Abstract 20343: Leptin and the Developmental Origins of Hypertension

Abstract

Introduction: Individuals with growth restriction through 2 years of age are relatively protected from adult obesity, but they are at increased risk of adult hypertension. Modeling this in mice, neonatal growth restriction (GR) leads to neonatal leptin deficiency, impaired neurodevelopment, adult growth restriction and adult hypertension. Hypothesis: We hypothesized that neonatal leptin deficiency during a window of developmental plasticity permanently increases central leptin sensitivity with subsequent renal sympathetic over-activation and hypertension. Methods: From day 4 to 14, C57BL/6 mice were randomized to vehicle (0.9% NaCl) or leptin at a dose shown to normalize the plasma levels of GR mice without impacting neonatal growth (1 mg/kg/d, intraperitoneal). GR mice were identified by weanling weights below the 10th percentile. Beginning at 4 months, adult phenotypes were assessed. Results: Compared to normal weight controls, adult GR mice had significantly increased leptin receptor mRNA expression within the arcuate nucleus of the hypothalamus (ARC), decreased adult food intake (0.09±0.01 vs. 0.13±0.02g/g/d; p<0.05), decreased adult body weight, and exaggerated leptin-triggered increases in both renal sympathetic nerve activity (29+/-11 vs. -9+/-6% change from baseline, p<0.01 for GR versus control) and systolic blood pressure (8+/-3 vs. -1+/-6% change from baseline, p<0.05 for icv leptin versus icv saline in GR mice). Leptin supplementation normalized the hypothalamic gene expression and leptin responsiveness of GR adult mice in association with a programmed suppression in leptin-triggered activation of signal transducer and activator of transcription 3 (STAT3). Conclusions: Neonatal GR-related leptin deficiency is associated with a sustained increase in ARC leptin receptor expression and enhanced adult leptin responsiveness. This heightened central leptin responsiveness may contribute to the increased risk of hypertension seen patients with a history of perinatal growth restriction. We are currently assessing the effects of neonatal GR and neonatal leptin administration on cell-specific leptin-mediated hypothalamic signaling pathways.