Neonatal growth restriction enhances central leptin sensitivity in adult mice

Abstract

Neonatal growth restriction (GR) leads to neonatal leptin deficiency and adult hypertension. We speculated leptin deficiency during a window of developmental plasticity permanently increases central leptin sensitivity. We thus hypothesized that neonatal GR enhances adult leptin signaling and that neonatal leptin supplementation would be protective. C57BL/6 mice were raised in litters of 6 or 12 to generate control and GR pups, respectively. Within each litter, pups were randomized to vehicle (0.9% NaCl) or leptin (1 mcg/g, ip) from P4 to P14. At 4 months, blood pressure and heart rate were measured by radiotelemetry. Additional mice underwent perfusion fixation after injection of vehicle or leptin (1 mcg/g ip). GR mice had decreased food intake (0.09±0.01 vs. 0.13±0.02g/g/d; p=0.02) and lower body weight (26±1.3 vs. 32±1.1g; p=0.01). Leptin supplementation normalized food intake (0.13±0.01g/g/d), but not adult body weight (28±1.4g; p=0.01). Adult GR mice had increased heart rates (576±5 vs. 546±bpm; p=0.004) and significantly increased pressor responses to leptin (2 mcg icv) that correlated with enhanced pSTAT3 signaling in the arcuate nucleus as well as increased c‐Fos expression in the subfornical organ. We conclude: 1) neonatal GR enhances central leptin sensitivity, and 2) leptin supplementation during a critical neurodevelopment window may be protective. (HL102659)