Maternal metformin treatment decreases fetal inflammation in a rat model of obesity and metabolic syndrome

OBJECTIVE: Obesity and metabolic syndrome are associated with systemic inflammation and increased perinatal morbidity. Metformin improves metabolic and inflammatory biomarkers in nonpregnant adults. Using in vivo and in vitro models, we examined the effect of metformin on maternal and fetal inflammation. STUDY DESIGN: Female Wistar rats (6-7 weeks old) were fed a normal diet (NORM) or a high-fat/high-sugar diet (HCAL) for 5-6 weeks to induce obesity/metabolic syndrome. After mating with NORM-fed male rats, one-half of the HCAL-fed female rats received metformin (300 mg/kg, by mouth daily). All dams continued their respective diets until gestational day 19, at which time maternal and fetal outcomes were assessed. Maternal and fetal plasma and placentas were analyzed for metabolic and inflammatory markers. Cultured human placental JAR cells were pretreated with vehicle or metformin (10 mu mol/L-2.5 mmol/L) before tumor necrosis factor alpha (TNF-alpha; 50 ng/mL), and supernatants were assayed for interleukin-6 (IL-6). RESULTS: HCAL rats gained more prepregnancy weight than NORM rats (P = .03), had higher levels of plasma insulin and leptin, and exhibited dyslipidemia (P < .05). Fetuses that were exposed to the HCAL diet had elevated plasma IL-6, TNF-alpha, and chemokine (C-C motif) ligand 2 levels (P < .05) and enhanced placental TNF-alpha levels (P < .05). Maternal metformin did not impact maternal markers but significantly decreased diet-induced TNF-alpha and chemokine (C-C motif) ligand 2 in the fetal plasma. Finally, metformin dose-dependently reduced TNF-alpha-induced IL-6 and I kappa B alpha levels in cultured placental JAR cells. CONCLUSION: Diet induced-obesity/metabolic syndrome during pregnancy significantly enhanced fetal and placental cytokine production; maternal metformin reduced fetal cytokine levels. Similarly, metformin treatment of a placental cell line suppressed TNF-alpha-induced IL-6 levels by NF kappa B inhibitor.