Document Detail

Obesity hypertension: the regulatory role of leptin.
Jump to Full Text
MedLine Citation:
PMID:  21253519     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Leptin is a 16-kDa-peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake and elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. While the relevance of endogenous leptin needs further clarification, it appears to function as a pressure and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular, and cardiac damage.
Shilpa Kshatriya; Kan Liu; Ali Salah; Tamas Szombathy; Ronald H Freeman; Garry P Reams; Robert M Spear; Daniel Villarreal
Related Documents :
21160999 - Physiopathology of splanchnic vasodilation in portal hypertension.
6758179 - Comparison of salbutamol given by intermittent positive-pressure breathing and pressure...
8617069 - Energy metabolism of thoracic surgical patients in the early postoperative period. effe...
24085809 - The jugular venous pressure revisited.
21635959 - Elucidating the responses and role of the cardiovascular system in crocodilians during ...
22113799 - Exploring the piezophilic behavior of natural cosolvent mixtures.
15244799 - Effect of large hydrostatic pressure on the dielectric loss spectrum of type- a glass f...
4764429 - Systemic arterial baroreceptors in ducks and the consequences of their denervation on s...
25492829 - The effect of simvastatin and pravastatin on arterial blood pressure, baroreflex, vasoc...
Publication Detail:
Type:  Journal Article     Date:  2011-01-03
Journal Detail:
Title:  International journal of hypertension     Volume:  2011     ISSN:  2090-0392     ISO Abbreviation:  Int J Hypertens     Publication Date:  2011  
Date Detail:
Created Date:  2011-01-21     Completed Date:  2011-07-14     Revised Date:  2011-07-20    
Medline Journal Info:
Nlm Unique ID:  101538881     Medline TA:  Int J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  270624     Citation Subset:  -    
Department of Internal Medicine, SUNY Upstate Medical University, Veterans Affairs Medical Center, Syracuse, NY 13210, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Int J Hypertens
Journal ID (publisher-id): IJHT
ISSN: 2090-0392
Publisher: SAGE-Hindawi Access to Research
Article Information
Download PDF
Copyright © 2011 Shilpa Kshatriya et al.
Received Day: 27 Month: 9 Year: 2010
Accepted Day: 15 Month: 12 Year: 2010
collection publication date: Year: 2011
Electronic publication date: Day: 3 Month: 1 Year: 2011
Volume: 2011E-location ID: 270624
ID: 3022168
PubMed Id: 21253519
DOI: 10.4061/2011/270624

Obesity Hypertension: The Regulatory Role of Leptin
Shilpa Kshatriya1
Kan Liu1
Ali Salah1
Tamas Szombathy1
Ronald H. Freeman2
Garry P. Reams2
Robert M. Spear1
Daniel Villarreal1, 3I3*
1Department of Internal Medicine, SUNY Upstate Medical University, Veterans Affairs Medical Center, Syracuse, NY 13210, USA
2Department of Internal Medicine and Physiology, University of Missouri-Columbia, Columbia, MO 65212, USA
3Department of Medicine, Division of Cardiology, SUNY Upstate Medical University, Room 6142, 750 East Adams Street, Syracuse, NY 13210, USA
Correspondence: *Daniel Villarreal:
[other] Academic Editor: Vasilios Papademetriou

1. Introduction

The prevalence of obesity in the adult population of the United States has risen markedly in the last three decades, contributing to the increased incidence of diabetes, hypertension, and heart disease [13]. Indeed, epidemiological studies suggest that 65–75% of the risk for hypertension is attributed to excess weight [4, 5]. Recently, a novel and most promising area of research in obesity and hypertension that links these two pathologic conditions is the endocrinology of adipose tissue. It is now apparent that adipose tissue is a prolific organ which secretes several immunomodulators and bioactive molecules [3, 6]. Of these various factors, leptin has emerged as an important hormone with significant pleiotropic actions on several organ systems [7, 8].

The first described major action of leptin was on the hypothalamus to control body weight and fat deposition through its effects on appetite inhibition, as well as stimulation of the metabolic rate and thermogenesis [9, 10]. However, increasing evidence suggests that the biology of leptin extends to other organs including the kidney, the heart, the sympathetic nervous system, and the systemic vasculature, areas in which it may have prominent effects [7, 8, 1114].

