FGF21 decreases body weight without reducing food intake or bone mineral density in high-fat fed obese rhesus macaque monkeys
Open accessAbstract
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 HbA 1C. 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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In mice, FGF21 has been reported to promote bone loss, but this effect has not been independently validated in rodents or obese non-human primates.
“In mice, FGF21 has been reported to promote bone loss96,97, but this effect has not been independently validated in rodents98 or obese non-human primates99.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [99]
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Direct activation of the fibroblast growth factor-21 pathway in overweight and obese cats
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Deletion of GFRAL blunts weight lowering effects of FGF21 in female mice
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Relationship Between Circulating FGF21 and Bone Mineral Density: An Exploratory StudyPreprint
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- Authors
- Andersen, B., Straarup, E. M., Heppner, K. M., Takahashi, D. L., Raffaele, V., Dissen, G. A., Lewandowski, K., Bödvarsdottir, T. B., Raun, K., Grove, K. L., & Kievit, P.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- Novo Nordisk (United States) (US)
- Oregon National Primate Research Center (US)
- Corresponding author
- Andersen, Birgitte
- Venue
- International Journal of Obesity
- Published
- 2018-06
- Volume
- 42
- Issue
- 6
- Pages
- 1151-1160
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- PMC
- PMC6733401
- OpenAlex
- W2808711495
- Cited by
- 66
- References
- 40
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 10 · 2023: 9 · 2022: 5 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 1
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Novo Nordisk
- National Institutes of Health (P51OD011092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- FGF21, obesity, weight loss, dietary intake, bone mineral density, bone mineral content, bone turnover markers, plasma cortisol, insulin sensitivity, glucose tolerance, triglycerides, VLDL cholesterol, high-fat diet, rhesus monkeys
- MeSH terms
- Animals, Blood Glucose, Disease Models, Animal, Dose-Response Relationship, Drug, Eating, Energy Metabolism, Fibroblast Growth Factors, Glucose Tolerance Test, Hydrocortisone, Macaca mulatta, Obesity, Weight Loss, Bone Density, Anti-Obesity Agents, Diet, High-Fat
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