1333-OR: Metformin Exposure In Utero Remodels Fetal Hepatic Mitochondrial Oxidation Capacity and Produces Early MASLD Hallmarks

Introduction and Objective: Metformin taken during pregnancy crosses the placenta. In vitro, it has robust metabolic stress effects in fetal hepatocytes. We hypothesized that metformin exposure in utero would disrupt oxidative metabolism and produce hepatocellular injury in the fetal liver, a major site of uptake. Methods: Pregnant Rhesus macaques received vehicle (VEH), or metformin (MET) and a control diet (CD) or western style (WD) (n=10/group) from 0.2 to 0.85 gestation; fetal liver and cord blood were collected via Cesarean delivery. Fetal cord blood nutrients and liver histology (PSR: picrosirius red), triglycerides, and gene expression were measured. Primary fetal hepatocytes were isolated for Seahorse respiration and fuel preference tests. Results: MET-exposed fetuses had increased liver triglycerides and periportal PSR staining, indicating collagen deposition. Maternal WD exposure augmented PSR staining but not triglycerides. Oxygen consumption rate (OCR) was higher in hepatocytes from MET-exposed fetuses with greater maximal OCR and spare respiratory capacity. Umbilical venous blood oxygen or glucose, entering the fetal liver, was similar across groups, yet lactate was higher in MET+WD fetuses. Fetal hepatocytes across groups robustly oxidize lactate and palmitate, but not glucose. However, inhibition of pyruvate (UK5099) or glutamine (BPTES) oxidation decreased maximal OCR only in MET+WD hepatocytes, supporting decreased fuel flexibility. In metformin-exposed fetuses, hepatic collagen correlated with NRF2, PGC1A, and HNF4A expression and higher lactate levels, while hepatic triglycerides correlated with maternal lipidemia and glycemia. Conclusion: Metformin exposure increases fetal hepatic triglycerides and collagen deposition and remodels hepatocyte mitochondrial oxidation capacity, regardless of maternal diet. Thus, metformin initiates fetal hepatic injury and MASLD hallmarks, adding to growing concerns about metformin’s fetal growth-restrictive and long-term metabolic risks in offspring. Disclosure D. Oldham: None. D. Wang: None. E. Dobrinskikh: None. T. Dean: None. M. Gannon: None. C.E. McCurdy: None. K. Aagaard-Tillery: None. P. Kievit: Consultant; Current; Crinetics Pharmaceuticals, Inc. Research Support; Ended; Flagship Pioneering. Research Support; Current; Eli Lilly and Company, Novo Nordisk A/S. Consultant; Current; Merck & Co., Inc. J. Friedman: None. S.R. Wesolowski: None. Funding National Institutes of Health (R01-DK128187)