Leptin: Linking Obesity, the Metabolic Syndrome, and Cardiovascular Disease

Sanjeev B. Patel, MD, Garry P. Reams, MD, Robert M. Spear, MS, Ronald H. Freeman, PhD, and Daniel Villarreal, MD

Corresponding authorDaniel Villarreal, MDDepartment of Medicine, Division of Cardiology, SUNY Upstate Medical University, Room 6142, 750 East Adams Street, Syracuse, NY 13210, USA.E-mail: Villarrd@upstate.edu

Current Hypertension Reports 2008, 10:131–137Current Medicine Group LLC ISSN 1522-6417Copyright © 2008 by Current Medicine Group LLC

The incidence and prevalence of obesity and the meta-bolic syndrome have risen markedly in the past decade, representing a serious cardiovascular health hazard with significant morbidity and mortality. The etiology of the metabolic syndrome and its various pathogenic mechanisms are incompletely defined and under intense investigation. Contemporary research suggests that the adipocyte-derived hormone leptin may be an important factor linking obesity, the metabolic syndrome, and cardiovascular disorders. Although recent evidence indicates that under normal conditions leptin may be an important factor in regulating pressure and volume, during situations of chronic hyperleptinemia and leptin resistance, this hormone may function pathophysiologi-cally for the development of hypertension and cardiac and renal diseases. Future research will determine if reduction of circulating leptin and/or blockade of its peripheral actions can confer cardiovascular and renal protection in hyperleptinemic patients with obesity and the metabolic syndrome.

IntroductionThe prevalence of obesity in the adult population of the United States has risen markedly in the past three decades and is presently greater than 30% [1]. This epidemic of obesity represents a serious health hazard with significant morbidity and mortality [1,2]. Indeed, obesity is associ-ated with multiple metabolic alterations, which in turn promote widespread atherogenesis [1,3]. This cluster of disturbances, collectively known as the metabolic syn-drome, includes dyslipidemia, insulin resistance, glucose intolerance, and hypertension, and may also be associ-

ated with proinflammatory and prothrombotic states [3]. Although it has become increasingly apparent that indi-viduals with the metabolic syndrome are at enhanced risk for cardiovascular and renal disease, the etiology of this disorder and the underlying mechanisms that link its vari-ous components are not well defined.

Pathogenesis of the Metabolic SyndromeIt has been suggested previously that three broad etio-logic categories for the components of the metabolic syndrome potentially are represented by obesity, insulin resistance, and other independent factors of molecular or immunologic origin [3]. Recently, it was proposed that in obesity, insulin resistance is not a primary event, but a response to lipid accumulation in lean tissues [4]. Under these conditions, insulin resistance could be viewed as a self-protective tissue reaction that reduces cellular uptake of glucose and therefore decreases glucose-derived lipo-genesis [4]. Moreover, it has also been suggested that insulin resistance may be secondary to leptin resistance, which is highly prevalent in obesity [4]. Leptin resistance would result in a reduction of leptin-induced inhibition of the sterol regulatory element-binding protein 1c, which regulates lipid deposition in tissues. The overexpression of this protein leads to the abnormal accumulation of lipids in nonadipose organs, including the liver and cardiac and skeletal muscle [4,5]. Furthermore, leptin resistance also results in reduced fatty acid oxidation, which in turn pro-motes insulin resistance [4,5]. Thus, the combination of these pathogenic mechanisms involved in obesity and the metabolic syndrome contribute significantly to the emer-gence of cardiovascular disease. Epidemiologic studies of different ethnic populations have indicated that hyperlep-tinemia and leptin resistance are strongly associated with the metabolic syndrome and enhanced cardiovascular morbidity and mortality [4,6].

Notwithstanding the potential role of hyperleptinemia and leptin resistance in the development of the metabolic syndrome, in the past 5 to 10 years increasing information indicates that leptin can uniquely and directly influence autonomic, cardiovascular, and renal functions in physi-ologic and pathophysiologic situations. Consequently,

132 Hypertension and Metabolic Disarray: Diabetes Mellitus, Insulin Resistance, and Obesity

leptin may be an important link in the pathogenesis of the hypertension and heart disease induced by obesity and the metabolic syndrome [7].

