  CAS  PubMed  Google Scholar 

  14. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–4.

    Article  CAS  PubMed  Google Scholar 

  15. 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;24:2050–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kurosu H, Choi M, Ogawa Y, et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007;282:26687–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. •• Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115:1627–35. Seminal paper describing the participation of FGFs in energy balance and glucose metabolism

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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;143:1741–7.

    Article  CAS  PubMed  Google Scholar 

  19. Newell FS, Su H, Tornqvist H, Whitehead JP, Prins JB, Hutley LJ. Characterization of the transcriptional and functional effects of fibroblast growth factor-1 on human preadipocyte differentiation. FASEB J. 2006;20:2615–7.

    Article  CAS  PubMed  Google Scholar 

  20. Kreuger J, Prydz K, Pettersson RF, Lindahl U, Salmivirta M. Characterization of fibroblast growth factor 1 binding heparan sulfate domain. Glycobiology. 1999;9:723–9.

    Article  CAS  PubMed  Google Scholar 

  21. Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2:217–25.

    Article  CAS  PubMed  Google Scholar 

  22. Schmidt DR, Holmstrom SR, Fon Tacer K, Bookout AL, Kliewer SA, Mangelsdorf DJ. Regulation of bile acid synthesis by fat-soluble vitamins A and D. J Biol Chem. 2010;285:14486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Henkel AS, Anderson KA, Dewey AM, Kavesh MH, Green RM. A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice. J Lipid Res. 2011;52:289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vergnes L, Lee JM, Chin RG, Auwerx J, Reue K. Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate bile acid and lipid levels. Cell Metab. 2013;17:916–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Holt JA, Luo G, Billin AN, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003;17:1581–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Potthoff MJ, Boney-Montoya J, Choi M, et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1alpha pathway. Cell Metab. 2011;13:729–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bhatnagar S, Damron HA, Hillgartner FB. Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis. J Biol Chem. 2009;284:10023–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kir S, Beddow SA, Samuel VT, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science. 2011;331:1621–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. • 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;3:19–28. This study provides evidence that FGF19 can signal in the hypothalamic arcuate nucleus improving peripheral insulin signaling through the induction of ERK1/2 signaling and the suppression of AGRP/NPY neurons activity in obese and insulin-resistant states

    Article  CAS  PubMed  Google Scholar 

  30. 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;154:9–15.

    Article  CAS  PubMed  Google Scholar 

  31. Yang C, Jin C, Li X, Wang F, McKeehan WL, Luo Y. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS One. 2012;7:e33870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu X, Ge H, Baribault H, et al. Dual actions of fibroblast growth factor 19 on lipid metabolism. J Lipid Res. 2013;54:325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hondares E, Iglesias R, Giralt A, et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem. 2011;286:12983–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Muise ES, Azzolina B, Kuo DW, et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol. 2008;74:403–12.

    Article  CAS  PubMed  Google Scholar 

  35. Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta. 2000;1492:203–6.

    Article  CAS  PubMed  Google Scholar 

  36. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5:426–37.

    Article  CAS  PubMed  Google Scholar 

  37. Inagaki T, Dutchak P, Zhao G, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–25.

    Article  CAS  PubMed  Google Scholar 

  38. Lundasen T, Hunt MC, Nilsson LM, et al. PPARalpha is a key regulator of hepatic FGF21. Biochem Biophys Res Commun. 2007;360:437–40.

    Article  CAS  PubMed  Google Scholar 

  39. Boutant M, Canto C. SIRT1 metabolic actions: integrating recent advances from mouse models. Mol Metab. 2014;3:5–18.

    Article  CAS  PubMed  Google Scholar 

  40. Lee JH, Giannikopoulos P, Duncan SA, et al. The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat Med. 2011;17:812–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Patel R, Bookout AL, Magomedova L, et al. Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop. Mol Endocrinol. 2015;29:213–23.

    Article  PubMed  CAS  Google Scholar 

  42. De Sousa-Coelho AL, Marrero PF, Haro D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J. 2012;443:165–71.

    Article  CAS  PubMed  Google Scholar 

  43. Laeger T, Henagan TM, Albarado DC, et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest. 2014;124:3913–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. De Sousa-Coelho AL, Relat J, Hondares E, et al. FGF21 mediates the lipid metabolism response to amino acid starvation. J Lipid Res. 2013;54:1786–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology. 2009;150:4931–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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;403:287–99.

