Article | Published:

Animal Models

FGF21 decreases body weight without reducing food intake or bone mineral density in high-fat fed obese rhesus macaque monkeys

International Journal of Obesityvolume 42pages11511160 (2018) | Download Citation

Abstract

Objective

Administration of FGF21 and FGF21 analogues reduce body weight; improve insulin sensitivity and dyslipidemia in animal models of obesity and in short term clinical trials. However potential adverse effects identified in mice have raised concerns for the development of FGF21 therapeutics. Therefore, this study was designed to address the actions of FGF21 on body weight, glucose and lipid metabolism and importantly its effects on bone mineral density (BMD), bone markers, and plasma cortisol in high-fat fed obese rhesus macaque monkeys.

Methods

Obese non-diabetic rhesus macaque monkeys (five males and five ovariectomized (OVX) females) were maintained on a high-fat diet and treated for 12 weeks with escalating doses of FGF21. Food intake was assessed daily and body weight weekly. Bone mineral content (BMC) and BMD were measured by DEXA scanning prior to the study and on several occasions throughout the treatment period as well as during washout. Plasma glucose, glucose tolerance, insulin, lipids, cortisol, and bone markers were likewise measured throughout the study.

Results

On average, FGF21 decreased body weight by 17.6 ± 1.6% after 12 weeks of treatment. No significant effect on food intake was observed. No change in BMC or BMD was observed, while a 2-fold increase in CTX-1, a marker of bone resorption, was seen. Overall glucose tolerance was improved with a small but significant decrease in HbA1C. Furthermore, FGF21 reduced concentrations of plasma triglycerides and very low density lipoprotein cholesterol. No adverse changes in clinical chemistry markers were demonstrated, and no alterations in plasma cortisol were observed during the study.

Conclusion

In conclusion, FGF21 reduced body weight in obese rhesus macaque monkeys without reducing food intake. Furthermore, FGF21 had beneficial effects on body composition, insulin sensitivity, and plasma triglycerides. No adverse effects on bone density or plasma cortisol were observed after 12 weeks of treatment.

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References

  1. 1.

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

  2. 2.

    Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annu Rev Physiol. 2016;78:223–41.

  3. 3.

    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;24:2050–64.

  4. 4.

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

  5. 5.

    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. 2012;2:31–7.

  6. 6.

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

  7. 7.

    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;115:1627–35.

  8. 8.

    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;148:774–81.

  9. 9.

    Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149:6018–27.

  10. 10.

    Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18:333–40.

  11. 11.

    Veniant 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;153:4192–203.

  12. 12.

    Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 2016;23:427–40.

  13. 13.

    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;58:250–9.

  14. 14.

    Adams AC, Halstead CA, Hansen BC, Irizarry AR, Martin JA, Myers SR, et al. LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys. PLoS ONE. 2013;8:e65763.

  15. 15.

    Thompson WC, Zhou Y, Talukdar S, Musante CJ. PF-05231023, a long-acting FGF21 analogue, decreases body weight by reduction of food intake in non-human primates. J Pharmacokinet Pharmacodyn. 2016;43:411–25.

  16. 16.

    Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab. 2008;8:77–83.

  17. 17.

    Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci USA. 2012;109:3143–8.

  18. 18.

    Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med. 2013;19:1153–6.

  19. 19.

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

  20. 20.

    Singhal G, Douris N, Fish AJ, Zhang X, Adams AC, Flier JS, et al. Fibroblast growth factor 21 has no direct role in regulating fertility in female mice. Mol Metab. 2016;5:690–8.

  21. 21.

    Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62:490–7.

  22. 22.

    Nygaard EB, Moller CL, Kievit P, Grove KL, Andersen B. Increased fibroblast growth factor 21 expression in high-fat diet-sensitive non-human primates (Macaca mulatta). Int J Obes. 2014;38:183–91.

  23. 23.

    Comstock SM, Pound LD, Bishop JM, Takahashi DL, Kostrba AM, Smith MS, et al. High-fat diet consumption during pregnancy and the early post-natal period leads to decreased alpha cell plasticity in the nonhuman primate. Mol Metab. 2012;2:10–22.

  24. 24.

    Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29:e45.

  25. 25.

