Abstract 12582: The Origin of Hypertension and Sympathetic Regulation in Diet Induced Obesity

Abstract

Obesity is closely associated with a greater risk of developing hypertension and there is a strong link between bodyweight gain and greater blood pressure (BP). Plasma leptin levels correlate with BP and renal sympathetic nerve activity (RSNA). The central effects of leptin are mediated primarily through the arcuate (ARC) nucleus of the hypothalamus from which peripheral signals are relayed downstream, to other hypothalamic nuclei, via a network of second order neurons. Dense projections of both Neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (α-MSH) containing neurons ascend from the ARC and terminate in several hypothalamic nuclei such as the ventromedial hypothalamus (VMH) which are the key centres of energy homeostasis, hemodynamics and sympathetic tone to brown adipose and renal vasculature. It is therefore possible that a change in the activity of either POMC or, NPY neurons or both may underlie the mechanism by which sympathetic output is increased in obesity, leading to hypertension. In the present study we assessed the contribution of α-MSH and NPY neurons in the VMH on development of diet-induced neurogenic hypertension. New Zealand White rabbits were instrumented with a VMH cannula and a renal sympathetic nerve electrode. Blood pressure (BP) was measured by means of an intra-arterial catheter. Rabbits were injected with α-MSH, SHU9119 (MC3/4R antagonist), NPY or Leptin receptor antagonist into the VMH, 60 minutes apart using an injector. Following 3 weeks of a high fat diet (HFD, 13.5% fat), conscious rabbits had higher BP (+7.6 ± 0.5mmHg, P<0.001) and RSNA (+4.6 ± 0.4nu, P<0.001) compared to control group (3.5% fat). α-MSH injection into the VMH increased BP (+7%) and RSNA (+35%) (P<0.001) and SHU9119 injection showed reduction (P<0.05) in BP (-7%), HR (-5%) and RSNA (-23%) in HFD rabbits. Leptin antagonist or NPY injection showed dose dependant reduction in BP (-7%), HR (-5%) and RSNA (-11%) (P<0.05) when given to HFD rabbits. NPY injection reduced BP in all groups. We conclude that the HFD feeding may induce pathway-specific changes in the VMH and VMH is the likely origin of leptin-mediated sympathoexcitation, α-MSH hypersensitivity and altered central responsiveness to NPY.