OP.8B.05] TRANSGENERATIONAL INHERITANCE OF OBESITY AND HYPERTENSION

Abstract

Objective: Maternal obesity increases the risk of developing hypertension in the offspring. Circulating leptin is closely linked to the control of sympathetic nerve activity (SNA) and blood pressure (BP) in the central nerve system. The ventromedial hypothalamus (VMH) is a key center of energy homeostasis, hemodynamic and sympathetic tone to renal vasculature. Exposure to overnutrition during early development changes the activity of the neurons and the receptors in the CNS, amplifying sympathetic output which leads to hypertension. We assessed the effects of maternal high fat diet (HFD) feeding during pregnancy on cardiovascular variables and sympathetic nerve activity (SNA) with changes in leptin and insulin signaling pathways in adulthood. Design and method: Breeder rabbits were fed a HFD (13%; HFD) or a control diet (4%; CD) during pregnancy and lactation. Offspring received CD after weaning. All rabbits had a VMH cannula and a renal nerve recording electrode. Mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were measured at baseline and after receiving increasing doses of αMSH (α-Melanocortin stimulating hormone, 0.3, 1nmol), SHU9119 (melanocortin receptor antagonist, 0.02, 0.04nmol), leptin receptor antagonist (5, 10 μg) or insulin receptor antagonist (0.01, 0.05U). Hypothalamic expression of leptin receptor (LepR) and Phosphoinositide 3-kinase (PI3K) was examined using real-time PCR. Results: Offspring from HFD fed rabbits (mHFD) showed higher MAP (+11%) and RSNA (+42%) than controls in adulthood (P < 0.05). αMSH into the VMH increased MAP, HR and RSNA (+6.6 ± 1mmHg, +23.4 ± 3.45 b/min and +3.66 ± 0.7nu) and SHU9119 reduced MAP and RSNA (−5.6 ± 0.8mmHg, −1.3 ± 0.13 nu) in mHFD rabbits. Leptin receptor antagonist normalized hypertension (−5.8 ± 0.8mmHg) in mHFD rabbits (P < 0.05). Insulin receptor antagonist administration into the VMH showed no changes in MAP, HR and RSNA in both mHFD and mCD rabbits. Offspring from maternal HFD rabbits exhibited an increase in LepR and PI3K expression in the hypothalamus compared to the control group (+47% and +74%). Conclusions: Exposure to over-nutrition during early development leads to permanently altered leptin and MC signaling pathways, due to programming of the key receptors and/or by neuronal plasticity, leading to sympathoexcitation and hypertension in adulthood.