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Symposium Report |
1 General Clinical Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Abstract
Obesity in humans causes hypertension, myocardial hypertrophy and coronary atherosclerosis, and increased cardiovascular morbidity and mortality that is thought to be related to sympathetic overactivity. Leptin is an adipocyte-derived hormone that acts in the hypothalamus to regulate appetite, energy expenditure and sympathetic nervous system outflow. One of the major mechanisms leading to the development of obesity-induced hypertension appears to be leptin-mediated sympatho-activation. Leptin adversely shifts the renal pressure–natriuresis curve, leading to relative sodium retention. Although obesity is generally associated with resistance to the anorexic and weight-reducing actions of leptin, our work has shown preservation of its sympatho-excitatory and pressor actions. This selective leptin resistance of obesity, coupled with hyperleptinaemia, may play a critical role in the cardiovascular complications of obesity. Increased information about leptin and its mechanisms of actions should help the development of safe and effective pharmacological treatments of obesity and obesity-related hypertension.
(Received 6 June 2005;
accepted after revision 8 August 2005; first published online 16 August 2005)
Corresponding author W. G. Haynes: General Clinical Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Email: william-g-haynes{at}iowa.edu
Obesity in humans is associated with the development of hypertension, coronary atherosclerosis and myocardial hypertrophy, and increased cardiovascular morbidity and mortality. Since the discovery of leptin in 1994, major advances have been made in the understanding of neuroendocrine mechanisms regulating appetite, metabolism, adiposity, sympathetic tone and blood pressure. Leptin, a 167-amino acid protein secreted by adipocytes, circulates at a concentration proportional to the adipose tissue mass and relays a satiety signal to the hypothalamus (Fig. 1). Leptin is transported to the central nervous system from plasma by a saturable, unidirectional system, involving binding of leptin to the short form of the leptin receptor located at the endothelium of the vasculature and the epithelium of choroid plexus (Bjorbaek et al. 1998). Leptin acts in the hypothalamus to regulate appetite, energy expenditure and sympathetic nervous system outflow.
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The leptin receptor is a single transmembrane protein from the cytokine-receptor superfamily. After binding to the leptin receptor, the signal is conducted via the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. This pathway is essential for transduction of the leptin signal, because interruption of the JAK/STAT pathway in mice results in increased food intake and accumulation of adipose tissue (Bates et al. 2003). Another important signalling pathway for the control of food intake by leptin is phosphoinositol-3 kinase, because the effect of leptin on appetite is reversed by blockade of this enzyme (Bjorbaek & Kahn, 2004). In addition, AMP-activated protein kinase (AMPK) has been implicated in leptin signal transduction. Activation of AMPK reduces the feeding and weight-reducing actions of leptin, and leptin has been shown to decrease AMPK activity in the hypothalamus.
Mechanisms of leptin action in the brain
The leptin receptor is expressed in several hypothalamic nuclei including the arcuate nucleus, ventromedial hypothalamus, paraventricular nucleus and dorsomedial hypothalamus (Schwartz et al. 2000). The arcuate nucleus is thought to be the major site of transduction of the signal from circulating leptin into a neuronal response (Satoh et al. 1997). Local injection of leptin in this area reduces food intake. Central neural administration of leptin does not affect food intake or sympathetic nerve activity after destruction of the arcuate nucleus (Haynes, 2000). Arcuate nucleus neurones project into the paraventricular nucleus and lateral hypothalamus, which are the locations of the second-order neurones in leptin signal transduction (Schwartz et al. 2000).
The anorexigenic, metabolic and sympathetic actions of leptin seem to involve different neuronal circuits. At least two main neuronal pathways account for the action of leptin in the brain. Leptin activates the catabolic pathway represented by proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurones and inhibits the anabolic pathway represented by the neuropeptide Y (NPY)/agouti-related protein (AgRP) neurones (Fig. 2). Both populations of neurones (POMC/CART and NPY/AgRP) project to the paraventricular nucleus and lateral hypothalamic area (Elmquist et al. 1999). POMC/CART neurones also project to the sympathetic preganglionic neurones in the medulla and spinal cord (Elmquist et al. 1999).
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The melanocortin system is important in mediating many of the actions of leptin in the central nervous system (Schwartz et al. 2000). The melanocortins are peptides (such as 
-melanocyte-stimulating hormone (-MSH)) that are processed from the polypeptide precursor POMC, which is produced by neurones in the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius. POMC deficiency leads to hyperphagia and obesity, and the effects of leptin on food intake and body weight are blunted in obese POMC (–/–) knockout mice (Challis et al. 2004). Leptin binding to the leptin receptor on POMC neurones leads to the secretion of -MSH, which subsequently binds to a number of members of a family of melanocortin receptors. Five melanocortin receptors (MC-1R to MC-5R) have been described. The MC-3R and MC-4R are highly expressed in the central nervous system. The MC-4R has an important role in energy balance, because disruption of the MC-4R gene induces hyperphagia and obesity in mice (Huszar et al. 1997).
