Paternal developmental thyrotoxicosis disrupts neonatal leptin leading to increased adiposity and altered physiology of the melanocortin system

Background The genetic code does not fully explain individual variability and inheritance of susceptibility to endocrine conditions, suggesting the contribution epigenetic factors acting across generations. Methods We used a mouse model developmental thyrotoxicosis ( Dio3-/- mouse) analyze outcomes in adult offspring males using standard methods for body composition, baseline fasting hormonal gene expression determinations serum tissues relevance control energy balance. Results Compared controls, females with an exposed father (EF females) exhibited higher weight fat mass, but lean phenotype that was much milder EF males. After fasting, both more pronounced decrease than controls. also showed markedly elevated leptin, increased white adipose tissue mRNA leptin mesoderm-specific transcript decreased type 2 deiodinase. ghrelin, which post-fasting changes females. female hypothalami revealed significant decreases pro-opiomelanocortin, agouti-related peptide, neuropeptide Y melanocortin receptor 4. These markers larger response Adult no abnormalities thyroid hormones, pituitary thyrotropin-releasing hormone 1 gland thyroid-stimulating receptor, peroxidase iodotyrosine deiodinase were at differential regulation after increase Trhr1 reductions Tshr , Tpo Iyd . In males, these generally milder. addition, postnatal day 14 (P14) reduced pups. Discussion A paternal excess during development modifies programming balance sexually dimorphic manner, dynamic range alterations leptin-melanocortin system gland, consequences adiposity phenotypes. conclude overexposure may have important implications non-genetic, inherited etiology metabolic pathologies.