Abstract
AimsDespite the wide use of metformin in metabolically challenged pregnancies, the long-term effects on the metabolism of the offspring are not known. We studied the long-term effects of prenatal metformin exposure during metabolically challenged pregnancy in mice.Materials and MethodsFemale mice were on a high fat diet (HFD) prior to and during the gestation. Metformin was administered during gestation from E0.5 to E17.5. Male and female offspring were weaned to a regular diet (RD) and subjected to HFD at adulthood (10-11 weeks). Body weight and several metabolic parameters (e.g. body composition and glucose tolerance) were measured during the study. Microarray and subsequent pathway analyses on the liver and subcutaneous adipose tissue of the male offspring were performed at postnatal day 4 in a separate experiment.ResultsPrenatal metformin exposure changed the offspring's response to HFD. Metformin exposed offspring gained less body weight and adipose tissue during the HFD phase. Additionally, prenatal metformin exposure prevented HFD-induced impairment in glucose tolerance. Microarray and annotation analyses revealed metformin-induced changes in several metabolic pathways from which electron transport chain (ETC) was prominently affected both in the neonatal liver and adipose tissue.ConclusionThis study shows the beneficial effects of prenatal metformin exposure on the offspring's glucose tolerance and fat mass accumulation during HFD. The transcriptome data obtained at neonatal age indicates major effects on the genes involved in mitochondrial ATP production and adipocyte differentiation suggesting the mechanistic routes to improved metabolic phenotype at adulthood.
Highlights
Metformin, a biguanide class anti-diabetic agent, is the most commonly prescribed oral drug for type 2 diabetes
C57/BL6NHsd mice (Harlan Laboratories, NL) were housed on a 12 h:12 h dark:light cycle and fed either a regular diet (i.e. RD; 69 kcal% carbohydrates, 22 kcal% protein and 9 kcal% fat resulting in digestible energy of 2.97 kcal/g and metabolisable energy of 2.71 kcal/g; CRM(E), SDS, UK) or high fat diet (i.e. HFD; 20 kcal% carbohydrates, 20 kcal% protein and 60 kcal% of fat resulting in total energy of 5.24 kcal/g; D12492, Research Diets, NJ, USA) ad libitum
Body weight development of the female mice was similar between RD and HFD feeding groups during the pre-gestational period (Fig. 2A), the caloric intake tended to be higher in the HFD group based on a 4-day follow-up (P50.061; data not shown)
Summary
A biguanide class anti-diabetic agent, is the most commonly prescribed oral drug for type 2 diabetes. Its main pharmacological effect in type 2 diabetes is mediated by decreased hepatic gluconeogenesis [1, 2]. Recent data has described that the glucose-lowering effect of metformin may not recruit AMPK in all cases [7] which demonstrate that the knowledge of metformin’s molecular and cellular mechanisms are still incomplete. The prevalence of obesity and obesity-associated diseases has increased in adults, and in children and adolescents [8]. The trend in obesity development has been associated with trans-generational effects (i.e. fetal programming) as diabetic environment in utero can predispose the offspring to impaired metabolism starting already at childhood [10,11,12,13]. Insulin is commonly used to decrease many of the diabetes-associated complications in gestational diabetes mellitus (GDM). Insulin treatment increases the risk of hypoglycemia and might result in poor compliance
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