    Article  CAS  PubMed  Google Scholar 

  47. 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;463:191–9.

    Article  CAS  PubMed  Google Scholar 

  48. Ding X, Boney-Montoya J, Owen BM, et al. betaKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 2012;16:387–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Markan KR, Naber MC, Ameka MK, et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes. 2014;63:4057–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fisher FM, Kleiner S, Douris N, et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26:271–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Samms RJ, Smith DP, Cheng CC, et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 2015;11:991–9.

    Article  CAS  PubMed  Google Scholar 

  52. Veniant MM, Sivits G, Helmering J, et al. Pharmacologic effects of FGF21 are independent of the “Browning” of white adipose tissue. Cell Metab. 2015;21:731–8.

    Article  CAS  PubMed  Google Scholar 

  53. 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;17:779–89.

    Article  CAS  PubMed  Google Scholar 

  54. Holland WL, Adams AC, Brozinick JT, et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 2013;17:790–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hsuchou H, Pan W, Kastin AJ. The fasting polypeptide FGF21 can enter brain from blood. Peptides. 2007;28:2382–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H, Randeva HS. Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity. Diabetes. 2011;60:2758–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bookout AL, de Groot MH, Owen BM, et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med. 2013;19:1147–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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;63:4064–75.

    Article  CAS  PubMed  Google Scholar 

  59. Owen BM, Ding X, Morgan DA, et al. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 2014;20:670–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ersoy FF. A short story of Klotho and FGF23: a deuce of dark side or the savior? Int Urol Nephrol. 2014;46:577–81.

    Article  CAS  PubMed  Google Scholar 

  61. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19:429–35.

    Article  CAS  PubMed  Google Scholar 

  62. Farrow EG, White KE. Recent advances in renal phosphate handling. Nat Rev Nephrol. 2010;6:207–17.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lanske B, Razzaque MS. Molecular interactions of FGF23 and PTH in phosphate regulation. Kidney Int. 2014;86:1072–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hanks LJ, Casazza K, Judd SE, Jenny NS, Gutierrez OM. Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults. PLoS One. 2015;10:e0122885.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Grethen E, Hill KM, Jones R, et al. Serum leptin, parathyroid hormone, 1,25-dihydroxyvitamin D, fibroblast growth factor 23, bone alkaline phosphatase, and sclerostin relationships in obesity. J Clin Endocrinol Metab. 2012;97:1655–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Itoh N, Ornitz DM. Fibroblast growth factors: From molecular evolution to roles in development, metabolism and disease. J Biochem. 2011;149:121–30.

    Article  CAS  PubMed  Google Scholar 

  67. Mouta Carreira C, Landriscina M, Bellum S, Prudovsky I, Maciag T. The comparative release of FGF1 by hypoxia and temperature stress. Growth Factors. 2001;18:277–85.

    Article  CAS  PubMed  Google Scholar 

  68. Jackson A, Friedman S, Zhan X, Engleka KA, Forough R, Maciag T. Heat shock induces the release of fibroblast growth factor 1 from NIH 3T3 cells. Proc Natl Acad Sci U S A. 1992;89:10691–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shin JT, Opalenik SR, Wehby JN, et al. Serum-starvation induces the extracellular appearance of FGF-1. Biochim Biophys Acta. 1996;1312:27–38.

    Article  PubMed  Google Scholar 

  70. Ananyeva NM, Tjurmin AV, Berliner JA, et al. Oxidized LDL mediates the release of fibroblast growth factor-1. Arterioscler Thromb Vasc Biol. 1997;17:445–53.

    Article  CAS  PubMed  Google Scholar 

  71. Friesel R, Maciag T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling. Thromb Haemost. 1999;82:748–54.

    CAS  PubMed  Google Scholar 

  72. Zakrzewska M, Marcinkowska E, Wiedlocha A. FGF-1: from biology through engineering to potential medical applications. Crit Rev Clin Lab Sci. 2008;45:91–135.

    Article  CAS  PubMed  Google Scholar 

  73. Hutley L, Shurety W, Newell F, et al. Fibroblast growth factor 1: a key regulator of human adipogenesis. Diabetes. 2004;53:3097–106.