Biology of Leptin and Its ReceptorsIn the past decade, it has become apparent that adipose tissue is a prolific organ that secretes several immuno-modulators and bioactive molecules, including leptin, adiponectin, tumor necrosis factor- , resistin, angioten-sinogen, interleukin-6, plasminogen activator inhibitor-1, and C-reactive protein [2,7]. Of these factors, leptin has emerged as an important hormone with potentially broad actions on several organ systems [7].

Leptin is synthesized and secreted into the circula-tion primarily by adipocytes. The first described major action of this hormone was on the hypothalamus to con-trol body weight and fat deposition through its effects on appetite inhibition and stimulation of metabolic rate and thermogenesis. The leptin receptor (LR), product of the lepr gene, is a member of the extended class I cytokine receptor family having at least six splice vari-ants LR (a–f) [8,9]. The long-form LRb isoform encodes a receptor with a long intracellular domain, which is essential for intracellular signal transduction and crucial for leptin’s actions [8,9]. The functions of the short-form LR (a, c, d, and f) and the secreted form of LRe are less clear, but their proposed roles include transport of leptin across the blood-brain barrier, clearance of leptin from the circulation, and regulation of free leptin [8,9].

High tissue levels of LR gene expression occur in the lung; moderate levels in the kidney; and low levels in the heart, brain, spleen, liver, and muscle [10]. Expression of the extracellular domain of the LR and the short-splice variant LRa has been shown in many peripheral tissues; however, the long-splice variant LRb has been detected in only a few organ systems including the adrenal gland, kidney, and heart [10]. This long-splice variant with long intracellular domain possesses two peptide motifs, which interact with an intracellular glycoprotein gp 130, which in turn activates Janus kinases (JAK; a family of tyrosine kinases) to promote transcription through activation of the signal transducer and activator of transcription (STAT)-3, phosphoinositol-3 kinase (PI3K), and inhibi-tion of adenosine monophosphate–activated protein kinase (AMPK). Of note, negative regulators of leptin signaling have been identified and include suppressor of cytokine signaling proteins (SOCS)-3 and protein tyrosine phosphatase 1b (PTB1b) [10,11].

Leptin and the Sympathetic Nervous SystemIt is now well established that leptin infusion can acti-vate the sympathetic nervous system both by local peripheral actions and centrally mediated effects on the hypothalamus. Studies with direct intracerebral infusion

of leptin have demonstrated an increase in lumbar and adipose tissue sympathetic nerve activity. Also, intrave-nous administration of leptin was shown to produce a slow, dose-dependent increase in sympathetic discharge from the renal nerves and the brown adipose tissue in Sprague-Dawley rats [11]. In these investigations, sym-pathoactivation was maintained even upon transection of the renal nerve distal to the recording site, indicating efferent rather than afferent nerve activation [11,12]. In a subsequent study, urinary norepinephrine excretion as an index of efferent renal sympathetic nerve activity was examined in normal Sprague-Dawley rats and spontane-ously hypertensive rats [13]. In both strains of rats, acute administration of leptin was associated with significant elevations in urinary norepinephrine excretion, further establishing the concept of leptin-induced activation of the renal efferent sympathetic nervous system [11]. To this end, and as discussed in the next section, it is of interest that this leptin-induced early activation of sympathetic nervous tone did not appear to be accompanied by paral-lel elevations in arterial blood pressure when the hormone was acutely infused intravenously in normotensive and hypertensive rats [14,15].

Leptin and the Regulation of Arterial Blood PressureIn contrast to the lack of effect of acute intravenous leptin on arterial blood pressure [14,15] are the studies with direct local infusion of leptin into the cerebral ven-tricles of normal rats. Dunbar et al. [12] reported that the intracerebral infusion of leptin leads to a slow increase of mean arterial pressure by approximately 10%. Consistent with this effect, lumbar sympathetic nerve activity also increased progressively to a maximum of 10% during the infusion. Interestingly, the unchanged renal flow, despite the rise in renal sympathetic nerve activity, may have been related to concurrent renal vasodilation. Thus, in the context of available information, it is evident that central administration of leptin acutely increases the sympathetic outflow similar to that observed with systemic adminis-tration of the hormone. However, the absence of arterial blood pressure elevation during the systemic infusion of leptin raises the possibility of the simultaneous local acti-vation of counterregulatory vasodilatory mechanisms to help maintain systemic hemodynamics.

