Diet-Induced Paternal Obesity Impairs Cognitive Function in Offspring by Mediating Epigenetic Modifications in Spermatozoa

Abstract

Objective: This study aimed to determine the effects of diet-induced paternal obesity on cognitive function in mice offspring. Methods: Male mice (F0) were randomized to receive either a control diet (10 kcal% fat) or a high-fat diet (HFD; 60 kcal% fat) for 10 weeks before being mated with normal females to generate F1 offspring. Male F1 offspring were mated with normal females to generate F2 offspring. Behavioral tests were used to assess cognitive functions in F1 and F2 offspring. Reduced representation bisulfite sequencing was used to the explore mechanisms of epigenetic inheritance. Results: HFD-induced paternal obesity resulted in cognitive impairments in F1 offspring, potentially due, at least in part, to increased methylation of the BDNF gene promoter, which was inherited from F0 spermatozoa. BDNF/tyrosine receptor kinase B signaling was associated with cognitive impairments in HFD-fed F1 offspring. However, there were no significant changes in F2 offspring. Conclusions: The findings provide evidence of intergenerational effects of paternal obesity on cognitive function in offspring occurring via epigenetic spermatozoan modifications.