Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs

Chao, S.; Lu, J.; Li, L.-J.; Guo, H.-Y.; Xu, K.; Wang, N.; Zhao, S.-X.; Jin, X.-W.; Wang, S.-G.; Yin, S.; Shen, W.; Zhao, M.-H.; Huang, G.-A.; Sun, Q.-Y.; Ge, Z.-J.

doi:10.1101/2024.04.24.590938

bioRxiv · 10.1101/2024.04.24.590938

Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs

Chao, S.·Lu, J.·Li, L.-J.·Guo, H.-Y.·Xu, K.·Wang, N.·Zhao, S.-X.·Jin, X.-W.·Wang, S.-G.·Yin, S.·Shen, W.·Zhao, M.-H.·Huang, G.-A.·Sun, Q.-Y.·Ge, Z.-J.

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Abstract

Maternal obesity has deleterious effects on the process of establishing oocyte DNA methylation; yet the underlying mechanisms remain unclear. In the present study, we found that maternal obesity induced by high-fat diet (HFD) disrupted the genomic methylation of oocytes, and that at least a part of the altered DNA methylation was transmitted to the F2 oocytes and the livers via females. We further examined the metabolome of serum and found that the altered metabolites such as melatonin may play a key role in the disrupted genomic methylation in the oocytes of obese mice. We further found that exogenous melatonin treatment significantly reduced the hyper-methylation of HFD oocytes, and the increased expression of DNMT3a and DNMT1 in HFD oocytes was also decreased. To address how melatonin regulates the expression of DNMTs, the function of melatonin was inhibited or activated upon oocytes. Results revealed that melatonin may regulate the expression of DNMTs via the cAMP/PKA/CREB pathway. These results suggest that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway.

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Chao, S., Lu, J., Li, L.-J., Guo, H.-Y., Xu, K., Wang, N., Zhao, S.-X., Jin, X.-W., Wang, S.-G., Yin, S., Shen, W., Zhao, M.-H., Huang, G.-A., Sun, Q.-Y., Ge, Z.-J.. 2024-04-28. Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs. https://doi.org/10.1101/2024.04.24.590938

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