Developmental programming by maternal obesity alters offspring lifespan and immune responses in a diet- and sex-specific manner

Maternal obesity is a growing health concern that predisposes offspring to metabolic dysfunction, immune system alterations, and neurodegenerative disorders. To investigate the intergenerational effects of maternal obesity, we used Drosophila melanogaster exposed to high-sugar (HSD) and high-fat diets (HFD) before mating. We found that maternal diet-induced obesity significantly altered offspring lifespan, immune responses, and neuronal health in a sex- and diet-specific manner. Male offspring were particularly susceptible, exhibiting reduced lifespan, impaired climbing ability, and increased axonal degeneration, especially following maternal HFD exposure. Transcriptomic analyses revealed age-dependent and diet-specific changes, with males showing pronounced alterations at 50 days of age. Developmental programming of hemocytes (blood-like cells) played a crucial role in these outcomes, as knockdown of key immune pathways such as Relish and upd3 in hemocytes further influenced lifespan in a diet-specific manner. These findings highlight the complex interplay between maternal diet and immune function, underscoring the impact of maternal obesity-induced imprinting on immune cells and subsequent long-term health consequences. Our study provides new insights into conserved mechanisms linking maternal metabolic health to offspring outcomes and emphasizes the continued need for animal models to understand intergenerational health impacts.