In support of this concept, in vitro studies performed by Lembo et al. [16] in the aortic rings of Wistar-Kyoto rats have demonstrated a dose-dependent, leptin-induced vasorelaxation, which could be largely abolished by N*-nitro-L-arginine methyl ester (L-NAME) administration or endothelial denudation, suggesting that nitric oxide (NO) and possibly endothelial-derived hyperpolarizing factor mediated the vasodilatory response. Consistent with these findings, it was demonstrated that leptin promotes NO through the stimulation of endothelial NO synthase [17].

Cardiovascular and Renal Actions of Leptin Patel et al. 133

Moreover, Fruhbeck [18] demonstrated a dose-dependent elevation in plasma NO produced by intravenous administra-tion of synthetic leptin in normal rats. This effect required an intact leptin receptor, because it could not be elicited in the fa/fa rat model, a strain that lacks a functional leptin recep-tor [14]. Of major interest in this study, NO blockade led to a leptin-induced enhancement of arterial blood pressure. Conversely, blockade of the sympathetic nervous system led to a leptin-mediated reduction in blood pressure [18]. Thus, it is possible to suggest that during acute systemic adminis-tration, leptin’s lack of effect on arterial blood pressure may represent a balanced action of vasodilation primarily medi-ated by NO, and vasoconstriction mediated primarily by the sympathetic nervous system, with a resultant “neutral” hemodynamic effect [18]. This postulate requires validation because the vasodilatory actions of leptin in different vas-cular beds have been found to be inconsistent [19,20], and because under certain conditions, leptin may promote other potent vasoconstrictive agents, including endothelin-1 [21], and perhaps reactive oxygen species [22], which may ulti-mately impact systemic hemodynamics. Finally, and from the physiologic perspective, the effects of acute fluctuations of endogenous plasma levels of leptin on the vasculature have not been examined and await clarification.

Chronic Hyperleptinemia, Leptin Resistance, and HypertensionIn chronic hyperleptinemic conditions such as obesity, the potential neutral effect of leptin on the peripheral vascu-lar resistance may not remain. Relevant to this concept, it is pertinent to point out that obesity is characterized by abnormal NO production and metabolism [23•]. The resultant NO deficiency, in turn, could lead to the pre-ponderance of leptin-induced vasoconstriction via the continuous and unopposed stimulation of sympathetic ner-vous system. To this end, previous studies have indicated that the agouti yellow mouse model of obesity is resistant to the hypothalamic actions of leptin for appetite suppres-sion, but not to the effects of leptin for the enhancement of the sympathetic nervous system [24]. From the latter findings, the concept of “selective leptin resistance” as a mechanism for the development of hypertension in obesity has emerged [24]. Accordingly, it has been suggested that in some obese animal models and patients with hyperlep-tinemia, there is resistance to the satiety action of leptin but the sympathetic overactivity leading to elevated blood pressure is preserved. The precise mechanisms behind this selectivity remain to be fully defined [24,25•]; however, they may include reductions of leptin transport through the blood-brain barrier and neuronal overexpression of the potent leptin inhibitor SOCS-3 [26].

Independent of the possibility of selective leptin resistance in obesity, a study by Shek et al. [27] in lean normal rats has demonstrated that chronic hyperleptinemia produced by continuous leptin administration for several days leads to a

persistent elevation in mean arterial blood pressure of 10 to 15 mm Hg, and this hypertensive effect is rapidly reversed upon the cessation of the hormone administration. Similarly, Aizawa-Abe et al. [28] showed that transgenic mice overex-pressing leptin displayed significant increases in the systolic blood pressure of approximately 15 to 20 mm Hg. This hypertension was abolished with the intraperitoneal injec-tion of an -blocker, suggesting critical involvement of the sympathetic system [28]. Finally, a study by Correia et al. [24] showed that mice with leptin deficiency (ob/ob) or with LR defect (db/db) exhibited significant obesity but did not develop hypertension. This last observation suggests that, at least in this animal model, leptin may play a role in regulat-ing systemic hemodynamics [24].

The relevance of this basic research information in the context of human hypertension remains to be established. However, increasing evidence indicates a significant posi-tive correlation between circulating levels of leptin and blood pressure in adolescents and adults, even indepen-dent of body weight [29,30]. Furthermore, it has been reported that elevated plasma levels of leptin exist in healthy offspring of hypertensive patients; this possible genetic predisposition could contribute to the develop-ment of hypertension [31]. Thus, this emerging collective knowledge suggests that chronic hyperleptinemia and leptin resistance may function pathophysiologically to elevate arterial blood pressure via its autonomic, vascular, and renal effects [31].

