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

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. (140 words) HighlightsO_LIPaternal HFD-Ex induces obesity, glucose intolerance and insulin resistance in CD1 males C_LIO_LISperm shows much stronger RNA response than four metabolic organs profiled C_LIO_LIDiet and exercise reversal restores metabolism and RNA profiles in sperm and four metabolic organs analyzed C_LIO_LIOffspring metabolic risk is reduced when sires conceive after reversal through diet and exercise intervention C_LI eTOC BlurbChen, Magalhaes, et al. show that paternal metabolic recovery before conception remodels sperm RNA and reduces transmission of HFD-associated metabolic risk to offspring in a within-sire mouse model.