Maternal palmitoleic acid supplementation attenuates neurodegenerative programming in aged offspring exposed to gestational diabetes

Background/Objectives: Maternal hyperglycemia is associated with adverse neurodevelopmental outcomes in offspring; however, its long-term effects on brain aging remain unclear. This study investigated whether maternal hyperglycemia induces persistent molecular and behavioral alterations in aged male offspring and whether maternal palmitoleic acid supplementation exerts protective effects. Methods: The pregnant rats were divided into four groups: PCM, PDM, PDM/CPA, and PDM/TPA. Male offspring were analyzed at 48 weeks of age. Results: Maternal hyperglycemia significantly increased cerebral RAGE expression (~1.6-fold) and tau phosphorylation (~1.8-fold), accompanied by reduced Akt phosphorylation, impaired Nrf2-related antioxidant responses, and increased inflammatory gene expression. These molecular alterations are associated with impaired recognition memory, as reflected by a marked reduction in the discrimination index in the novel object recognition test. Maternal CPA/TPA supplementation partially attenuated these abnormalities. Conclusions: These findings suggest that maternal hyperglycemia may induce long-lasting molecular alterations associated with neuroinflammation, impaired insulin-related signaling, and cognitive dysfunction in aged offspring. Maternal palmitoleic acid supplementation may partially mitigate the adverse developmental alterations associated with intrauterine hyperglycemic exposure.