Fetal hyperglycemia and the origin of adult obesity

Abstract

Fetal Hyperglycemia (FH) plays a critical role in adult obesity. FH occurs upon fetal exposure to high maternal glucose during Gestational Diabetes, resulting in hyperinsulinemia and increased fetal fat deposition. At birth, these infants are larger than normal babies, hypoglycemic and hyperinsulinemic and have a higher risk of adult-onset metabolic disorders such as obesity, Type 2 Diabetes and non-alcoholic fatty liver disease (NAFLD). Although in utero glucose exposure provides evidence in the above-mentioned conditions the molecular mechanisms remain unclear. Using a Zebrafish model of FH, we aim to test the hypothesis that FH increases hepatic de novo lipogenesis causing obesity later in life. Methods: We developed a novel Zebrafish model of FH by exposing embryos to high glucose (4.5% w/v) at day 4 post fertilization (4 dpf) during the last day of embryogenesis. At 5 dpf the glucose media was replaced by regular media with or without the Acetyl-CoA Carboxylase (acca) inhibitor ND646 for additional 24 hrs followed by embryo collection. Adult fish were raised from glucose-exposed embryos on a normal diet. Fat mass was assessed by Echo-MRI and glucose levels by glucometer. The substrate of de novo lipogenesis, malonyl CoA level was quantified by ELISA and triglycerides by colorimetry. Insulin expression (visualized by whole mount in-situ hybridization), lipogenic (acca), beta oxidation [(Carnitine palmitoyltransferase, (cpt1/2)] and gluconeogenic [(Glucagon (gcga), Glucose-6-Phosphatase (G6Pase), Phosphoenolpyruvate carboxykinase (pck1)] markers were quantified by RT-qPCR. Oil-Red-O staining (ORO) was used to detect lipid accumulation and quantified using spectrophotometry, while Nile red staining was used to detect adipocyte accumulation. Results: Zebrafish embryos become transiently hyperglycemic and hyperinsulinemic after 24 hrs of glucose exposure at 5 dpf. Surprisingly, despite being normoglycemic glucose-exposed embryos at 6 dpf showed significantly higher levels of hepatic lipid accumulation (48%) and de novo lipogenesis (acca and malonyl CoA) as well as markers of gluconeogenesis (gcga, G6Pase, pck1) and beta oxidation (cpt1/2), compared to controls. Interestingly, adult fish (3 months) become obese (fat mass, 2.5±0.2 vs 3.7±0.2) and develop epicardial fat deposition, despite being normoglycemic. At the molecular level, adult fish have increased fasting hepatic de novo lipogenesis, as indicated by elevated acca expression and malonyl CoA levels which was associated with higher hepatic triglyceride levels (1.5-fold) compared to adult fish raised from unexposed embryos. ND 646 administration reduced lipid accumulation in embryos. The effect of ND 646 on adult fish is under evaluation. Conclusion: Together our results show that FH induces persistent increase in whole embryonic and adult hepatic de novo lipogenesis and its pharmacological inhibition could be promising therapeutic intervention to rescue FH-induced adulthood obesity. National Institute of Health grant (P20 GM104357) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.