Leptin and the Kidney As outlined previously, in vitro studies have indicated that the renal medulla, and particularly the inner medullary collecting duct, contain the long-tail LRb leptin receptor [10,32], which in turn suggests a functional role of this hormone in renal biology. Pertinent to this concept, in the rat, three- to sixfold elevations in plasma leptin occur postprandially, a condition characterized by intravascular sodium and volume surfeit [33]. Accordingly, the renal effects of leptin may not only be viewed as the result of plasma hormone level elevation, but also as highly dependent on the underlying regional and systemic hemo-dynamics, baseline sodium, and water balance. Numerous studies have demonstrated that acute administration of synthetic leptin in the rat produces a significant elevation in urinary sodium and water excretion [14,15,32,34]. Serradeil-Le et al. [32] reported that in normal, hydrated, conscious rats intraperitoneal injections of synthetic murine leptin were associated with a significant two- to threefold increase in urinary volume. This effect was most apparent within 2 hours of leptin administration. Also, Jackson and Li [15] reported that acute ipsilateral intrare-nal infusions of synthetic human leptin in rats produced a significant two- to threefold elevation in urinary sodium and volume excretion without significant effects on renal or systemic hemodynamics. Because the natriuresis and

134 Hypertension and Metabolic Disarray: Diabetes Mellitus, Insulin Resistance, and Obesity

diuresis were confined to the infused kidney, these results suggested a direct local effect. Interestingly, the renal excretory actions of leptin required approximately 1.5 hours to be fully expressed [15]. This delayed time course is consistent with alterations at the level of gene transcrip-tion with the de novo synthesis of proteins and turnover of existing proteins to achieve the biologic response [15]. This, in turn, is consonant with the JAK-STAT signal transduction pathway characteristic of the LRb isoform of the LR that predominates in the kidney [10].

In a different study, Villarreal et al. [14] examined the renal and hemodynamic actions of acute infusions of synthetic murine leptin in normotensive (Sprague-Dawley), hypertensive (spontaneously hypertensive), and obese (lean and obese Zucker) rat models. In the normotensive animals, an intravenous bolus of leptin produced a robust six- to sevenfold elevation in urinary sodium excretion and the fractional excretion of sodium. In contrast, the hypertensive and obese Zucker rats were refractory to the renal effects of leptin. Mean arterial pressure, creatinine clearance, urinary potassium excre-tion, plasma renin activity, and plasma aldosterone concentration remained unchanged with the acute infu-sion of the hormone in all the rat strains. Collectively, these findings were interpreted to suggest that leptin might be a natriuretic hormone primarily acting at the tubular level to promote sodium excretion in normal rats, and that it may function pathophysiologically in obesity and hypertension, where chronic hyperleptinemia may contribute to a preferential stimulation of the sym-pathetic nervous system with further elevation in blood pressure and reduced sodium excretion [2,13]. More-over, in rat models of diet-induced obesity that closely resemble human obesity, studies from our laboratory have shown markedly attenuated natriuretic and diuretic effects of synthetic leptin and markedly reduced urinary excretion of NO [2,7]. These findings suggest that in obesity, alterations in leptin-induced renal NO produc-tion and/or metabolism may account, at least in part, for the blunted natriuretic effects. However, additional observations in the diet-induced obese rats indicate that long-term caloric restriction was associated with restora-tion of the natriuretic actions of leptin and with the renal generation of NO [7]. In the aggregate, these studies are consistent with the concept that obesity is associated with renal leptin resistance, and this resistance, at least in part, is reversible with weight loss [14,35].

The significance of NO in the direct modulation or mediation of leptin-induced sodium excretion has been further investigated in anesthetized rats treated chroni-cally with L-NAME to inhibit NO production [36]. Under these conditions, an intravenous bolus of leptin to L-NAME–treated rats failed to produce significant natriuresis. However, the same rats chronically treated with L-NAME exhibited a two- to threefold elevation in sodium excretion induced by leptin with the restoration

of NO by sodium nitroprusside [36]. This natriuretic effect occurred in spite of a significant reduction in arterial blood pressure with consequential reduction in renal perfusion pressure. Thus, similar to the vascu-lature, these observations indicate that NO may play an important role in the tubular natriuretic effects of leptin through various potential mechanisms, including Na-K-2Cl cotransport inhibition, reduction of Na/H exchanger, or inhibition of Na channels [37].

