Skip to main content

Fibroblast Growth Factor-21 and the Beneficial Effects of Long-Chain n-3 Polyunsaturated Fatty Acids

Abstract

Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) in the diet protect against insulin resistance and obesity. Fibroblast growth factor-21 (Fgf21) is a hormonal factor released mainly by the liver that has powerful anti-diabetic effects. Here, we tested whether the beneficial metabolic effects of LC n-3 PUFA involve the induction of Fgf21. C57BL/6 J mice were exposed to an obesogenic, corn-oil-based, high-fat diet (cHF), or a diet in which corn oil was replaced with a fish-derived LC n-3 PUFA concentrate (cHF + F) using two experimental settings: short-term (3 weeks) and long-term treatment (8 weeks). CHF + F reduced body weight gain, insulinemia, and triglyceridemia compared to cHF. cHF increased plasma Fgf21 levels and hepatic Fgf21 gene expression compared with controls, but these effects were less pronounced or absent in cHF + F-fed mice. In contrast, hepatic expression of peroxisome proliferator-activated receptor (PPAR)-α target genes were more strongly induced by cHF + F than cHF, especially in the short-term treatment setting. The expression of genes encoding Fgf21, its receptors, and Fgf21 targets was unaltered by short-term LC n-3 PUFA treatment, with the exception of Ucp1 (uncoupling protein 1) and adiponectin genes, which were specifically up-regulated in white fat. In the long-term treatment setting, the expression of Fgf21 target genes and receptors was not differentially affected by LC n-3 PUFA. Collectively, our findings indicate that increased Fgf21 levels do not appear to be a major mechanism through which LC n-3 PUFA ameliorates high-fat-diet-associated metabolic disorders.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

Acox1:

Acyl-coenzyme A oxidase

BAT:

Brown adipose tissue

CPT2:

Carnitine palmitoyltransferase-2

DHA:

Docosahexaenoic acid

Ehhadh:

Bifunctional enzyme or enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase

EPA:

Eicosapentaenoic acid

FGF21:

Fibroblast growth factor-21

FGFR:

Fibroblast growth factor receptor

Slc2a1:

Glucose transporter-1

Acadm:

Medium chain acyl-CoA dehydrogenase

Ppargc1a:

PPARgamma-coactivator-1α

PPAR:

Peroxisome proliferator-activated receptor

PUFA:

Polyunsaturated fatty acids

UCP1:

Uncoupling protein-1

WAT:

White adipose tissue

References

  1. Flachs P, Rossmeisl M, Bryhn M, Kopecky J (2009) Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci (Lond) 116:1–16

    Article  CAS  Google Scholar 

  2. Mori TA, Bao DQ, Burke V, Puddey IB, Watts GF, Beilin LJ (1999) Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects. Am J Clin Nutr 70:817–825

    PubMed  CAS  Google Scholar 

  3. Flachs P, Horakova O, Brauner P, Rossmeisl M, Pecina P, Franssen-van HN et al (2005) Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat. Diabetologia 48:2365–2375

    PubMed  Article  CAS  Google Scholar 

  4. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L et al (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310:314–317

    PubMed  Article  CAS  Google Scholar 

  5. Jelenik T, Rossmeisl M, Kuda O, Jilkova ZM, Medrikova D, Kus V et al (2010) AMP-activated protein kinase alpha2 subunit is required for the preservation of hepatic insulin sensitivity by n-3 polyunsaturated fatty acids. Diabetes 59:2737–2746

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  6. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ et al (2012) Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell 148:556–567

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  7. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ et al (2005) FGF-21 as a novel metabolic regulator. J Clin Invest 115:1627–1635

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  8. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y et al (2008) Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149:6018–6027

    PubMed  Article  CAS  Google Scholar 

  9. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T et al (2011) Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 286:12983–12990

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  10. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V et al (2007) Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 5:415–425

    PubMed  Article  CAS  Google Scholar 

  11. Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R et al (2007) BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 104:7432–7437

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  12. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E (2007) Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5:426–437

    PubMed  Article  CAS  Google Scholar 

  13. Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F (2010) Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 11:206–212

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  14. Flachs P, Ruhl R, Hensler M, Janovska P, Zouhar P, Kus V et al (2011) Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids. Diabetologia 54:2626–2638

    PubMed  Article  CAS  Google Scholar 

  15. Horakova O, Medrikova D, van Schothorst EM, Bunschoten A, Flachs P, Kus V et al (2012) Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese mice. PLoS ONE 7:e43764

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  16. Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9:327–338

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  17. Diaz-Delfin J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F (2012) TNF-alpha represses beta-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology 153:4238–4245

    PubMed  Article  CAS  Google Scholar 

  18. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F et al (2008) Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57:1246–1253

    PubMed  Article  CAS  Google Scholar 

  19. Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS et al (2010) Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 59:2781–2789

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  20. Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M et al (2013) Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 17:779–789

    PubMed  Article  CAS  Google Scholar 

  21. Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X et al (2010) Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 53:934–940

    PubMed  Article  CAS  Google Scholar 

  22. Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM et al (2010) Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139:456–463

    PubMed  Article  CAS  Google Scholar 

  23. Yang C, Lu W, Lin T, You P, Ye M, Huang Y et al (2013) Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol 13:67

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  24. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS et al (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 94:4318–4323

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  25. Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I et al (2008) The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab 8:169–174

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

Supported by Ministerio de Ciencia e Innovación (SAF2011-23636) and Instituto de Salud Carlos III (PI11/00376) Spain; and the Czech Science Foundation (13-00871S), Czech Republic. IR-A was supported by a pre-doctoral fellowship from Gobierno Vasco (Programa de Formación de Investigadores del DEUI).

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anna Planavila.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 14 kb)

About this article

Verify currency and authenticity via CrossMark

Cite this article

Villarroya, J., Flachs, P., Redondo-Angulo, I. et al. Fibroblast Growth Factor-21 and the Beneficial Effects of Long-Chain n-3 Polyunsaturated Fatty Acids. Lipids 49, 1081–1089 (2014). https://doi.org/10.1007/s11745-014-3948-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-014-3948-x

Keywords

  • Fibroblast growth factor-21
  • Long-chain n-3 polyunsaturated fatty acids