Regular parental pre-mating exercise reduces offspring white adiposity and is associated with hypothalamic neurodevelopmental changes during lactation.

Physical inactivity is highly prevalent worldwide and affects not only individual health but also the health of future generations. However, the impact of physical activity limited to the pre-mating period on offspring body weight and composition remains poorly understood. Using a voluntary wheel running approach in mice, we uncovered that post-weaning offspring body weight and composition are modulated by the combined effects of parental pre-mating exercise and parental age. During the mid-stage of lactation, pre-mating exercise in young parents reduced offspring visceral and subcutaneous adiposity, shortened tibial length in female offspring, and influenced offspring transcriptomic profiles of the hypothalamus, the central regulator of energy balance. Pre-mating exercise also led to modest long-lasting changes in the expression of lactation-related genes in maternal subcutaneous fat, as well as breastmilk nutritional composition and miRNA content. Nevertheless, these subtle milk-derived miRNA changes may influence offspring hypothalamic regulatory networks, providing initial evidence of how pre-mating maternal exercise may affect offspring hypothalamic development during the mid-stage of lactation. Together, these data provide a comprehensive understanding of how parental age and pre-mating exercise interact to shape post-weaning offspring body weight and composition, and offer deeper insights into how regular parental pre-mating exercise may influence offspring physiology and neurodevelopmental adaptations during lactation.