Metabolic programming in the offspring after gestational overfeeding in the mother: toward neonatal rescuing with metformin in a swine model.

OBJECTIVES: Maternal overfeeding during gestation may lead to adverse metabolic programming in the offspring mediated by epigenetic alterations. Potential reversal, in early life, of these alterations may help in the prevention of future cardio-metabolic conditions. In this context, our aims were: (1) to study the effects of maternal overfeeding on the metabolic and epigenetic programming of offspring's adipose tissue; and (2) to test the potential of postnatal metformin treatment to reverse these changes. METHODS: We used a swine animal model where commercial production sows were either overfed or kept under standard diet during gestation, and piglets at birth were randomly assigned to metformin (n = 16 per group) or vehicle treatment during lactation (n = 16 per group). RESULTS: Piglets born to overfed sows showed a worse metabolic profile (higher weight, weight gain from birth and abdominal circumference; all p < 0.05) together with altered serological markers (increased HOMA-IR, fructosamine, total cholesterol, C-Reactive Protein and lower HMW adiponectin; all p < 0.05). The visceral adipose tissue also showed altered morphology (increased adipocyte area, perimeter and diameter; all p < 0.05), as well as changes in gene expression (higher CCL2 and INSR, lower DLK1; all p < 0.05), and in DNA methylation (96 hypermethylated and 99 hypomethylated CpG sites; FDR < 0.05). Metformin treatment significantly ameliorated the abnormal metabolic profile, decreasing piglets' weight, weight gain from birth, abdominal circumference and fructosamine (all p < 0.05) and reduced adipocyte area, perimeter, and diameter in visceral adipose tissue (all p < 0.05). In addition, metformin treatment potentiated several associations between gene expression in visceral adipose tissue and the altered metabolic markers. CONCLUSIONS: Maternal overfeeding during gestation leads to metabolic abnormalities in the offspring, including adipose tissue alterations. Early metformin treatment mitigates these effects and could help rescue the offspring's metabolic health.

Altered Circulating miRNA Expression Profile in Pregestational and Gestational Obesity.

CONTEXT: MicroRNAs (miRNAs) are valuable circulating biomarkers and therapeutic targets for metabolic diseases. OBJECTIVE: The objective of the study was to define the pattern of circulating miRNAs in pregestational and gestational obesity and to explore their associations with maternal metabolic parameters and with markers for pre- and postnatal growth. design, settings, and main outcome measure: TaqMan low-density arrays were used to profile plasma miRNAs in six women with pregestational obesity (PregestOB), six with gestational obesity (GestOB), and six with normal pregnancies (control) during the second trimester of gestation. The most relevant miRNAs were validated in 70 pregnant women (20 PregestOB, 25 GestOB, and 25 control). Maternal metabolic parameters including glucose, glycated hemoglobin, homeostasis model assessment index of insulin resistance, C-peptide, and lipids were assessed. Placentas were weighed at delivery and newborns also during 6 months of life. RESULTS: We identified 13 circulating miRNAs differentially expressed in maternal obesity, including decreased levels of miR-29c, miR-99b, miR-103, miR-221, and miR-340 and increased levels of miR-30a-5p, miR-130a, and miR-150 in GestOB; and decreased levels of miR-122, miR-324-3p, miR-375, and miR-652 and increased levels of miR-625 in both PregestOB and GestOB (P < .05 to P < .0001 vs control). Decreased levels of several of these miRNAs associated with a more adverse maternal metabolic status (more pregnancy weight gain, glucose, glycated hemoglobin, homeostasis model assessment index of insulin resistance, C-peptide, and triacylglycerol and less high density lipoprotein cholesterol), with more placental weight, weight at birth, and weight at 6 months of life (all P < .05 to P < .001). CONCLUSIONS: This study provides the first identification of altered circulating miRNAs in maternal obesity and suggests a possible role of such miRNAS as markers for pre- and postnatal growth.