Maternal metformin treatment in obese pregnancy alters priming of offspring metabolic dysfunction and non-alcoholic fatty liver disease in mice

Abstract

Background: Interventions to protect offspring from the deleterious long-term effects of maternal obesity during pregnancy have been sought but have proven largely ineffective in humans. Metformin, an antidiabetic drug used to control gestational diabetes, failed to reduce obesity-associated fetal overgrowth in two human trials, yet long-term follow-up of these children will take many years. Thus, this thesis aims to characterize the effect of metformin on offspring in a mouse model of maternal obesity.

Methods: Female mice were fed normal chow (C; 7% kcal fat) or obesogenic high-fat diet (HF; 45% kcal fat) for 6 weeks prior to mating. Metformin (m) was given in drinking water (250mg/kg) to half of dams during pregnancy and lactation. Dam and fetal parameters were assessed in a subgroup at gestation day 16.5. At weaning, offspring received C or HF diet. Offspring metabolic parameters were assessed at 28 weeks, and offspring were killed and tissue collected at 30 weeks. Plasma metabolic and inflammatory markers and hepatic gene expression, lipid levels and pathology were evaluated.

Results: In fetuses, metformin treatment altered fetal hepatic gene expression and reduced fetal weight. Metformin had no effect on obese dam glucose homeostasis. In adult female offspring of obese dams, maternal metformin reduced adiposity, improved glucose homeostasis and reduced nonalcoholic fatty liver disease (NAFLD) severity. In adult male offspring of obese dams, metformin had no beneficial effects. In adult offspring of either sex born to lean dams, maternal metformin increased offspring adiposity, impaired glucose homeostasis and worsened NAFLD severity.

Conclusions: Metformin treatment in obese dams partially protects female offspring from the effects of maternal obesity, yet male offspring do not benefit. Offspring of metformin-treated lean dams, of either sex, have more severe metabolic disease. These data urge investigation of mechanisms priming adverse offspring responses to maternal metformin.

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Identifiers

ORCID for Christopher Byrne: orcid.org/0000-0001-6322-7753

ORCID for Felino Cagampang: orcid.org/0000-0003-4404-9853

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