Division of Renal Medicine, Department of Clinical Science, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden
Introduction
It is well recognized that an increased body weight is often associated with metabolic disorders (hyperinsulinaemia and glucose intolerance), as well as increased blood pressure. Indeed, obesity activates both the sympathetic nervous and reninangiotensin systems and causes insulin resistance and hyperinsulinaemia, all of which have been thought to raise blood pressure. The association between obesity and hypertension suggests that the adipose mass may serve as an important tissue in the regulation of blood pressure although the mechanism(s) underlying this are not yet evident. Recently it has become evident that adipocytes may function not only as energy storage depots but also as a rich source of metabolically active substances including free fatty acids, tumour necrosis factor-alpha, angiotensinogen (AGT), prostaglandins, oestrogen, and the ob gene product, leptin. Obesity and hyperinsulinism are major stimulators of leptin production, and this production is strongly and positively correlated with body fat mass [1]. There is no doubt that the discovery of leptin has markedly increased our understanding of the complex physiological system that regulates satiety and eating behaviour. Since leptin binding sites have been found in regions of the brain that are also important in cardiovascular control, there is reason to believe that leptin could affect cardiovascular function through its effects on the central nervous system. Indeed, some evidence suggests that the functional role of leptin appears to extend beyond the regulation of feeding and metabolism to include other biological functions influencing autonomic, cardiovascular, renal and endocrine functions [1]. For some of these actions, leptin may act as a signalling mechanism to activate compensatory mechanisms for the potentially deleterious effects of an increased body fat mass. Recently, several animal studies [24] have shown that leptin increases sympathetic nervous system activity. Much interest has therefore focused on the hypothesis that leptin may act as a mediator linking body fat mass with changes in insulin action, sympathetic neuronal outflow and renal sodium excretion.
Is hypertension associated with hyperleptinaemia?
Whereas data from available animal studies clearly indicate an association between leptin and hypertension [5,6], results of human studies are less consistent. Some studies have reported significantly higher leptin levels in essential hypertensive patients than in controls, as well as a significant correlation between leptin levels and blood pressure [7,8]. These results were not confirmed by Kokot et al. [9], who found no difference in plasma leptin levels between hypertensive patients and controls. In another study, Hirose et al. [10] reported a correlation between mean blood pressure and leptin also after adjustment for age and body mass index (BMI). However, no association was found between the 24-h diastolic blood pressure and BMI-adjusted leptin by Narkiewicz et al. [11]. That plasma levels of leptin in general are higher in women is an important factor to be considered in the evaluation of the association between leptin and blood pressure. Suter et al. [12] reported a significant relation between systolic blood pressure and plasma leptin levels in hypertensive women but not in hypertensive men. On the other hand, Kennedy et al. [13] demonstrated a relationship between elevated systolic and diastolic blood pressures and plasma leptin levels in hypertensive men only. Recently, Makris et al. [14] demonstrated higher leptin and insulin levels in healthy offspring of patients with hypertension compared to healthy offspring of normotensive patients, which support the hypothesis that hyperleptinaemia may contribute to hypertension. The reasons for the divergent findings in the literature are not obvious, but may be due to factors such as race, selection criteria, limited numbers of patients, statistical methods, insulin resistance, and differences in anti-hypertensive treatment. Taken together, although the clinical evidence for the view that leptin causes high blood pressure is still not very strong, leptin does, indeed, have peripheral physiological effects that suggest it may be a link in the triad of obesity, hyperinsulinaemia and hypertension.
Leptin and insulin affect tubular sodium handling
Insulin resistance and hyperinsulinaemia usually characterize obesity. Leptin, insulin concentrations, and body weight are interrelated and there is a direct correlation between insulin and leptin levels [15]. It can be speculated that insulin and leptin interact and modulate each others effects and contribute to hypertension via effects on tubular sodium handling. It is of interest that, whereas insulin infusion causes anti-natriuresis in healthy subjects [16], leptin infusion increases renal sodium and water excretion [17], apparently via a direct tubular action. Thus, increasing leptin levels, as observed during prolonged (3 days) hyperinsulinaemia [18], could be a factor counteracting the antinatriuretic effects of insulin. Indeed, Hall et al. [19] have noted that in glucose-clamped dogs, the antinatriuretic effect of insulin is of brief duration and, following a reduction in sodium excretion during the first 23 days, natriuresis returns to basal values by an escape-mechanism of unknown aetiology. In this respect, it is of interest that Villarreal et al. [20] have found that, whereas an intravenous bolus of leptin causes a six- to sevenfold increase in sodium excretion in normal rats, spontaneously hypertensive rats (SHR) and obese rats are refractory to the natriuretic effects of leptin. Thus, these results may indicate the existence of tubular leptin resistance, which ought to be selective in nature since SHR rats tend to be leaner than their normotensive counterparts.
