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FGF21 negatively affects long-term female fertility in mice
Beat Moeckli1,2, Thuy-Vy Pham1, Florence Slits2
1Department of Visceral Surgery, Geneva University Hospital, Geneva, Switzerland.
Objective:
Obesity and associated liver disease are a growing public health concern. Pharmacological agents to treat non-alcoholic fatty liver disease are limited. FGF21, a hormone secreted by the liver and potent metabolic modulator, is a promising therapeutic target for this indication with several analogs currently in clinical development. However, concerns about a negative effect of FGF21 on female fertility have not been fully addressed.
Methods:
After induction of obesity, female C57BL/6N mice received a 7-day course of subcutaneously administered FGF21. Control groups received either high-fat diet (HFD) or a normal diet (ND). The mothers were then mated with lean males for 12 weeks. The estrous cycle was recorded for two weeks after breeding. The metabolic phenotype, liver steatosis and reproductive organs were assessed at sacrifice 14 weeks after treatment.
Results:
A short-course treatment of FGF21 leads to weight reduction during treatment but has no long-term impact on liver steatosis. A treatment with FGF21 leads to a reduction in the number of pregnancies (0 vs 1, p = 0.019) and no viable pup was born to a mother previously treated with FGF21. The FGF21 treatment affected the number of cycles (1 vs 3, p = 0.048) and amount in diestrus (54 vs 75%, p = 0.008) 12 weeks after the treatment. Additionally, the number of corpora lutea (0.8 vs 3.0, p = 0.016), and mature follicles (0 vs 1, p = 0.037) was reduced compared to the ND group while uterine histology remained unaffected.
Conclusion:
A short-term treatment with FGF21 has a long-term effect on female fertility in mice. This represents a potential safety concern for FGF21 analogs currently in clinical development. Reproductive health outcomes should be included in upcoming clinical trials.
Insights
Short-term fibroblast growth factor 21 (FGF21) treatment reduced obesity in mice but impaired female fertility long-term. This highlights potential reproductive safety concerns for FGF21 analogs in clinical development.
Area of Science:
- Endocrinology
- Reproductive Biology
- Hepatology
Background:
- Obesity and non-alcoholic fatty liver disease (NAFLD) are significant public health issues.
- Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone and metabolic regulator, showing therapeutic promise for NAFLD.
- Potential adverse effects of FGF21 on female fertility require thorough investigation.
Purpose of the Study:
- To evaluate the long-term impact of a short-term FGF21 treatment course on female reproductive function in an obese mouse model.
- To assess the safety profile of FGF21 analogs concerning fertility in preclinical studies.
Main Methods:
- Obese female mice received a 7-day subcutaneous FGF21 treatment or were controls (high-fat diet or normal diet).
- Mice were mated post-treatment, and estrous cycles were monitored.
- Metabolic parameters, liver steatosis, and reproductive organs were analyzed after 14 weeks.
Main Results:
- FGF21 treatment led to weight reduction during administration but did not improve long-term liver steatosis.
- A significant reduction in pregnancies and absence of viable pups were observed in FGF21-treated mice.
- FGF21 treatment negatively impacted estrous cycling, corpora lutea count, and mature follicle development, indicating impaired fertility.
Conclusions:
- Short-term FGF21 administration has persistent detrimental effects on female fertility in mice.
- These findings raise safety concerns for ongoing clinical development of FGF21-based therapies.
- Reproductive health assessments are crucial for future clinical trials involving FGF21 analogs.
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