    Article  CAS  PubMed  Google Scholar 

  74. Hutley LJ, Newell FS, Kim YH, et al. A putative role for endogenous FGF-2 in FGF-1 mediated differentiation of human preadipocytes. Mol Cell Endocrinol. 2011;339:165–71.

    Article  CAS  PubMed  Google Scholar 

  75. Jonker JW, Suh JM, Atkins AR, et al. A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature. 2012;485:391–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Miller DL, Ortega S, Bashayan O, Basch R, Basilico C. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol. 2000;20:2260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Angelin B, Larsson TE, Rudling M. Circulating fibroblast growth factors as metabolic regulators—a critical appraisal. Cell Metab. 2010;16:693–705.

    Article  CAS  Google Scholar 

  78. Owen BM, Mangelsdorf DJ, Kliewer SA. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol Metab. 2015;26:22–9.

    Article  CAS  PubMed  Google Scholar 

  79. Morton GJ, Matsen ME, Bracy DP, et al. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest. 2013;123:4799–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Reiche M, Bachmann A, Lossner U, Bluher M, Stumvoll M, Fasshauer M. Fibroblast growth factor 19 serum levels: relation to renal function and metabolic parameters. Horm Metab Res. 2010;42:178–81.

    Article  CAS  PubMed  Google Scholar 

  81. • Gallego-Escuredo JM, Gómez-Ambrosi J, Catalán 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. 2015;39:121–9. This study reports that obesity is associated with an increase in FGF21 as well as with a decrease in FGF19 circulating levels. Moreover, opposite changes in β-klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGF-s in obesity

    Article  CAS  Google Scholar 

  82. Gerhard GS, Styer AM, Wood GC, et al. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care. 2013;36:1859–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gómez-Ambrosi J, Gallego-Escuredo JM, Catalán V, et al. FGF19 and FGF21 serum concentrations in human obesity and type 2 diabetes behave differently after diet- or surgically-induced weight loss. Clin Nutr. 2016; doi:10.1016/j.clnu.2016.04.027

  84. Mraz M, Lacinova Z, Kavalkova P, et al. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment. Physiol Res. 2011;60:627–36.

    CAS  PubMed  Google Scholar 

  85. 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;52:1455–64.

    Article  CAS  PubMed  Google Scholar 

  86. Coskun T, Bina HA, Schneider MA, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149:6018–27.

    Article  CAS  PubMed  Google Scholar 

  87. Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes. 2009;58:250–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Murphy M, Samms R, Warner A, et al. Increased responses to the actions of fibroblast growth factor 21 on energy balance and body weight in a seasonal model of adiposity. J Neuroendocrinol. 2013;25:180–9.

    Article  CAS  PubMed  Google Scholar 

  89. Kharitonenkov A, Wroblewski VJ, Koester A, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology. 2007;148:774–81.

    Article  CAS  PubMed  Google Scholar 

  90. •• Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18:333–40. This study examines that daily administration of LY, a human FGF21 analog, provides clear evidence of its clinically meaningful effects on several metabolic comorbidities associated with type 2 diabetes

    Article  CAS  PubMed  Google Scholar 

  91. Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D. 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. 2009;32:1542–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dushay J, Chui PC, Gopalakrishnan GS, et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology. 2010;139:456–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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;57:1246–53.

    Article  CAS  PubMed  Google Scholar 

  94. 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;53:934–40.

    Article  CAS  PubMed  Google Scholar 

  95. Fisher FM, Chui PC, Antonellis PJ, et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes. 2010;59:2781–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Berglund ED, Li CY, Bina HA, et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology. 2009;150:4084–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Diaz-Delfin J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F. TNF-alpha represses beta-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology. 2012;153:4238–45.

    Article  CAS  PubMed  Google Scholar 

  98. Hale C, Chen MM, Stanislaus S, et al. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology. 2012;153:69–80.

    Article  CAS  PubMed  Google Scholar 

  99. 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;89:52–7.

    Article  CAS  PubMed  Google Scholar 

  100. Li X, Fan X, Ren F, et al. Serum FGF21 levels are increased in newly diagnosed type 2 diabetes with nonalcoholic fatty liver disease and associated with hsCRP levels independently. Diabetes Res Clin Pract. 2011;93:10–6.

    Article  CAS  PubMed  Google Scholar 

  101. Mraz M, Bartlova M, Lacinova Z, et al. 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;71:369–75.

    Article  CAS  Google Scholar 

  102. 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:E54–8.