Stimulation of hypothalamic MC-4R receptors increases sympathetic nerve activity to brown adipose tissue (BAT) and kidney (Haynes et al. 1999). Surprisingly, MC-4R blockade prevents the sympatho-excitatory effects of leptin to the kidneys, but not to BAT (Haynes et al. 1999). These results suggest that leptin controls sympathetic nerve activity in a tissue-specific manner through different neuronal pathways.
The NPY-containing neurones of the arcuate nucleus produce AgRP, which is a potent antagonist of MC-3R and MC-4R. The production of AgRP is increased by fasting and by leptin deficiency. By antagonizing melanocortin receptors, AgRP increases appetite and decreases energy expenditure (Fekete et al. 2004).
Neuropeptide Y
NPY is synthesized by neurones of the arcuate nucleus and released from their terminals in the paraventricular nucleus and lateral hypothalamus. NPY increases food intake and promotes obesity (Inui, 2000). These effects of NPY on appetite and body weight are mediated by the NPY-Y1 and NPY-Y5 receptors in the hypothalamus. Leptin inhibits NPY gene expression, and knockout of the NPY gene reduces obesity by about 50% in leptin-deficient ob/ob mice (Erickson et al. 1996). Intracerebroventricular administration of neuropeptide Y to animals, decreases sympathetic activity to interscapular BAT and kidney (Chen et al. 1990). Therefore, inhibition of the NPY pathway appears to be an important component of central leptin action to control energy homeostasis.
Corticotrophin-releasing factor
Leptin-dependent sympathetic activation to BAT appears to be mediated by corticotrophin-releasing factor (CRF) because the sympatho-excitatory effect of leptin to this tissue is substantially inhibited by a CRF receptor antagonist (Correia et al. 2001). These findings support the concept that leptin controls sympathetic nerve activity in a tissue-specific manner through different pathways.
Role of sympatho-activation in obesity-associated hypertension
Several lines of evidence suggest that increased sympathetic nervous system activity plays a major role in obesity-associated hypertension. Plasma and urinary catecholamine concentrations are increased in animal models of obesity and in obese humans. Adrenoreceptor blockade markedly decreases obesity-induced hypertension in dogs fed a high-fat diet (Hall et al. 2000). Obese human subjects have increased muscle sympathetic nerve activity and renal noradrenaline (norepinephrine) spillover compared to lean individuals (Grassi et al. 1995; Vaz et al. 1997). Reduction in body weight decreases both muscle sympathetic nerve activity and plasma noradrenaline levels (Grassi et al. 1998).
Physiological and pathophysiological roles of leptin
Leptin promotes weight loss by reducing appetite and by increasing energy expenditure through stimulation of sympathetic nerve activity. In animal studies, leptin increases sympathetic nerve activity to the kidneys, hindlimb and adrenal glands (Haynes et al. 1997). Chronic infusion of leptin increases arterial pressure and heart rate in conscious rats (Shek et al. 1998). Leptin-deficient ob/ob mice have low arterial pressure (Mark et al. 1999), which strongly suggests a critical physiological role for leptin in maintenance of arterial pressure. Transgenic mice overexpressing leptin have elevated arterial pressure that is fully reversed by sympathetic inhibition (Aizawa-Abe et al. 2000).
Renal and vascular effects of leptin
Despite some studies showing a natriuretic effect of leptin, leptin appears to elevate blood pressure without increasing natriuresis, thereby adversely shifting the pressure–natriuresis curve (Jackson & Li, 1997; Carlyle et al. 2002). Increased renal sympathetic activity combined with decreased natriuresis is likely to produce hypertension (Coatmellec-Taglioni et al. 2003; Beltowski et al. 2004). Leptin has also been shown to stimulate endothelial nitric oxide release in Wistar rats but not in leptin receptor-deficient Zucker rats (Fruhbeck, 1999). High doses of leptin increase forearm blood flow (Nakagawa et al. 2002) and cause coronary vasodilatation (Matsuda et al. 2003) in humans independently of nitric oxide. However, only sympathectomized rats have a depressor response to leptin, which suggests that leptin-induced sympatho-excitation opposes the direct vasodilatory effect of leptin in vivo (Fruhbeck, 1999). Given the strong association of leptin and hypertension demonstrated by multiple studies, the in vivo vasodilator effects of leptin seem to be minimal compared to its sympathetic pressor effects (Fig. 3).
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Studies in humans have shown that plasma leptin levels are significantly elevated in obese individuals relative to lean subjects (Considine et al. 1996). Therefore, it appears that most obese humans are resistant to the metabolic actions of leptin, because hyperleptinaemia fails to normalize adipose tissue mass in these subjects. If leptin were to contribute to obesity-related hypertension, then there would have to be preservation of its sympatho-excitatory and pressor actions in obese subjects, despite resistance to its anorexic and thermogenic weight-reducing effects (i.e. selective leptin resistance).
