SUN-692 Generational Transition to Obesity in Young Adult Women Links to Grandparental Prenatal Metabolic Profiles

Abstract Disclosure: D. Wang: None. P.M. Cirillo: None. N.M. Krigbaum: None. B. Minasenko: None. V. Tran: None. Y. Go: None. D. Jones: None. X. hu: None. B.A. Cohn: None. Background: Obesity is increasing across generations. We investigated the relationship between key metabolite concentrations in prenatal blood samples from grandmothers and grandfathers, and the incidence of obesity in their young adult granddaughters. Methods: Metabolites were extracted and analyzed using previously established untargeted metabolic profiling methods in prenatal serum samples from 250 pairs of grandparents residing in the Oakland, California area between 1959 and 1967 (Child Health and Development Studies). Body mass was categorized as lean (BMI <25 kg/m2), overweight ( BMI 25–30 kg/m2), and obese (BMI≥30 kg/m2). One-way ANOVA (p value < 0.05) and Partial Least Squares Discriminant Analysis (PLS-DA, VIP score > 2) compared grandparental metabolism by granddaughter BMI groups. Pathway analysis and significant metabolite identification were performed using https://rodin-meta.com. Linear regression models estimated associations between grandparental metabolites with granddaughter BMI in lean/lean grandmother and grandfather pairs compared to lean/overweight grandmother and grandfather pairs. Results: In lean grandmothers, the tyrosine pathway was associated with granddaughter obesity. In contrast, among overweight grandmothers, inflammatory lipid and tryptophan pathways were associated with granddaughter obesity. Grandmaternal glutamine concentration was significantly associated with granddaughter obesity in linear regression models controlled for grandmother BMI. When both grandparents were lean, androgen and estrogen biosynthesis and metabolism, the carnitine shuttle, and caffeine metabolism were associated with granddaughter’s obesity. In contrast, when grandmothers were lean and grandfathers were overweight, the tyrosine and urea cycle/amino group metabolism were associated with granddaughter obesity. Findings support a grandpaternal contribution to granddaughter obesity that interacts with grandmaternal prenatal metabolism. We confirmed interactions between lean grandmaternal and grandpaternal metabolite levels for valine, leucine, and isoleucine degradation, carnitine shuttle, and fatty acid metabolism. Conclusion: Grandparental prenatal metabolism is linked to generational increases in obesity in young adult women even among lean grandparents. Presentation: Sunday, July 13, 2025