    Article  CAS  PubMed  Google Scholar 

  103. Vienberg SG, Brons 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;167:49–57.

    Article  CAS  PubMed  Google Scholar 

  104. Mirza MA, Alsio J, Hammarstedt A, et al. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arterioscler Thromb Vasc Biol. 2011;31:219–27.

    Article  CAS  PubMed  Google Scholar 

  105. Holecki M, Chudek J, Wiecek A, Titz-Bober M, Dulawa J. The serum level of fibroblast growth factor-23 and calcium-phosphate homeostasis in obese perimenopausal women. Int J Endocrinol. 2011;2011:707126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Marsell R, Mirza MA, Mallmin H, et al. Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men. Osteoporos Int. 2009;20:1167–73.

    Article  CAS  PubMed  Google Scholar 

  107. Fernandez-Real JM, Puig J, Serrano M, et al. Iron and obesity status-associated insulin resistance influence circulating fibroblast-growth factor-23 concentrations. PLoS One. 2013;8:e58961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Tsuji K, Maeda T, Kawane T, Matsunuma A, Horiuchi N. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. J Bone Miner Res. 2010;25:1711–23.

    Article  CAS  PubMed  Google Scholar 

  109. Wahl P, Xie H, Scialla J, et al. Earlier onset and greater severity of disordered mineral metabolism in diabetic patients with chronic kidney disease. Diabetes Care. 2012;35:994–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Vervloet MG, van Zuilen AD, Heijboer AC, et al. Fibroblast growth factor 23 is associated with proteinuria and smoking in chronic kidney disease: an analysis of the MASTERPLAN cohort. BMC Nephrol. 2012;13:20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Fajol A, Chen H, Umbach AT, Quarles LD, Lang F, Foller M. Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by beta-blocker treatment. FASEB J. 2016;30:994–1001.

    Article  CAS  PubMed  Google Scholar 

  112. Winther K, Nybo M, Vind B, Pedersen SM, Hojlund K, Rasmussen LM. Acute hyperinsulinemia is followed by increased serum concentrations of fibroblast growth factor 23 in type 2 diabetes patients. Scand J Clin Lab Invest. 2012;72:108–13.

    Article  CAS  PubMed  Google Scholar 

  113. Hu X, Ma X, Luo Y, et al. Elevation in fibroblast growth factor 23 and its value for identifying subclinical atherosclerosis in first-degree relatives of patients with diabetes. Sci Rep. 2016;6:34696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Reyes-Garcia R, Garcia-Martin A, Garcia-Fontana B, Morales-Santana S, Rozas-Moreno P, Munoz-Torres M. FGF23 in type 2 diabetic patients: relationship with bone metabolism and vascular disease. Diabetes Care. 2014;37:e89–90.

    Article  CAS  PubMed  Google Scholar 

  115. Wojcik M, Dolezal-Oltarzewska K, Janus D, Drozdz D, Sztefko K, Starzyk JB. FGF23 contributes to insulin sensitivity in obese adolescents—preliminary results. Clin Endocrinol. 2012;77:537–40.

    Article  CAS  Google Scholar 

  116. Holecki M, Chudek J, Owczarek A, et al. Inflammation but not obesity or insulin resistance is associated with increased plasma fibroblast growth factor 23 concentration in the elderly. Clin Endocrinol. 2015;82:900–9.

    Article  CAS  Google Scholar 

  117. Gómez-Ambrosi J, Salvador J, Paramo JA, et al. Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors. Clin Biochem. 2002;35:315–20.

    Article  PubMed  Google Scholar 

  118. Ortega FJ, Mayas D, Moreno-Navarrete JM, et al. The gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue of obese subjects. Obesity (Silver Spring). 2010;18:13–20.

    Article  CAS  Google Scholar 

  119. Rodríguez A, Catalán V, Gómez-Ambrosi J, Frühbeck G. Aquaglyceroporins serve as metabolic gateways in adiposity and insulin resistance control. Cell Cycle. 2011;10:1548–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Moreno-Navarrete JM, Catalán V, Whyte L, et al. The L-alpha-lysophosphatidylinositol/GPR55 system and its potential role in human obesity. Diabetes. 2012;61:281–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gómez-Ambrosi J, Pascual E, Catalán V, et al. Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes. J Clin Endocrinol Metab. 2014;99:E2004–9.