There is evidence that leptin resistance in genetic and acquired murine obesity models is selective to the metabolic actions of leptin, sparing its sympathetic pressor actions. Yellow obese agouti mice, a model of monogenic obesity due to overexpression of agouti protein (endogenous melanocortin receptor inhibitor), are resistant to the anorexigenic effect of leptin but have an intact sympatho-excitatory response to leptin (Correia et al. 2002). Similar results have been demonstrated in mice with diet-induced obesity (Rahmouni et al. 2005). Mice with diet-induced obesity demonstrate preserved renal sympatho-excitation, but reduced lumbar sympatho-excitation, in response to systemic leptin administration (Rahmouni et al. 2005). This preserved renal sympatho-activation could contribute to the pressor effects of leptin while the reduced lumbar sympathetic nerve activity may represent impaired thermogenic actions of leptin.
Several mechanisms have been suggested to underlie leptin resistance. Saturation in the transport of leptin into the central nervous system represents one potential mechanism of leptin resistance in obesity. In support of this idea is the observation of decreased cerebrospinal fluid (CSF)/serum ratio for leptin with increasing obesity in humans (Van Heek et al. 1997). However, obese humans still have higher CSF leptin concentrations than lean subjects. Another potential mechanism of leptin resistance involves alteration in intracellular leptin signalling pathways in the hypothalamus. The ability of leptin to stimulate the JAK/STAT pathway is impaired in mice with high-fat diet-induced obesity (El-Haschimi et al. 2000). In addition, a member of the suppressors of the cytokine signalling family (SOCS-3) is activated in the obese mice and potently inhibits leptin signalling (Bjorbaek et al. 1999). SOCS-3 protein acts intracellularly to inhibit STAT phosphorylation induced by the leptin receptor. Leptin resistance caused by activation of SOCS-3 occurs selectively in the arcuate nucleus of diet-induced obese mice (Munzberg et al. 2004). Another potential mechanism of leptin resistance is the protein tyrosine phosphatase 1b (PTP1b). This system exerts an inhibitory effect on leptin signalling, shown by the fact that PTP1b-deficient mice are resistant to diet-induced obesity and have increased leptin sensitivity (Zabolotny et al. 2002). Defects in the leptin receptor can lead to leptin resistance, but leptin receptor mutations are rare in humans.
A dichotomy between metabolic and cardiovascular sympathetic actions of leptin is also supported by the response of leptin-induced sympathetic baroreflex activation. Baroreflex activation selectively inhibits leptin-induced renal sympatho-activation but has no effect on leptin-dependent BAT sympathetic nerve activity (Hausberg et al. 2002). Therefore, it seems that leptin-dependent renal sympatho-excitation is involved in the pressor effect of leptin and is modulated by the baroreflex, whereas leptin-induced BAT sympatho-activation is responsible for metabolic actions of leptin. The metabolic and pressor components of leptin-induced sympatho-activation seem to involve different neuronal pathways. Microinjections of leptin into the dorsomedial hypothalamic nucleus caused significant increases in arterial pressure and heart rate, but not renal sympathetic nerve activity, whereas microinjections of leptin into the ventromedial hypothalamic nucleus caused significant increases in arterial pressure and renal sympathetic nerve activity, but not heart rate (Marsh et al. 2003). Antagonists of the MC-4R inhibit renal sympatho-activation to intracerebral administration of leptin but do not affect BAT sympatho-activation (Haynes et al. 1999). However, leptin-induced BAT sympatho-excitation is inhibited by a CRF receptor antagonist (Fig. 3) (Correia et al. 2001).
It seems plausible that obese individuals could have different relative degrees of metabolic versus sympathetic leptin resistance, perhaps explaining different propensity to hypertension in obese individuals. This could explain the fact that overweight hypertensive women have higher leptin levels than obese normotensive women with the same total body and abdominal fat mass (Itoh et al. 2002). Weight loss decreases blood pressure and 24-h noradrenaline excretion in hypertensive but not in normotensive women, despite a reduction in leptin concentration in both groups (Itoh et al. 2002). In addition, a graded positive relationship between plasma leptin levels and blood pressure was observed in human subjects independent of body mass index, abdominal adiposity or insulin resistance (Barba et al. 2003).
Implications for treatment of hypertension
Selective leptin resistance may be a crucial mechanism linking adiposity and hypertension. As humans become obese, leptin levels increase due to adipocyte accumulation. However, this hyperleptinaemia fails to cause weight loss because resistance develops to the anorexic and thermogenic actions of leptin (probably at the post-receptor neuronal level). However, if there is selective resistance and the cardiovascular sympatho-excitatory actions of leptin are preserved, then hyperleptinaemia will increase arterial pressure in obese subjects. Given the strong associations between leptin, sympatho-activation and hypertension, further research on leptin signalling is expected to lead to development of safe and effective pharmacological treatments of obesity-induced hypertension.
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