Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Increased fibroblast growth factor 21 expression in high-fat diet-sensitive non-human primates (Macaca mulatta)

International Journal of Obesity volume 38, pages 183–191 (2014)Cite this article

Subjects

Abstract

Objective:

Fibroblast growth factor 21 (FGF21) is a metabolic regulator of glucose and lipid metabolism. The physiological role of FGF21 is not yet fully elucidated, however, administration of FGF21 lowers blood glucose in diabetic animals. Moreover, increased levels of FGF21 are found in obese and diabetic rodents and humans compared with lean/non-diabetic controls.

Methods:

Adult male rhesus macaque monkeys were chronically maintained on a high-fat diet (HFD) or a standard diet (control, CTR). Plasma levels of FGF21, triglycerides and cholesterol were measured and body weight was record. Glucose-stimulated insulin secretion (GSIS) and glucose clearance was determined during an intravenous glucose tolerance test. Furthermore, expression of FGF21 and its receptors were determined in liver, pancreas, three white adipose tissues (WATs) and two skeletal muscles.

Results:

A cohort of the high-fat fed monkeys responded to the HFD with increasing body weight, plasma lipids, total cholesterol, GSIS and decreased glucose tolerance. These monkeys were termed HFD sensitive. Another cohort of monkeys did not become obese and maintained normal insulin sensitivity. These animals were defined as HFD resistant. Plasma FGF21 levels were significantly increased in all HFD fed monkeys compared with the CTR group. The HFD-sensitive monkeys showed a significant increase in FGF21 mRNA expression in all examined tissues compared with CTR, whereas FGF21 expression in the HFD-resistant group was only increased in the liver, pancreas and the retroperitoneal WAT. In the WAT, the co-receptor β-klotho was downregulated in the HFD-sensitive monkeys compared with the HFD-resistant group.

Conclusion:

This study demonstrates that HFD changes FGF21 and FGF21 receptor expression in a tissue-specific manner in rhesus monkeys; differential regulation is moreover observed between HFD-sensitive and -resistant monkeys. Monkeys that maintain normal levels of the FGF21 co-receptor β-klotho in the WAT on HFD were protected toward development of dyslipidemia and hyperglycemia.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. 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: 426–437.

    Article  CAS  Google Scholar 

  2. 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: 4931–4940.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A, Sandusky GE 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: 2470–2478.

    Article  CAS  Google Scholar 

  6. Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007; 27: 3417–3428.

    Article  CAS  Google Scholar 

  7. Itoh N, Ornitz DM . Functional evolutionary history of the mouse Fgf gene family. Dev Dyn 2008; 237: 18–27.

    Article  CAS  Google Scholar 

  8. Fon TK, Bookout AL, Ding X, Kurosu H, John GB, Wang L et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010; 24: 2050–2064.

    Article  Google Scholar 

  9. Nishimura T, Nakatake Y, Konishi M, Itoh N . Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 2000; 1492: 203–206.

    Article  CAS  Google Scholar 

  10. Hojman P, Pedersen M, Nielsen AR, Krogh-Madsen R, Yfanti C, Akerstrom T et al. Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 2009; 58: 2797–2801.

    Article  CAS  Google Scholar 

  11. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K . FGF21 is an Akt-regulated myokine. FEBS Lett 2008; 582: 3805–3810.

    Article  CAS  Google Scholar 

  12. Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D 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: 369–375.

    Article  CAS  Google Scholar 

  13. Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol 2008; 74: 403–412.

    Article  CAS  Google Scholar 

  14. Wang H, Qiang L, Farmer SR . Identification of a domain within peroxisome proliferator-activated receptor gamma 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: 188–200.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Gupte J, Yang L, Wu X, Weiszmann J, Hecht R, Lemon B et al. The FGFR D3 domain determines receptor selectivity for fibroblast growth factor 21. J Mol Biol 2011; 408: 491–502.

    Article  CAS  Google Scholar 

  17. Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV 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: 26687–26695.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M et al. BetaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol 2008; 22: 1006–1014.

    Article  CAS  Google Scholar 

  20. Ge H, Baribault H, Vonderfecht S, Lemon B, Weiszmann J, Gardner J et al. Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism. PLoS One 2012; 7: e33603.

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Yie J, Wang W, Deng L, Tam LT, Stevens J, Chen MM et al. Understanding the physical interactions in the FGF21/FGFR/beta-klotho complex: structural requirements and implications in FGF21 signaling. Chem Biol Drug Design 2012; 79: 398–410.

    Article  CAS  Google Scholar 

  23. Lundasen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B, Alexson SE et al. PPARalpha is a key regulator of hepatic FGF21. Biochem Biophys Res Commun 2007; 360: 437–440.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  25. Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R et al. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 2009; 106: 10853–10858.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Oishi K, Konishi M, Murata Y, Itoh N . Time-imposed daily restricted feeding induces rhythmic expression of Fgf21 in white adipose tissue of mice. Biochem Biophys Res Commun 2011; 412: 396–400.

    Article  CAS  Google Scholar 

  28. Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H, Arai H et al. Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor? PLoS One 2011; 6: e22976.

