40 Trainee Award: Fetal hepatic consequences of metformin exposure in utero
Year: 2025
Type: article
Abstract: Abstract: Introduction Metformin is used in adults with diabetes and by pregnant women. However, metformin crosses the placenta and may restrict fetal growth. In primary fetal hepatocytes, we demonstrated that metformin decreases O2 consumption and glucose production, consistent with its effects in adults, yet induces fetal-specific metabolic stress. Objective Determine whether metformin, in combination with Western diet (WD), impairs oxidative metabolism, injuring the fetal liver. Methods Pregnant Rhesus macaques received vehicle (VEH) or metformin (MET) and a healthy control diet (CD) or WD (n = 10/group) from 0.2 to 0.85 gestation. After cesarean delivery, cord blood samples, fetal weights, and isolated fetal hepatocytes were obtained. Results Hepatocytes from MET vs. VEH fetuses had higher O2 consumption rates with greater maximal (P = 0.015) and spare respiratory capacity (P = 0.05). There were tendencies for increased MFN2 protein (P = 0.09) and PGC1A gene expression (P = 0.06) in liver tissue, indicating increased mitochondrial fusion and biogenesis. MET-exposure did not affect WD-induced liver triglyceride accumulation nor cord blood glucose or O2 levels. However, histology showed increased collagen with MET and WD exposure. Furthermore, WD+MET fetuses had increased blood lactate concentrations. Fetal weight was similar across groups; however, CD+MET versus CD+VEH female fetuses weighed less (interaction, P = 0.02). Conclusions Metformin is associated with fetal metabolic stress, resulting in mitochondrial remodeling and increased oxygen consumption capacity. Further, increased lactate may underlie collagen deposition and hepatocellular injury. Ongoing studies are underway to understand if liver metabolic effects are linked with sex-dependent growth effects. (Supported by NIH-R01-DK128187)
Source: Journal of Animal Science
Institutions: University of Colorado Anschutz, Oregon National Primate Research Center, Baylor College of Medicine, Texas Children's Hospital, Vanderbilt University Medical Center, University of Oregon, Boston Children's Hospital, Harvard University, HCA Healthcare, University of Oklahoma Health Sciences Center
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4417494165
FWCI:
Cites:
Cited by:
Related to: