2135-P: Developmental Origins of Obesity and Nonalcoholic Fatty Liver Disease: Role of Peroxisome Homeostasis

Introduction and Objective: Maternal overnutrition during pregnancy, such as obesity, is a major risk factor that predisposes offspring to lifelong risk of metabolic diseases, including obesity and fatty liver disease. Peroxisome is a pivotal organelle that plays essential roles in lipid oxidation, homeostasis of reactive oxygen species, and synthesis of bile acids and ether lipids. However, little is known about the effects of maternal overnutrition on peroxisomal remodeling and how peroxisomal defects during early development contribute to offspring’s long-term metabolic diseases. Methods: Female C57/B6J mice were fed with chow, high-fat diet (HFD), or HFD with supplementation of 4-phenylbutyric acid (4-PBA), a peroxisome proliferator, throughout gestation and lactation. Peroxisomal gene expressions were examined in fetal tissues. Metabolic outcomes in young offspring following HFD were assessed. Results: Targeted proteomic analysis revealed that multiple key peroxisomal molecules, including peroxisomal transporter ABCD3, were significantly reduced in the fetal liver of maternal HFD-fed mice. Maternal supplementation of 4-PBA increased expression of peroxisomal genes, including Abcd3, catalase, and Peroxisomal membrane protein (Pxmp4) in the fetal liver. Upon HFD challenge, male offspring of the maternal 4-PBA-treated HFD group exhibited decreased body weight and adiposity, improved glucose tolerance and insulin sensitivity, as well as reduced hepatic steatosis, compared to offspring of the untreated HFD group. In addition, offspring of mice with maternal HFD exhibited increased hepatic and systemic oxidative stress, which were attenuated by maternal 4-PBA treatment. Conclusion: These findings revealed peroxisome defects as an important early-life component involved in the developmental programming of metabolic diseases. Maternal 4-PBA supplementation restores peroxisomal gene expression during early development and confers long-lasting protective effects against HFD-induced metabolic disorders in offspring. Disclosure A. Tuerdiguli: None. S. Jiang: None. Funding This study is supported by Yale Diabetes Research Center Pilot grant (P30 DK045735).