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

  26. 26.

    McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387:83–90.

  27. 27.

    Milan G, Dalla Nora E, Pilon C, Pagano C, Granzotto M, Manco M, et al. Changes in muscle myostatin expression in obese subjects after weight loss. J Clin Endocrinol Metab. 2004;89:2724–7.

  28. 28.

    Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Jarvinen H. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology. 2008;135:122–30.

  29. 29.

    Mello NK, Mendelson JH, Bree MP, Skupny A. Alcohol effects on LH and FSH in ovariectomized female monkeys. Alcohol. 1989;6:147–59.

  30. 30.

    Stanislaus S, Hecht R, Yie J, Hager T, Hall M, Spahr C, et al. A novel Fc FGF21 with improved resistance to proteolysis, increased affinity towards beta-Klotho and enhanced efficacy in mice and cynomolgus monkeys. Endocrinology. 2017;158:1314–27 https://doi.org/10.1210/en.2016-1917.

  31. 31.

    Muise ES, Souza S, Chi A, Tan Y, Zhao X, Liu F, et al. Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21. PLoS ONE. 2013;8:e73011.

  32. 32.

    Samms RJ, Smith DP, Cheng CC, Antonellis PP, Perfield JW 2nd, Kharitonenkov A, et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 2015;11:991–9.

  33. 33.

    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;26:271–81.

  34. 34.

    de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, et al. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest. 2001;108:1379–85.

  35. 35.

    Douris N, Stevanovic DM, Fisher FM, Cisu TI, Chee MJ, Nguyen NL, et al. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology. 2015;156:2470–81.

  36. 36.

    Quabbe HJ, Gregor M, Bumke-Vogt C, Hardel C. Pattern of plasma cortisol during the 24-hour sleep/wake cycle in the rhesus monkey. Endocrinology. 1982;110:1641–6.

  37. 37.

    Czoty PW, Gould RW, Nader MA. Relationship between social rank and cortisol and testosterone concentrations in male cynomolgus monkeys (Macaca fascicularis). J Neuroendocrinol. 2009;21:68–76.

  38. 38.

    Li X, Stanislaus S, Asuncion F, Niu QT, Chinookoswong N, Villasenor K, et al. FGF21 Is not a major mediator for bone homeostasis or metabolic actions of PPARalpha and PPARgamma agonists. J Bone Miner Res. 2016;32:834–45 https://doi.org/10.1002/jbmr.2936.

  39. 39.

    McKenzie R, Reynolds JC, O’Fallon A, Dale J, Deloria M, Blackwelder W, et al. Decreased bone mineral density during low dose glucocorticoid administration in a randomized, placebo controlled trial. J Rheumatol. 2000;27:2222–6.

  40. 40.

    Hinton PS, Rector RS, Linden MA, Warner SO, Dellsperger KC, Chockalingam A, et al. Weight-loss-associated changes in bone mineral density and bone turnover after partial weight regain with or without aerobic exercise in obese women. Eur J Clin Nutr. 2012;66:606–12.

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Acknowledgements

Funding

This work was supported by the National Institutes of Health (NIH) Grant P51 OD011092 (to PK and Oregon National Primate Research Center) and Novo Nordisk Grant SRA-11-061 (to PK).

Author information

Affiliations

  1. Diabetes Research, Novo Nordisk A/S, DK-2760, Måløv, Denmark

    • Birgitte Andersen
    • , Ellen M. Straarup
    • , Thóra B. Bödvarsdottir
    •  & Kirsten Raun
  2. Obesity Research, Novo Nordisk A/S, Seattle, WA, 98109, USA

    • Kristy M. Heppner
    •  & Kevin L. Grove
  3. Division of Diabetes, Obesity & Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA

    • Diana L. Takahashi
    • , Virginia Raffaele
    • , Gregory A. Dissen
    • , Katherine Lewandowski
    •  & Paul Kievit

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Conflict of interest

BA, EMS, KMH, TBB, KR, KLG are employers and minor stock holders of Novo Nordisk A/S. DLT, VR, GD, KL, and PK have no conflict of interest.

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Correspondence to Birgitte Andersen.

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DOI

https://doi.org/10.1038/s41366-018-0080-7