Metformin in Obese Pregnancy: Developmental Reprogramming of Offspring Liver and MASLD Risk by Age and Sex

Maternal obesity before and during pregnancy causes maladaptive fetal development with long-term effects on offspring's metabolic health, including a higher risk of metabolic dysfunction-associated steatotic liver disease. Treatment with metformin during obese pregnancy has been suggested to prevent adverse fetal programming, but its long-term effects on offspring liver metabolism remain uncertain. In wild-type C57BL/6NCrl mice, obesity was induced by feeding a high-fat/high-sucrose Western-style diet before and throughout gestation and lactation. A subset of obese dams received metformin during gestation. Offspring from control, obese (OB), and obese with metformin-treated (OB + M) dams were analyzed at postnatal days (P) 21 and 56 for their metabolic phenotype, hepatic histomorphology, and key metabolic proteins. At P21, maternal metformin treatment worsened obesity-related traits in male OB + M offspring, including increased body weight, length, and fat volume, higher plasma leptin, insulin, and resistin levels, and impaired glucose tolerance. Female OB + M offspring also showed a worsening of obesity traits, though less pronounced. Hepatic lipid accumulation displayed sex-specific patterns; male OB + M offspring exhibited reduced lipid accumulation, whereas female OB + M offspring demonstrated increased lipid accumulation. By P56, phenotypic parameters returned to normal, but molecular alterations persisted, involving shifts in hepatic fatty acid metabolism and mitochondrial respiratory chain complexes. Maternal metformin during obese pregnancy has age- and sex-specific effects on offspring, aggravating early obesity traits in a sex-dependent manner and prompting adaptations in hepatic metabolism during adolescence. These findings highlight the controversy surrounding metformin use during obese pregnancy, given its potential to induce sex-specific obesity and metabolic disturbances in offspring.