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

Area of Science:

• Reproductive Biology
• Metabolic Health
• Developmental Programming

Background:

• Maternal obesity during pregnancy leads to adverse fetal development and increased offspring risk of metabolic dysfunction-associated steatotic liver disease (MASLD).
• Metformin is proposed to prevent adverse fetal programming, but its long-term effects on offspring liver metabolism are unclear.

Purpose of the Study:

• To investigate the long-term effects of metformin treatment in obese pregnant mice on offspring metabolic health and liver metabolism.
• To determine the sex-specific impacts of maternal metformin exposure on offspring development and metabolic phenotype.

Main Methods:

• Obesity was induced in C57BL/6NCrl mice using a high-fat/high-sucrose diet before and during gestation.
• Obese dams received metformin during gestation; offspring were analyzed at postnatal days 21 and 56.
• Metabolic phenotype, hepatic histomorphology, and key metabolic proteins were assessed in offspring.

Main Results:

• At postnatal day 21, metformin treatment worsened obesity-related traits in male offspring, including increased body weight and impaired glucose tolerance.
• Female offspring also showed exacerbated obesity traits, with sex-specific patterns in hepatic lipid accumulation (reduced in males, increased in females).
• While early phenotypic parameters normalized by postnatal day 56, persistent molecular alterations in hepatic fatty acid metabolism and mitochondrial function were observed.

Conclusions:

• Maternal metformin during obese pregnancy exerts age- and sex-specific effects on offspring, potentially aggravating early obesity traits and inducing hepatic metabolic adaptations.
• Findings suggest a controversy regarding metformin use in obese pregnancies due to potential sex-specific adverse effects on offspring metabolism.
• Further research is needed to understand the long-term consequences and sex-specific mechanisms of metformin exposure in utero.