OS 29-01 TRANS-GENERATIONAL PROGRAMMING OF OBESITY RELATED HYPERTENSION

Abstract

Objective: Obesity during pregnancy is associated with a greater risk of developing hypertension in the offspring. Plasma leptin levels correlate strongly with blood pressure and renal sympathetic nerve activity (RSNA). The ventromedial hypothalamus (VMH) is a key centre of energy homeostasis, haemodynamic and sympathetic tone to renal vasculature. It is possible that exposure to over-nutrition during development change the activity of the neurons, amplifying sympathetic output leading to hypertension in the offspring. We assessed the contribution of leptin and melanocortin (MC) signaling pathway in the VMH of offspring that were born from obese mothers. Design and Method: Female New Zealand White rabbits were fed a high fat diet (13%; mHFD) or a control diet (4%; mCD) during pregnancy and lactation. Offspring received CD after weaning. All offspring received a VMH cannula and a renal nerve recording electrode. Experiments were conducted in conscious rabbits and mean arterial pressure (MAP), hear rate (HR) and RSNA were measured. Rabbits received 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). Results: mHFD rabbits exhibited higher MAP and RSNA than mCD rabbits (P < 0.05). αMSH injection into the VMH increased MAP (+6%), HR (+12%) and RSNA(+80%) and SHU9119 reduced MAP (−7%) in mHFD rabbits. Leptin receptor antagonist normalised hypertension in mHFD rabbits (P < 0.05). By contrast, no changes were observed following insulin receptor antagonist injections into the VMH. mCD did not respond to any drug injections into the VMH. Conclusions: Exposure to over-nutrition during development alters leptin and MC signaling pathway in the VMH of the offspring.