Does leptin affect the reninangiotensin system?
The importance of the classical reninangiotensin system in the regulation of blood pressure is well established. Recent evidence has suggested that AGT, the substrate from which the hypertensive hormone angiotensin II (ANG II) is formed, is expressed in adipose tissue, and adipocytes have been shown to synthesize ANG II [21]. Thus, adipose tissue-derived ANG II could be a factor contributing to the association between obesity and hypertension and it is of interest that AGT expression in adipose tissue is modulated by nutritional status and related to diet-induced changes in blood pressure in rodents [22]. In normotensive men AGT levels are related to both fat mass and plasma leptin levels [23] and a significant positive relationship between plasma leptin and plasma renin activity has been found in hypertensive patients [8,12]. Since several hormones, such as insulin and steroids [24,25], affect AGT mRNA, more studies are needed to investigate whether leptin up-regulates the activity of this gene in adipocytes and thus contributes to hypertension.
Leptin causes sympathico-activation
Obese patients are frequently characterized by sympathetic hyperactivity and higher plasma levels of adrenaline and noradrenaline [26]. One factor that may contribute to an increase in sympathetic nervous activity in obesity is plasma leptin. Chronic leptin infusion has been shown to increase heart rate and blood pressure in animal models [3,27] via stimulation of sympathetic nervous system activity [24]. An intracerebroventricular injection of leptin increases the activity of both lumbar and renal sympathetic nerve activity and reduces arterial blood flow to skeletal muscle [27]. As leptin penetrates the blood cerebrospinal fluid barrier by active transport, it seems likely that leptin activates sympathetic nerve activity in the central nervous system. The link between plasma leptin and the autonomic nervous system is strengthened by evidence of a direct relationship between muscle sympathetic nerve activity and plasma leptin concentrations [28]. Moreover, a direct relationship between plasma leptin and heart rate has been observed in hypertensive patients [11,12]. This relationship seems to be independent of body mass index, plasma insulin, blood pressure, smoking, and physical activity [11], suggesting that leptin may influence cardiovascular neuronal control also in humans.
Summary and perspectives
In summary, most recent studies suggest a relationship between the ob gene product leptin and blood pressure in patients with essential hypertension. Whether this association is independent of other hypertensive factors, such as insulin and the sympathetic and reninangiotensin systems, is not known and needs to be investigated. It should be emphasized that the demonstration of a relationship between leptin and blood pressure in the literature, in general, has not been very strong statistically, which may mean that leptin plays only a minor role in the pathogenesis of hypertension. The fact that women are less predisposed to hypertension, although they usually have much higher plasma leptin levels than men, due to their higher content of body fat tissue, also appears to argue against an important role for leptin in the genesis of essential hypertension. Finally, Rutkowski et al. [29] found in a sib-pair analysis that the ob gene is not a major contributor to the phenotype of essential hypertension in African Americans. However, leptin has several effects, such as stimulation of the reninangiotensin and sympathetic nervous systems, which may affect blood pressure levels in humans. On the other hand, leptin also stimulates natriuresis, so it is possible that a blunted effect of leptin (i.e. peripheral leptin resistance) may predispose to hypertension in humans. One might therefore speculate that if patients with hyperleptinaemia are resistant to the facilitative effects of leptin on sodium excretion, but are not resistant to the stimulatory effects of leptin on sympathetic and/or reninangiotensin activity, this would explain why hypertension occurs so often in obesity.
Recent research has demonstrated that leptin is a pleiotropic hormone with multiple actions that are potentially relevant not only to the control of feeding but also to cardiovascular function, insulin secretion, angiogenesis, immune response, and haematopoiesis [1]. Probably other actions of leptin will also soon be discovered. Indeed, Ducy et al. [30] have recently demonstrated that infusion of leptin into the central nervous system decreased bone mass in mice, suggesting that leptin is also a major regulator of bone formation. It is thus possible that future pharmacological manipulations of the leptin pathway may be a novel therapeutic approach to the treatment of osteoporosis, in addition to affecting blood pressure.
Acknowledgments
This study was supported by the Swedish Medical Research Fund (K9819X-1267601) and the Trone-Holsts Foundation.
Notes
Correspondence and offprint requests to: P. Stenvinkel, Division of Renal Medicine, K56, Huddinge University Hospital, S-141 86 Huddinge, Sweden.
References