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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 Obesity volume 42, pages 1151–1160 (2018)Cite this article

Subjects

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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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).

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Authors and 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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  1. Birgitte Andersen
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Correspondence to Birgitte Andersen.

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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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Andersen, B., Straarup, E.M., Heppner, K.M. et al. FGF21 decreases body weight without reducing food intake or bone mineral density in high-fat fed obese rhesus macaque monkeys. Int J Obes 42, 1151–1160 (2018). https://doi.org/10.1038/s41366-018-0080-7

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