Maternal Metformin Intervention during Obese Glucose-Intolerant Pregnancy Affects Adiposity in Young Adult Mouse Offspring in a Sex-Specific Manner

Abstract

Background: Metformin is commonly used to treat gestational diabetes mellitus. This study investigated the effect of maternal metformin intervention during obese glucose-intolerant pregnancy on the gonadal white adipose tissue (WAT) of 8-week-old male and female mouse offspring. Methods: C57BL/6J female mice were provided with a control (Con) or obesogenic diet (Ob) to induce pre-conception obesity. Half the obese dams were treated orally with 300 mg/kg/d of metformin (Ob-Met) during pregnancy. Gonadal WAT depots from 8-week-old offspring were investigated for adipocyte size, macrophage infiltration and mRNA expression of pro-inflammatory genes using RT-PCR. Results: Gestational metformin attenuated the adiposity in obese dams and increased the gestation length without correcting the offspring in utero growth restriction and catch-up growth caused by maternal obesity. Despite similar body weight, the Ob and Ob-Met offspring of both sexes showed adipocyte hypertrophy in young adulthood. Male Ob-Met offspring had increased WAT depot weight (p < 0.05), exaggerated adipocyte hyperplasia (p < 0.05 vs. Con and Ob offspring), increased macrophage infiltration measured via histology (p < 0.05) and the mRNA expression of F4/80 (p < 0.05). These changes were not observed in female Ob-Met offspring. Conclusions: Maternal metformin intervention during obese pregnancy causes excessive adiposity, adipocyte hyperplasia and WAT inflammation in male offspring, highlighting sex-specific effects of prenatal metformin exposure on offspring WAT.

Developmental programming by maternal obesity: Lessons from animal models

“…The only study to date investigating gestational (but not lactational) metformin treatment in obese glucose intolerant pregnancy found adiposity and adipose tissue inflammation in male, but not female, young adult offspring. 50 The heterogeneity of evidence highlights that post-weaning diet, timing of metformin exposure and the interaction between metformin and the maternal environment are critical. In addition, long-term follow-up in both male and female offspring will be vital to explore potential sexual dimorphism and age-related effects.…”

Impact of Metformin Treatment on Human Placental Energy Production and Oxidative Stress

“…This is an important focus of future research. A further future aim is to understand the consequences of reduced placental energy production for the fetus, which is not possible in our current primary cell model system, but amenable to investigation in animal models (Schoonejans et al, 2021;Hufnagel et al, 2022).…”

“…However, concerns have been raised about the impact of metformin on the developing fetal-placental unit. Fetal exposure to metformin is associated with decreased birthweight followed by increased BMI and adiposity in midchildhood, in both meta-analysis of human studies and animal models (Tarry-Adkins et al, 2019Schoonejans et al, 2021;Hufnagel et al, 2022). This growth pattern of low birth-weight followed by post-natal catch-up growth has an established association with adverse programming of long-term cardiometabolic outcomes (Kesavan and Devaskar, 2019).…”

Lactational High Fat Diet in Mice Causes Insulin Resistance and NAFLD in Male Offspring Which Is Partially Rescued by Maternal Metformin Treatment

“…Metformin is the most commonly used oral anti-diabetes medication and can lower circulating insulin levels (18). It has been studied during the critical windows of pregnancy and lactation with some evidence for improved offspring health, following this exposure, although the results vary, depending on maternal health and dosing strategy (19)(20)(21)(22)(23). The lactation period is an underutilized window for intervention, and pharmacologic interventions may be more readily adopted by mothers than making a change in dietary fat consumption.…”