2. Leptin Receptors: Localization and Function

The leptin receptor (LR), a product of the lepr gene, is a member of the extended class I cytokine receptor family having at least six splice variants LR (a-f) [1519]. Significant expression of the lepr gene occurs in the lung and adipocytes, while only moderate levels appear in the kidney, with relatively lower levels demonstrated in other tissues like the heart, brain, spleen, liver, and muscle [20]. Though the extracellular domain of the leptin receptor and the short splice variant (LRa) have been detected in many peripheral tissues, the long splice variant (LRb) is expressed in fewer organ systems including the adrenal gland, kidney, and heart [20]. This long splice variant leads to activation of the Janus Kinases (a family of tyrosine kinases) to promote transcription through activation of the STAT-3 (signal transduction and activator of transcription) and PI3K (phosphoinositol-3 kinase), and inhibition of AMPK (AMP-activated protein kinase) [1520]. LRa and LRb can also stimulate MAPK (mitogen activated protein kinase) which may be involved in the induction of hypertrophy [21]. Finally, SOCS-3 (suppression of cytokine signaling protein) and PTB1b (protein tyrosine phosphatase 1b) have been identified as negative regulators of leptin signaling [1519].

3. Leptin, Sympathetic Nervous System, and the Regulation of Arterial Blood Pressure

It is now well established that leptin can activate the sympathetic nervous system both by local peripheral actions as well as through centrally mediated effects on the hypothalamus [22]. Studies with direct infusion of leptin into the cerebral ventricles of normal rats have demonstrated a slow increase of mean arterial pressure (MAP) of approximately 10% [13]. Moreover, recent investigations have suggested that leptin signaling in the nucleus tracti solitarii increased renal sympathetic flow in normal rats but not in obese Zucker rats, indicating that intact leptin receptors are essential for this vasoactive response [22]. In agreement with these concepts, human studies have suggested that genetically mediated leptin deficiency is associated not only with morbid obesity, but also impairment in the sympathetic nervous system activity and postural hypotension in homozygous children and adults [23].

However, it is important to point out that in other investigations conducted both in normotensive as well as hypertensive rats [12, 14, 24], the acute systemic administration of leptin was associated with the peripheral activation of the sympathetic nervous system without elevation in MAP. This raises the possibility of the simultaneous local activation of counter-regulatory vasodilatory mechanisms [14, 25, 26]. In vitro studies have demonstrated a dose-dependent leptin-induced vasorelaxation in the aortic rings of Wistar-Kyoto rats [25] which is mediated by nitric oxide (NO) and possibly by endothelial-derived hyperpolarizing factor (EDHF). An elevation in plasma NO with intravenous administration of synthetic leptin in normal rats has also been demonstrated [26]. In these studies blockade of NO led to a leptin-induced enhancement of arterial blood pressure while blockade of the sympathetic nervous system led to leptin-mediated reduction in blood pressure [26]. Thus, leptin's lack of effect on arterial blood pressure in normal subjects may represent a balanced action of vasodilatation primarily mediated by NO and vasoconstriction primarily mediated by the sympathetic nervous system, with a resultant neutral hemodynamic effect [26, 27]. This concept requires further validation because the vasodilatory actions of leptin in other vascular beds have been found to be inconsistent [28, 29]. In high-calorie fed obese rats, however, recent studies by Beltowski et al have indicated that acutely infused leptin was associated with a hypertensive effect related, at least in part, to impaired vascular NO and EDHF production characteristic of obesity [30].

4. Chronic Hyperleptinemia, Leptin Resistance, and Hypertension

In chronic hyperleptinemic conditions such as obesity, the potential neutral effect of leptin on peripheral vascular resistance may no longer be present. It has been previously demonstrated that the agouti yellow obese mouse model is resistant to the satiety actions of leptin but not to the effects of leptin on the sympathetic nervous system [31, 32], although this stimulation may be attenuated with the progression of obesity [33]. From these findings, the concept of “selective leptin resistance” as a mechanism for the development of hypertension in obesity has emerged [31, 32]. The precise factors behind this selectivity are yet to be fully defined [32, 34], but may involve alterations in the SOCS3 signaling pathway or IRS-1 (insulin receptor substrate-1) serine residue phosphorylation [30, 35, 36].