    Article  PubMed  CAS  Google Scholar 

  122. Mejhert N, Galitzky J, Pettersson AT, et al. Mapping of the fibroblast growth factors in human white adipose tissue. J Clin Endocrinol Metab. 2010;95:2451–7.

    Article  CAS  PubMed  Google Scholar 

  123. Gerhard GS, Styer AM, Strodel WE, et al. Gene expression profiling in subcutaneous, visceral and epigastric adipose tissues of patients with extreme obesity. Int J Obes. 2014;38:371–8.

    Article  CAS  Google Scholar 

  124. Choi Y, Jang S, Choi MS, Ryoo ZY, Park T. Increased expression of FGF1-mediated signaling molecules in adipose tissue of obese mice. J Physiol Biochem. 2016;72:157–67.

    Article  CAS  PubMed  Google Scholar 

  125. •• Suh JM, Jonker JW, Ahmadian M, et al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 2014;513:436–9. This study demonstrates that recombinant FGF1 (rFGF1) produces glucose lowering and insulin sensitization without mitogenic effects, indicating that rFGF1 and its derivates may hold therapeutic promises

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Scarlett JM, Rojas JM, Matsen ME, et al. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med. 2016;22:800–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Seeley RJ, Sandoval DA. Targeting the brain as a cure for type 2 diabetes. Nat Med. 2016;22:709–11.

    Article  CAS  PubMed  Google Scholar 

  128. Perry RJ, Lee S, Ma L, Zhang D, Schlessinger J, Shulman GI. FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat Commun. 2015;6:6980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. •• Li M, Page-McCaw P, Chen W. FGF1 mediates overnutrition-induced compensatory β-cell differentiation. Diabetes. 2016;65:96–109. This study describes Fgf1 signaling as a key component of the overnutrition-induced β-cell differentiation signal

    PubMed  Google Scholar 

  130. Wang S, Yang Q, Yu S, et al. Fibroblast growth factor 1 levels are elevated in newly diagnosed type 2 diabetes compared to normal glucose tolerance controls. Endocr J. 2016;63:359–65.

    Article  PubMed  Google Scholar 

  131. 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;160:2295–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Birrer MJ, Johnson ME, Hao K, et al. Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas. J Clin Oncol. 2007;25:2281–7.

    Article  CAS  PubMed  Google Scholar 

  133. Wu X, Ge H, Lemon B, et al. Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19). Proc Natl Acad Sci U S A. 2010;107:14158–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wu AL, Coulter S, Liddle C, et al. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PLoS One. 2011;6:e17868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. French DM, Lin BC, Wang M, et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One. 2012;7:e36713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhou M, Wang X, Phung V, et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res. 2014;74:3306–16.

    Article  CAS  PubMed  Google Scholar 

  137. Wu X, Lemon B, Li X, et al. C-terminal tail of FGF19 determines its specificity toward Klotho co-receptors. J Biol Chem. 2008;283:33304–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Luo J, Ko B, Elliott M, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. 2014;6:247ra100.

    Article  PubMed  CAS  Google Scholar 

  139. Wu X, Li Y. Therapeutic utilities of fibroblast growth factor 19. Expert Opin Ther Targets. 2011;15:1307–16.

    Article  CAS  PubMed  Google Scholar 

  140. Adams AC, Halstead CA, Hansen BC, et al. LY2405319, an engineered FGF21 variant. Improves the Metabolic Status of Diabetic Monkeys PLoS One. 2013;8:e65763.

    CAS  PubMed  Google Scholar 

  141. Kharitonenkov A, Beals JM, Micanovic R, et al. Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319. PLoS One. 2013;8:e58575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Huang Z, Wang H, Lu M, et al. A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol. PLoS One. 2011;6:e20669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Camacho RC, Zafian PT, Achanfuo-Yeboah J, Manibusan A, Berger JP. Pegylated Fgf21 rapidly normalizes insulin-stimulated glucose utilization in diet-induced insulin resistant mice. Eur J Pharmacol. 2013;715:41–5.

    Article  CAS  PubMed  Google Scholar 

  144. Bendele A, Seely J, Richey C, Sennello G, Shopp G. Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. Toxicol Sci. 1998;42:152–7.

