Maternal metformin treatment in obese pregnant dams normalizes neonatal sensory-motor reflexes.

Abstract

Background: Maternal overweight and obesity have reached epidemic proportions over recent decades, with detrimental effects on offspring metabolism and neurodevelopment. Metformin, commonly used to treat type 2 diabetes mellitus and gestational diabetes, is being investigated for use in maternal obesity due to its weight-loss-promoting, glucose-lowering, and insulin-sensitizing effects. Metformin may improve maternal metabolic state and support early sensory-motor development in offspring.

Methods: Three-week-old female C57BL/6NCrl mice were fed either a standard diet (SD, 9 kJ% fat, low sucrose content; CO group) or a Western-style diet (WSD, 45 kJ% fat, high sucrose content; OB group) from weaning through mating, gestation, and lactation. A subgroup of pregnant WSD-fed mice received metformin hydrochloride (target dose 380 mg/kg/d; OB + M group), dissolved in drinking water during gestation. At mid-gestation, a small cohort of pregnant dams was assessed for their metabolic profile. After delivery, pups were culled to six per litter at postnatal day (P) 2, and reflex ontogeny - such as righting, negative geotactic, and cliff-avoidance responses - was evaluated until P9 as a measure of early neurodevelopment.

Results: Feeding a WSD resulted in approximately 20% heavier dams in the OB group by the time of mating. Metformin administration led to gestational weight gain of about 56%, compared to OB weight gain of approximately 64%. Plasma leptin levels, perigonadal white adipose tissue, fasting glucose, and HbA1c in OB + M dams were numerically intermediate between OB and CO at mid-gestation, without reaching statistical significance, while glucose tolerance remained impaired to a similar extent as in OB dams. Metformin reduced placental weight in female fetuses and increased the fetal-to-placental weight ratio compared with the CO group. Metformin had no effect on neonatal survival but accelerated postnatal weight gain in both sexes and improved sensory-motor reflex maturation compared to OB neonates, most consistently for the geotactic reflex in both sexes and the cliff avoidance reflex in females.

Conclusions: Metformin did not restore maternal metabolic parameters at mid-gestation, despite the numerically intermediate phenotype across several markers, but it significantly attenuated gestational weight gain. Although neonatal survival was not improved, gestational metformin was associated with accelerated postnatal weight gain and improved sensory-motor reflex maturation in offspring, though effects varied across reflex types. Accelerated postnatal weight gain warrants cautious interpretation and long-term follow-up, as it is a risk factor for childhood obesity and metabolic disorders in later life.