Independent of the possibility of selective leptin resistance in obesity, studies in normal rats have demonstrated that chronic hyperleptinemia leads to a persistent elevation in MAP and this hypertensive effect is rapidly reversed upon cessation of the hormone administration [37]. Similar increases in systolic blood pressure have been demonstrated in transgenic mice overexpressing leptin where the endogenous level of the hormone was elevated twenty-fold [38]. In this regard, it is pertinent to point out that hyperleptinemia may increase vascular smooth muscle cell proliferation [38], an effect that could contribute to the development and/or perpetuation of hypertension. Moreover, mice with leptin deficiency (ob/ob) or with a leptin receptor defect (db/db) exhibit significant obesity but do not develop hypertension, suggesting that at least in animal models, leptin may play a role in the regulation of systemic hemodynamics [32]. In humans, emerging evidence suggests a direct relationship between hyperleptinemia and hypertension in both men and women [39, 40], and this effect may be independent of BMI and insulin resistance. In a recent study by Shankar and Xiao of 5,599 Americans, higher plasma leptin levels were positively associated with hypertension after adjusting for multiple covariates including age, sex, race/ethnicity, education, smoking, body mass index, diabetes mellitus, and serum cholesterol [41]. In this regard, recent studies indicating a reduction in serum leptin levels with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers suggest a potential interaction between leptin and the renin-angiotensin-aldosterone system for hemodynamic regulation in obesity [42, 43].

Finally, an additional potential mechanism involved in leptin's regulation of blood pressure implicates the melanocortin system [44]. Recent investigations have suggested that the acute actions of leptin to raise renal sympathetic activity are abolished in Melanocortin 4 receptor-(MC4R-) deficient (−/−) mice, suggesting that the MC4R may mediate the sympathoexcitatory actions of leptin [45]. To this end, Greenfield et al. demonstrated a lower prevalence of hypertension in obese subjects with a loss-of-function mutation in MC4R gene compared to obese controls with the intact gene again implicating melanocortinergic signaling in the control of systemic hemodynamics [46].

5. Leptin and the Regulation of Sodium-Volume Balance

Previous studies have indicated that the LRb leptin receptor is localized in the renal medulla [20, 47] which suggests a functional role of this hormone in renal biology. In the last 5–10 years, numerous studies have demonstrated that acute administration of synthetic leptin in the rat produces a significant elevation in urinary sodium and water excretion [14, 4749].

Villarreal et al. [14] demonstrated that in normotensive rats, an intravenous bolus of leptin produced a robust six to sevenfold elevation in urinary sodium excretion and fractional excretion of sodium; in contrast, hypertensive rats were refractory to the renal effects of leptin. Interestingly, the natriuretic effect was attenuated in obese Zucker rats [14]. MAP and creatinine clearance remained unchanged in all of the rat strains with the acute infusion of the hormone. Collectively, these findings were interpreted to suggest that leptin might be a natriuretic hormone primarily acting at the tubular level for promotion of sodium and water excretion in normal rats, and that leptin may function pathophysiologically in obesity and hypertension, where chronic hyperleptinemia may contribute to a preferential stimulation of the sympathetic nervous system with further elevation in blood pressure and reduced sodium and water excretion [2, 7, 50]. Moreover, in a rat model of diet-induced obesity, initial studies by Patel et al. have shown markedly attenuated natriuretic and diuretic effects of synthetic leptin as well as reduced urinary excretion of NO [51]. These findings suggest that in obesity, alterations in leptin-induced renal NO production and/or metabolism may account, at least in part, for the blunted natriuretic effects. However, additional observations in diet-induced obese rats indicate that caloric restriction was associated with the restoration of the natriuretic actions of leptin as well as with the renal generation of NO [51]. In the aggregate, these studies are consistent with the concept that obesity is associated with renal leptin resistance [14, 52], and this resistance, at least in part, is reversible with caloric restriction and weight loss.

