Paternal Metabolic Reversal Remodels Sperm RNA Profiles and Ameliorates Intergenerational Metabolic Disorder in Mice

Authors

Chen, S., Magalhaes, R. D. M., Wang, Z., Cayabyab, F., Choi, J., Yoshihara, E., Wang, R., McSwiggin, H., Chavez, L., Rossiter, H. B., Bross, R., Lue, Y., Wang, C., Swerdloff, R. S., McCarrey, J. R., Zheng, H., Yan, W.

Abstract

Paternal obesity increases metabolic risk in offspring, but whether this risk can be reduced by restoring paternal health before conception remains unresolved. We developed a within-sire induction-and-reversal model in outbred CD1 mice in which high-fat diet (HFD)-exposed males generated offspring before and after transition to an ingredient-matched control diet with voluntary exercise. HFD caused obesity, glucose intolerance, insulin resistance, and extensive remodeling of sperm mRNA, lncRNA, and sncRNA profiles, together with transcriptomic changes in metabolic tissues. Diet and exercise reversal normalized paternal metabolic indices and broadly restored tissue RNA profiles, although sperm retained a limited transcriptional memory of prior HFD exposure. Offspring sired before reversal developed sex-dependent metabolic dysfunction despite control-diet rearing, whereas offspring sired after reversal showed substantial improvement. These findings show that paternal metabolic risk is modifiable before conception and that this reversibility is linked to remodeling of sperm RNA.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Aug 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.