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bioRxiv · 10.1101/2022.10.11.511721

Maternal age, obesity and hyperglycaemia are associated with a delay in preimplantation development in a mouse model of type 2 diabetes

Lilao-Garzon, J.·Brito-Casillas, Y.·Quesada-Canales, O.·Wagner, A. M.·Munoz-Descalzo, S.
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Abstract

Aims/hypothesisDelayed maternal age, obesity and diabetes are associated with reduced fertility. We investigated how age and obesity/metabolic syndrome impact fertility and hypothesized that its decrease is due to defects in preimplantation embryo development. MethodsThree groups of female C57Bl6 mice (12 weeks, 9 months and 1 year old) were fed either a high fat diet for 8 weeks, to induce obesity and the metabolic syndrome, or a control chow diet. Body weight and composition, glucose tolerance and insulin resistance were assessed. Fecundity was evaluated by mating and pregnancy rates, as well as number of embryos. Embryo quality was assessed morphologically, and cell fate composition was analysed in preimplantation embryos by state-of-the-art single cell quantitative confocal image analysis. ResultsThe high fat diet was associated with increased adiposity, glucose intolerance and insulin resistance, especially in the older mice. Fecundity was affected by age, more than by the diet. Both age and high fat diet were associated with reduced cell fate allocation, indicating a delay in preimplantation embryo development, and with increased expression of GATA3, an inhibitor of placentation. Conclusion/InterpretationThese results support that age and the metabolic syndrome reduce fertility through mechanisms which are present at conception very early in pregnancy. What is already known about this subject?O_LILifestyle changes in modern societies have led to an increase in obesity and type 2 diabetes, and women tend to become pregnant later than ever. These factors have a negative influence on female fecundity. C_LIO_LIIn mice, diet induced obesity is associated with poor quality oocytes that affect overall embryonic development. C_LI What is the key question?O_LIDo age and high fat diet influence cell fate differentiation during preimplantation embryo development? C_LI What are the new findings?O_LIBody composition and glucose metabolism are altered due to high fat diet even when weight is not affected in young animals. C_LIO_LIAlthough there are no differences in mating and fertilization rates, embryo quality is lower with high fat diet. C_LIO_LICells not fully committed to a cell fate (epiblast or primitive endoderm) are increased in embryos from mature dams or fed a high fat diet, indicating a delay in preimplantation embryo development. C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur findings show a delay in early embryo development associated to obesity and maternal age. This delay could be responsible for the low fertility observed in women with type 2 diabetes and obesity. C_LI

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Lilao-Garzon, J., Brito-Casillas, Y., Quesada-Canales, O., Wagner, A. M., Munoz-Descalzo, S.. 2022-10-12. Maternal age, obesity and hyperglycaemia are associated with a delay in preimplantation development in a mouse model of type 2 diabetes. https://doi.org/10.1101/2022.10.11.511721

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