    Article  CAS  PubMed  Google Scholar 

  145. Webster R, Didier E, Harris P, et al. PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos. 2007;35:9–16.

    Article  CAS  PubMed  Google Scholar 

  146. Xu J, Bussiere J, Yie J, et al. Polyethylene glycol modified FGF21 engineered to maximize potency and minimize vacuole formation. Bioconjug Chem. 2013;24:915–25.

    Article  CAS  PubMed  Google Scholar 

  147. 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:e49345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Huang J, Ishino T, Chen G, et al. Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody. J Pharmacol Exp Ther. 2013;346:270–80.

    Article  CAS  PubMed  Google Scholar 

  149. Weng Y, Chabot JR, Bernardo B, et al. Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice. PLoS One. 2015;10:e0119104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Giragossian C, Vage C, Li J, et al. Mechanistic investigation of the preclinical pharmacokinetics and interspecies scaling of PF-05231023, a fibroblast growth factor 21-antibody protein conjugate. Drug Metab Dispos. 2015;43:803–11.

    Article  CAS  PubMed  Google Scholar 

  151. Dong JQ, Rossulek M, Somayaji VR, et al. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol. 2015;80:1051–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wu AL, Kolumam G, Stawicki S, et al. Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci Transl Med. 2011;3:113ra126.

    Article  PubMed  CAS  Google Scholar 

  153. Ussar S, Vienberg SG, Kahn CR. Receptor antibodies as novel therapeutics for diabetes. Sci Transl Med. 2011;3:113ps147.

    Article  CAS  Google Scholar 

  154. Foltz IN, Hu S, King C, et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the betaKlotho/FGFR1c receptor complex. Sci Transl Med. 2012;4:162ra153.

    Article  PubMed  CAS  Google Scholar 

  155. Smith R, Duguay A, Bakker A, et al. FGF21 can be mimicked in vitro and in vivo by a novel anti-FGFR1c/beta-Klotho bispecific protein. PLoS One. 2013;8:e61432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Kwabi-Addo B, Ozen M, Ittmann M. The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer. 2004;11:709–24.

    Article  CAS  PubMed  Google Scholar 

  157. Kingwell K. Obesity and diabetes: FGF1 goes long to tackle diabetes. Nat Rev Drug Discov. 2014;13:652–3.

    Article  CAS  PubMed  Google Scholar 

  158. Wente W, Efanov AM, Brenner M, et al. 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. 2006;55:2470–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by ISCIII-Subdirección General de Evaluación y FEDER (PI13/00460 and PI16/01217; Plan Estatal I + D + I/2013-2016) and by Fundación Caja Navarra (20-2014). CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the ISCIII, Spain.

The authors gratefully acknowledge the valuable collaboration of all the members of the Multidisciplinary Obesity Team, Clinica Universidad de Navarra, Pamplona, Spain.

Author information

Authors and Affiliations

  1. Metabolic Research Laboratory, Clínica Universidad de Navarra, Avda. Pío XII, 36, 31008, Pamplona, Spain

    Maitane Izaguirre, Gema Frühbeck & Victoria Catalán

  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain

    Maitane Izaguirre, Gema Frühbeck & Victoria Catalán

  3. Department of Biochemistry, Clínica Universidad de Navarra, Pamplona, Spain

    María J. Gil & Ignacio Monreal

  4. Department of Internal Medicine, University of Genoa, Genoa, Italy

    Fabrizio Montecucco

  5. IRCCS AOU San Martino—IST, Genoa, Italy

    Fabrizio Montecucco

  6. Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    Gema Frühbeck & Victoria Catalán

  7. Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain

    Gema Frühbeck

Authors
  1. Maitane Izaguirre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María J. Gil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ignacio Monreal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fabrizio Montecucco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gema Frühbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Victoria Catalán
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Victoria Catalán.

Ethics declarations

Conflict of Interest

Maitane Izaguirre, María J. Gil, Ignacio Monreal, Fabrizio Montecucco, Gema Frühbeck, and Victoria Catalán declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Izaguirre, M., Gil, M.J., Monreal, I. et al. The Role and Potential Therapeutic Implications of the Fibroblast Growth Factors in Energy Balance and Type 2 Diabetes. Curr Diab Rep 17, 43 (2017). https://doi.org/10.1007/s11892-017-0866-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-017-0866-3

Keywords

Search

Navigation