Also pertinent to the involvement of NO in the media-tion of leptin-induced sodium excretion, Beltowski and Wojcicka [35] have suggested that leptin may produce a time- and dose-dependent reduction of renal medullary Na-K-ATPase, and this effect may be, at least in part, reg-ulated by NO [37]. In agreement with our observations described earlier, Beltowski and Wojcicka [35] reported that diet-induced obese rats display significant attenuation of leptin-induced stimulation of plasma NO, and impair-ment of leptin-mediated reductions in renal Na-K-ATPase and natriuresis. To date, the mechanisms for this renal resistance to leptin in obesity and hypertension are not completely defined, but may include receptor down-regu-lation [7,11], postreceptor signaling alterations [8,9,11], excessive degradation of NO produced by oxidative stress [2,22], or increased activation of the efferent renal sympa-thetic nervous system leading to antinatriuresis.

The latter hypothesis was examined by a study that evaluated the hemodynamic and renal excretory effects of leptin in anesthetized spontaneously hypertensive rats with either acute or chronic renal denervation [34]. In rats with acute renal denervation, an intravenous bolus of leptin produced a significant two- to fourfold eleva-tion in sodium excretion. Chronic renal denervation was associated with qualitatively and quantitatively similar increases in sodium excretion in response to leptin. Overall, the results of this investigation indicate that the sympathetic nervous system is an important counter-regulatory mechanism impeding leptin-induced sodium excretion in hypertension, and perhaps also during obe-sity, which is similarly characterized by a heightened sympathetic nervous tone [2,13].

The previously described in vivo studies that addressed the renal effects of leptin consisted of pharmacologic infusions of the hormone, and therefore the relevance of endogenous leptin as a distinct sodium-volume regulatory hormone remained undetermined. However, in separate studies, our laboratory recently addressed this question [38•]. Experiments were conducted in normal Sprague-Daw-ley rats that chronically received water ad libitum containing 0.9% saline for 7 consecutive days to produce mild sodium/volume expansion. Urinary sodium and volume excretion were significantly reduced by approximately 20% to 25% in the rats receiving a polyclonal antibody against leptin [38•] (Fig. 1). These results indicate that, under conditions of sodium and water surfeit, blockade of endogenous leptin significantly reduced natriuresis and diuresis, suggesting a

Cardiovascular and Renal Actions of Leptin Patel et al. 135

physiologic role for this hormone in the daily renal control of salt and water balance. In support of this concept, recent investigations indicate that leptin expression in adipose tis-sue is directly proportional to dietary sodium, a response that would be expected for mechanisms involved in the regu-lation of sodium balance [39].

Thus, the collective information suggests that leptin’s net effect on renal sodium metabolism may reflect both direct natriuretic and indirect antinatriuretic actions. The responsiveness to leptin at the renal, neural, and possi-bly other sites may differ under various physiologic and pathophysiologic conditions, and this, in turn, will deter-mine the overall magnitude of leptin-induced urinary sodium excretion.

Leptin and the HeartIt is now well recognized that the role of leptin in energy homeostasis extends to cardiac metabolism. The effects of leptin include inhibition of insulin signaling with enhanced lipid oxidation, and therefore inhibiting anabolic pathways and reducing energy storage. These actions are effected through LR, primarily the LRb variant, which has been demonstrated to exist in the heart [8,10,32].

Similar to the kidney, chronic hyperleptinemia may be important indirectly in the development of cardiac disease via sympathetic activation, pressor effects, enhancement of platelet aggregation, impairment of fibrinolysis, and pro-angiogenic effects [11,27,40,41]. In addition, and although still controversial, leptin may be involved in the pathogenesis of myocyte hypertrophy and cardiac dysfunction through direct actions. Indeed, leptin can proliferate, differentiate, and functionally activate hemopoietic and embryonic cells

to promote myocyte growth [42,43]. Among the suggested mechanisms involved are the stimulation of endothelin-1 and reactive oxygen species levels [44,45•]. It has been reported that this hypertrophic effect on ventricular myocytes, as evi-denced by increased cell surface area, protein synthesis, and expression of the fetal gene, -skeletal actin, and MLC-2,a constitutive gene, can occur with physiologically relevant concentrations of leptin [46].

