Bravo et al obesity hormone, based on the hypothetical fact that high leptin levels would prevent the occurrence of obesity. Unfortunately, this is not the case, and so the strong correlation between serum leptin levels and body fat mass found in obese individuals now suggests the existence of an endogenous leptin-resistant mechanism in obesity (Considine et al 1996). In addition to regulating food intake and adipose tissue mass, leptin has been found to be involved in cardiovascular physiological processes like sympathetic nerve system activation, renal hemodynamics, blood vessel tone, and blood pressure. This review will focus on the leptin-mediated sympathetic activation and its relevance to the mechanism of obesity-related hypertension. Concept of selective leptin resistance As stated above, obesity is associated with high leptin levels, reflecting the increased amount of adipose tissue in obese individuals. As a consequence, it has been postulated that the apparent loss of the anorexic and weight-reducing effects of leptin in obesity, is a result of a leptin-resistance mechanism. Nevertheless, obesity is associated with increased sympathetic nerve activity, and leptin has been proven to participate in autonomic nervous system control, in part, by increasing renal sympathetic nerve activity (RSNA). Therefore, it is contradictory that, in the presence of a leptin resistance state, the hormone can contribute to the sympathetic activation seen in obesity. This has led to the novel concept of selective leptin resistance, in which resistance appears to be primarily limited to the metabolic (satiety and weight-reducing) actions of leptin, sparing the renal sympathetic activation effects. This concept has emerged from observations made first in agouti yellow obese (Ay) mice (Correia et al 2002; Rahmouni et al 2002), and corroborated recently in a diet-induced obesity model (Rahmouni et al 2005). In these studies, leptin administered peripherally produced increase in RSNA in both obese and lean mice, but failed to decrease food intake and body weight in the obese mice to a similar degree as it did in their lean littermates. Interestingly, this same effect was observed when leptin was injected into the lateral ventricle of the brain (Rahmouni et al 2002, 2005). Here, leptin increased RSNA again, without changing significantly food intake and body weight in Ay and diet-induced obese mice, as compared with their respective lean littermates. These latter studies also served to demonstrate that is unlikely that leptin 164 resistance is due to an impaired leptin transport mechanism across the blood–brain barrier as intracerebroventricular administration of the hormone also failed to enhance food intake and weight loss. Moreover, the increased RSNA achieved by central leptin administration was not accompanied by changes in plasma leptin levels, suggesting that leptin-induced RSNA was centrally-mediated. In agreement with these observations, Munzberg et al (2004) recently described that leptin resistance is not global within the hypothalamus, and found that the arcuate nuclei, which contains leptin-mediated anorexigenic neurons, becomes resistant to leptin in very early stages of diet- induced obesity in mice. On the contrary, other hypothalamic and extrahypothalamic sites appear to continue relatively sensitive to the actions of leptin, including the ventromedial hypothalamic nuclei, which has been previously shown to mediate leptin-induced sympathetic nerve activation (Satoh et al 1999). This hypothesis, however, must be proved in human studies as well, and if true, it would help explain how leptin could contribute to sympathetic activation and hypertension despite the fact that there is resistance to the satiety and weight-reducing effects of leptin in obesity. Renal effects of leptin: the role of the sympathetic nervous system and nitric oxide In the kidney, leptin may affect blood pressure mainly by two opposing ways: the first is through renal sympathetic activation (Haynes, Sivitz, et al 1997), and the second is related to nitric oxide (NO) synthesis (Vecchione et al 2002). The renal effect of leptin also depends on the exposure time to the hormone. As it has been observed, acutely administered leptin usually does not increase blood pressure in animal or human studies, but when given for longer periods of time, leptin does elevate blood pressure in animal models. Acute effects Traditionally, obesity-induced renal sympathetic activation has been thought to contribute to the development of hypertension by enhancing sodium retention, since renal denervation attenuates the antinatriuretic and hypertensive effect of obesity in dogs (Kassab et al 1995). Although systemic administration of leptin stimulates sympathetic nerve activity to the kidney (Haynes, Morgan, et al 1997), if infused for short Vascular Health and Risk Management 2006:2(2)