(PTFS15-03-26) Effects of Fish Oil Supplementation in Reducing Paternal Obesity and improving Offspring Muscle Health in Mice

Objectives: Obesity affects 42% of U.S. adults and is a well-established driver of metabolic disease. Emerging evidence indicates that paternal obesity reshapes offspring metabolic programming through epigenetic mechanisms; however, the precise pathways remain incompletely understood, and dietary strategies to interrupt this intergenerational transmission are lacking.

We investigated whether paternal fish oil (n-3 polyunsaturated fatty acid; n-3 PUFA) supplementation could mitigate the adverse metabolic consequences of paternal obesity on male offspring skeletal muscle metabolic function.

Methods: Male C57BL/6J mice were assigned to one of three diets prior to mating: low-fat (LF), high-fat (HF), or high-fat with fish oil supplementation (HF+FO). Both male and female offspring from each paternal group were then challenged with either LF or HF diets postweaning, yielding six experimental groups per sex. Body weight trajectories were monitored throughout, and skeletal muscle gene expression was assessed in both sexes to evaluate key metabolic pathways, including fatty acid oxidation and lipid metabolism.

Results: Paternal HF+FO supplementation significantly attenuated offspring body weight gain compared to paternal HF alone, with sex-specific differences observed in the magnitude of response. Male offspring exhibited more pronounced improvements, including greater reductions in body weight and more robust upregulation of genes governing fatty acid oxidation and oxidative metabolism, suggesting enhanced mitochondrial and metabolic capacity in skeletal muscle. Female offspring showed a similar but attenuated pattern of response, indicating that the protective effects of paternal fish oil supplementation are sex-dependent and more pronounced in male offspring.

Conclusions: Paternal fish oil supplementation represents a promising preconceptional dietary strategy to reduce intergenerational transmission of obesity-associated metabolic dysfunction, with male offspring deriving greater metabolic benefit than females. These sex-specific findings advance our understanding of the paternal diet–offspring health axis and underscore the importance of considering offspring sex when designing translational interventions targeting metabolic disease across generations.

Funding Sources: American Heart Association