Paternal obesity by lactation overnutrition induces sex-related metabolic and reproductive changes in their offspring.

The prenatal period, childhood, and adolescence are critical periods of development characterized by high plasticity. As an extension of the Developmental Origins of Health and Disease (DOHaD) paradigm, known as Origins of Paternal Health and Disease (POHaD), recent studies in rodents provide evidence that paternal obesity is associated not only with infertility but also with an increased risk of metabolic disorders in the offspring. In rodents, litter size reduction is used to induce lactational overfeeding by increasing the amount of breast milk to pups, which causes metabolic and reproductive disorders in adulthood. This work evaluated the metabolic and reproductive alterations in the offspring of males raised in normal or small litter (SL) in the prepubertal period and in adult life. The results show that paternal obesity due to early overfeeding affects the offspring in a sex-specific manner. During the prepubertal period, male offspring of SL fathers showed decreased Lee index, tibia length, and HDL plasma levels, and increased weight of gastrocnemius muscle, while female offspring of SL fathers only showed reduced HDL plasma levels. In adulthood, male offspring of overfed males showed glucose intolerance and reduced food intake and triglycerides plasma levels, signs of metabolic dysfunction. Female offspring of overfed males showed delayed puberty onset and higher prevalence of infertile periods in the estrous cycles, indicating a potential susceptibility to reproductive dysfunction. The results of the current study show that paternal obesity due to early overfeeding affects energy balance and reproduction of their offspring in a sex-specific manner.