Abstract
Maternal high-fat (HF) diet is associated with offspring metabolic disorder. This study intended to determine whether maternal metformin (MT) administration during gestation and lactation prevents the effect of maternal HF diet on offspring’s skeletal muscle (SM) development and metabolism. Pregnant Sprague-Dawley rats were divided into four groups according to maternal diet {CHOW (11.8% fat) or HF (60% fat)} and MT administration {control (CT) or MT (300 mg/kg/day)} during gestation and lactation: CH-CT, CH-MT, HF-CT, HF-MT. All offspring were weaned on CHOW diet. SM was collected at weaning and 18 weeks in offspring. Maternal metformin reduced plasma insulin, leptin, triglyceride and cholesterol levels in male and female offspring. Maternal metformin increased MyoD expression but decreased Ppargc1a, Drp1 and Mfn2 expression in SM of adult male and female offspring. Decreased MRF4 expression in SM, muscle dysfunction and mitochondrial vacuolization were observed in weaned HF-CT males, while maternal metformin normalized them. Maternal metformin increased AMPK phosphorylation and decreased 4E-BP1 phosphorylation in SM of male and female offspring. Our data demonstrate that maternal metformin during gestation and lactation can potentially overcome the negative effects of perinatal exposure to HF diet in offspring, by altering their myogenesis, mitochondrial biogenesis and dynamics through AMPK/mTOR pathways in SM.
Highlights
CH-MT and HF-MT dams weighed significantly less than CH-CT and HF-CT dams both on gestation day (GD) 10 and GD20
Data were analyzed by two-way ANOVA, # main effect of maternal metformin, p < 0.05 versus control, § main effect of maternal HF diet, p < 0.05 versus maternal CHOW diet, * interaction effect of maternal HF diet and metformin, p < 0.05
We demonstrated that maternal metformin exposure during gestation reduced maternal body weight over the course of pregnancy
Summary
Several studies have suggested that high-fat (HF) diets during gestation and lactation may lead to the development of obesity and insulin resistance in adulthood, and affect the structural and functional development of skeletal muscle (SM) in offspring [1,2]. Recent literature has proposed that metformin inhibits glucose production and ameliorates insulin resistance, mainly through mediating AMP-activated protein kinase (AMPK) [17]. There are several studies reporting effects of metformin administration to obese mothers during gestation and lactation on liver and subcutaneous adipose [26], brain [27] and brown adipose tissue [28] in the offspring, while there are few studies on the effect of maternal metformin on offspring’s SM. We tried to determine whether maternal metformin administration during gestation and lactation can improve the adverse effects of maternal HF diet on the SM development and metabolism of offspring in this study
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