In contrast to these investigations, however, histo-logic and echocardiographic studies in leptin-deficient (ob/ob) mice have suggested that leptin can exert pro-tective cardiac effects with reversal of baseline myocyte hypertrophy during leptin supplementation [47]. Rel-evant to this concept, Tajmir et al. [48] have indicated that leptin can activate extracellular signal-regulated kinases 1/2 and PI3K-dependent signaling pathway in cardiomyocytes to promote physiologic repair of myocar-dium. Presently, the reasons for the apparent discrepant effects of leptin on myocyte growth are unclear, but may be related to different experimental conditions, includ-ing the variable response of leptin in neonatal compared with adult cells, as well as the quantitatively and qualita-tively differential effects of leptin, depending on baseline metabolic background [49].

In addition to its potential actions on myocardial cell growth, leptin has been shown to exert a direct negative inotropic effect on adult rat ventricular myocytes [50]. The suggested mechanisms involve activation of fatty acid oxidation leading to decreased triglyceride con-tent, or an altered adenylate cyclase function [44,47]. Alternatively, Nickola et al. [50] reported that leptin may abnormally increase expression of NO synthases in cardiac myocytes, promoting oxidative stress and depressed cardiac function. Interestingly, this effect is blunted in the cardiomyocytes of the spontaneously hypertensive rat despite normal density of LR. This attenuated response, in turn, may be related to defec-tive NO synthesis in these rats [51].

The applicability of these studies to human physiology and pathophysiology are unclear, and presently only lim-ited information is available on the cardiac effects of the hormone in hyperleptinemic patients. Although evidence suggests a direct relationship between the hyperleptinemia of obesity with cardiac hypertrophy [43,52] and pos-sibly heart failure [53], these are not consistent findings [23•,54]. Moreover, the potential direct effects of leptin on cardiac myocytes may be worsened by the possible role of this hormone in the development of atherogenesis. The suggested mechanisms include the promotion of oxidative stress and oxidized low-density lipoprotein, and the gen-eration of prothrombotic and proinflammatory cytokines [26]. However, whether hyperleptinemia—independent of obesity or the metabolic syndrome—is associated with increased cardiovascular events remains controver-sial. Indeed, although the West of Scotland Coronary Prevention Study found a positive correlation between

UN

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in

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1500

500

1000

2500

2000

Leptin antibody vehicle

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E1E2

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*P < 0.05 vs correspondingperiod between groups

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Figure 1. Effects of leptin antibody or leptin antibody vehicle on urinary sodium excretion (UNaV) in Sprague-Dawley rats (n = 10 for each group). Values are means plus or minus SE. Experimental periods (E1 and E2) were 45 minutes each. *P < 0.05 versus cor-responding period between groups. (From Villarreal et al. [38•]; with permission.)

136 Hypertension and Metabolic Disarray: Diabetes Mellitus, Insulin Resistance, and Obesity

circulating leptin and the prediction of future coronary events, regardless of body mass index [55], the Quebec Cardiovascular Study failed to establish a relationship between leptin levels and ischemic heart disease [56]. Thus, it is clear that additional basic research and clinical studies are needed to better define and characterize the potential links between leptin and cardiac disease.

ConclusionsIt is well established that cardiovascular and renal func-tions require the activation of multiple neurohormonal mechanisms designed to maintain stability. Leptin, the recently discovered antiobesity hormone, has mul-tiple actions that may be important not only for energy metabolism, but also in physiologic and pathophysiologic cardiovascular and renal regulation (Fig. 2). Potentially prominent are its effects on renal sodium excretion, sym-pathetic nervous system activation, and vascular tone. The interaction among the vasoconstricting, vasodila-tory, and natriuretic effects of leptin that help to achieve volume and pressure homeostasis in normal conditions may be disrupted during chronic hyperleptinemia, an effect likely to contribute to hypertension. Further research awaits the characterization of additional direct and indirect mechanisms of action of leptin, including its interface with other important hormonal sodium-volume-pressure regulatory systems in both health and disease, particularly in obesity and related comorbidi-ties. This information could lead to the development of leptin analogues and LR blockers that, under specific circumstances, could optimize the beneficial actions of the hormone and minimize its deleterious effects.

DisclosuresNo potential conflicts of interest relevant to this article were reported.

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