    Article  CAS  Google Scholar 

  29. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58: 250–259.

    Article  CAS  Google Scholar 

  32. Xu J, Stanislaus S, Chinookoswong N, Lau YY, Hager T, Patel J et al. 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 2009; 297: E1105–E1114.

    Article  CAS  Google Scholar 

  33. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007; 148: 774–781.

    Article  CAS  Google Scholar 

  34. Véniant MM, Komorowski R, Chen P, Stanislaus S, Winters K, Hager T et al. Long-Acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys. Endocrinology 2012; 153: 4192–4203.

    Article  Google Scholar 

  35. Adams AC, Yang C, Coskun T, Cheng CC, Gimeno RE, Luo Y et al. The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue. Mol Metab 2013; 2: 31–37.

    Article  CAS  Google Scholar 

  36. Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ et al. Beta-klotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012; 16: 387–393.

    Article  CAS  Google Scholar 

  37. Badman MK, Kennedy AR, Adams AC, Pissios P, Maratos-Flier E . A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am J Physiol Endocrinol Metab 2009; 297: E1197–E1204.

    Article  CAS  Google Scholar 

  38. Chen WW, Li L, Yang GY, Li K, Qi XY, Zhu W et al. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2008; 116: 65–68.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  40. Li H, Bao Y, Xu A, Pan X, Lu J, Wu H et al. Serum fibroblast growth factor 21 is associated with adverse lipid profiles and gamma-glutamyltransferase but not insulin sensitivity in chinese subjects. J Clin Endocrinol Metab 2009; 94: 2151–2156.

    Article  CAS  Google Scholar 

  41. Li L, Yang G, Ning H, Yang M, Liu H, Chen W . Plasma FGF-21 levels in type 2 diabetic patients with ketosis. Diabetes Res Clin Pract 2008; 82: 209–213.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Hale C, Chen MM, Stanislaus S, Chinookoswong N, Hager T, Wang M et al. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology 2012; 153: 69–80.

    Article  CAS  Google Scholar 

  44. Hansen BC . Primates in the experimental pharmacology of obesity. In: Lockwood Dean H and Heffner Thomas C (eds). Obesity: Pathology and therapy; Springer: Berlin, Heidelberg 2000. pp 461–489.

  45. Schäfer SA, Hansen BC, Völkl A, Fahimi HD, Pill J . Biochemical and morphological effects of K-111, a peroxisome proliferator-activated receptor (PPAR)alpha activator, in non-human primates. Biochem Pharmacol 2004; 68: 239–251.

    Article  Google Scholar 

  46. Winegar DA, Brown PJ, Wilkison WO, Lewis MC, Ott RJ, Tong WQ et al. Effects of fenofibrate on lipid parameters in obese rhesus monkeys. J Lipid Res 2001; 42: 1543–1551.

    CAS  PubMed  Google Scholar 

  47. Rozen S, Skaletsky H . Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 2000; 132: 365–386.

    CAS  Google Scholar 

  48. Johnson CL, Weston JY, Chadi SA, Fazio EN, Huff MW, Kharitonenkov A et al. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 2009; 137: 1795–1804.

    Article  CAS  Google Scholar 

  49. Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010; 24: 2050–2064.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  51. Vienberg SG, Brøns C, Nilsson E, Astrup AV, Vaag A, Andersen B . Impact of short term high fat feeding and insulin stimulated FGF21 levels in subjects with low birth weight and controls. Eu J Endocrinol 2012; 167: 49–57.

    Article  CAS  Google Scholar 

  52. Fisher fM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26: 271–281.

    Article  CAS  Google Scholar 

  53. Tontonoz P, Spiegelman BM . Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 2008; 77: 289–312.

    Article  CAS  Google Scholar 

  54. Mashili FL, Austin RL, Deshmukh AS, Fritz T, Caidahl K, Bergdahl K et al. Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity. Diabetes Metab Res Rev 2011; 27: 286–297.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Birgitte Wulff and Louise Degn Nielsen from Novo Nordisk A/S for helpful discussions and for technical assistance, respectively. Eva B Nygaard has received scholarships from the graduate research school In Vivo Pharmacology, Novo Nordisk A/S and the Faculty of Health and Medical Sciences, University of Copenhagen. This work was partially supported by NIH grants P51 OD011092 (Kevin L Grove) and RC4 DK090956.

Author information

Authors and Affiliations

  1. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    E B Nygaard & C L Møller

  2. Department of Diabetes NBEs and Obesity Biology, Novo Nordisk A/S, Måløv, Denmark

    E B Nygaard & B Andersen

  3. Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA

    P Kievit & K L Grove

Authors
  1. E B Nygaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C L Møller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Kievit
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K L Grove
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E B Nygaard.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nygaard, E., Møller, C., Kievit, P. et al. Increased fibroblast growth factor 21 expression in high-fat diet-sensitive non-human primates (Macaca mulatta). Int J Obes 38, 183–191 (2014). https://doi.org/10.1038/ijo.2013.79

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2013.79

Keywords

This article is cited by

Search

Advanced search

Quick links