O besity is now a large-scale global epidemic that develops from a complex interaction between genotype and environment, including social, behavioral, cultural, physiological, and metabolic factors. 1 The consequences of being overweight or obese include increased incidence of hypertension, hyperlipidemia and hyperinsulinemia, insulin resistance, and diabetes mellitus.2 Clinical evidence suggests that sympathetic activation participates not only in the initial elevation in blood pressure but also in maintaining the hypertension.3 Obesity is closely linked to increased sympathetic nerve activity (SNA) to the kidneys and skeletal muscle vasculature and is linked to the accumulation of body fat. 4 Our focus has been on the mechanism underlying the increase in blood pressure and, in particular, the role of the sympathetic nervous system in the development of the hypertensive state. We have demonstrated that 3 weeks of high-fat diet (HFD) feeding leads to increased mean arterial pressure (MAP), heart rate (HR), and renal SNA (RSNA) in rabbits. 5 Importantly, we have shown that ganglion blockade completely abolishes the increase in blood pressure suggesting that this model of obesity hypertension is neurogenic. 6 We suggested that the mechanism of the hypertension involved sympathetic activation and increased responsiveness to central sympathoexcitatory effects of leptin owing to increased plasma leptin arising from visceral fat accumulation. 5,6 Leptin is an adipokine that plays an important role in regulating energy intake and energy expenditure, including appetite and metabolism, and acts as a key peripheral hormone in distinct neurons in the hypothalamus.7 Leptin is secreted primarily by adipocytes and is present in serum in direct proportion to the amount of adipose tissue.8 Chronic leptin infusion has been shown to increase HR and blood pressure in animal models 9,10 via stimulation of the sympathetic nervous system. 9,11 In addition to the rise in leptin, we also observed a marked increase in plasma insulin in rabbits fed a HFD suggesting that insulin may also contribute to the hypertension and increased RSNA in rabbits particularly early in the onset of the HFD before significant accumulation of visceral fat. 5,6 Thus, both leptin and insulin may contribute to the hypertension, and with the development of specific antagonists it is now possible to determine their relative roles. In the present study, we administered either the insulin receptor antagonist or the leptin receptor antagonist intracerebroventricularly to conscious rabbits at 1 or 3 weeks after the onset of a HFD.
Materials and MethodsTwenty-seven male New Zealand White rabbits (initial body weight, 2.6-3.1 kg) were housed under controlled light (lights on 6:00 Abstract-Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased bl...