Neonatal leptin administration alters regional brain volumes and blocks neonatal growth restriction-induced behavioral and cardiovascular dysfunction in male mice

摘要

Premature delivery is often complicated by neonatal growth restriction and neurodevelopmental impairment. Because global over-nutrition increases the risk of adult metabolic syndrome, we sought a targeted intervention. Premature delivery and perinatal growth restriction decrease circulating levels of the neurotrophic hormone leptin. We hypothesized leptin supplementation would normalize the outcomes of mice with incipient neonatal growth restriction. Pups were fostered into litters of 6 or 12 to elicit divergent growth patterns. Pups in each litter received injections of saline or leptin from day 4–14. At 4 months, mice underwent tail cuff blood pressure measurement, behavioral testing and MRI. Mice fostered in litters of 12 had decreased weanling weights and leptin levels. Neonatal leptin administration normalized plasma leptin levels without influencing neonatal growth. Leptin replacement also normalized the hypertension, stress-linked immobility, conditioned fear, and amygdala enlargement seen in neonatal growth restricted male mice. In control males, neonatal leptin administration led to hypothalamic enlargement, without overt neurocardiovascular alterations. Female mice were less susceptible to the effects of neonatal growth restriction or leptin supplementation. In conclusion, the effects of neonatal leptin administration are modulated by concurrent growth and gender. In growth restricted male mice, physiologic leptin replacement improves adult neurocardiovascular outcomes.