The significance of NO in the direct modulation of leptin-induced sodium excretion has been investigated in rats chronically treated with L-NAME to inhibit NO production [53]. L-NAME-treated rats failed to produce significant natriuresis. However, there was a two to threefold elevation in sodium excretion induced by leptin with the restoration of NO by sodium nitroprusside [53], indicating that NO may play an important role in mediating or modulating the tubular natriuretic effects of leptin. These observations are supported by the studies of Beltowski et al., [52] which demonstrated that leptin produces a time- and dose-dependent reduction of renal medullary Na-K-ATPase, which may in part be regulated by NO [53, 54]. Beltowski et al., [52] also reported that in diet-induced obese rats, leptin-induced stimulation of plasma NO, reduction of renal Na-K-ATPase, and natriuresis are all significantly impaired.

The mechanisms for renal resistance to leptin in obesity and hypertension are not completely defined but may include receptor down regulation [12, 51], postreceptor signaling alterations [12, 16, 17], excessive degradation of NO produced by oxidative stress [55], or increased activation of the efferent renal sympathetic nervous system leading to antinatriuresis [49]. Indeed, studies which [49] have examined this latter hypothesis using an animal model of renal denervation indicate that the renal efferent sympathetic nervous system is an important counter-regulatory mechanism impeding leptin-induced sodium excretion in hypertension, and perhaps also during obesity, which is similarly characterized by a heightened sympathetic nervous tone [2, 7].

The relevance of endogenous leptin as a distinct sodium-volume regulatory hormone has been examined in normal Sprague Dawley rats that were in a state of mild sodium/volume expansion [56]. Urinary sodium and volume excretion were significantly reduced by approximately 20–25% after blockade of leptin with a polyclonal antibody, indicating an important physiologic role for this hormone in the daily renal control of salt and water balance. The importance of leptin as a regulator of sodium and volume is further supported by recent investigations [56, 57] which have demonstrated that leptin expression in adipose tissue is directly proportional to dietary sodium, a response that would be expected for mechanisms regulating sodium balance.

Thus, the available information to date suggests that leptin's net effect on renal sodium metabolism and ultimately systemic hemodynamics may reflect both direct natriuretic and indirect antinatriuretic actions. The responsiveness to leptin at neural, renal, and other sites which regulate natriuresis and vascular resistance may differ under diverse physiological and pathophysiological conditions, and this in turn, will be a determinant for the overall magnitude of leptin-induced sodium, water, and hemodynamic balance.

6. Leptin and Chronic Renal Insufficiency

Leptin's role in renal physiology and pathophysiology is complex. As previously discussed, leptin may play a significant role in the regulation of sodium and water balance in normal situations. However, in conditions of chronic hyperleptinemia, the hormone has been linked to renal structural changes that specifically have been associated with obesity [58]. Elegant studies by Wolf et al. [59] have determined that in glomerular endothelial cells, leptin can stimulate cellular proliferation, expression of TGF-β1 and type IV collagen synthesis leading to fibrosis. Indeed, chronic infusion of leptin in normal rats promoted the development of glomerulosclerosis and proteinuria [59]. It is of interest that similar renal abnormalities have been found in mice with chronic high fat diet and the metabolic syndrome [60], which is characterized by sustained elevations of circulating leptin [61].

Inappropriate elevation in serum leptin levels has been demonstrated in patients with chronic kidney disease [6264]. The origin and significance of hyperleptinemia in these patients are not completely defined, but it is important to emphasize that the marked elevation of leptin is out of proportion to obesity and persists after correction for body mass index [65]. Since the kidney is involved in clearance of leptin, its elevated levels in renal insufficiency are primarily due to reduced renal filtration and metabolism [62, 66]. It remains to be determined whether an increased rate of leptin production also contributes to the high serum leptin levels in renal insufficiency.

Leptin levels appear to be higher in patients receiving peritoneal dialysis (PD) compared to hemodialysis (HD) [67]. The reasons for this phenomenon are multifactorial. It is likely that the elevated body fat mass in patients with PD contributes to the increase in serum leptin [67]. However, other factors are probably involved. For instance, the continuous glucose load in PD results in chronic hyperinsulinemia, an important finding considering that insulin upregulates lepr gene expression [63]. In this regard, it is of interest that even higher leptin levels are observed in patients with renal insufficiency with elevated insulin levels compared to patients with low insulin levels [63, 68].

The pathophysiological significance of hyperleptinemia in renal insufficiency is not completely understood. High levels of leptin have been associated with weight loss in dialysis patients [65, 6971], and therefore it has been suggested that hyperleptinemia may be a contributing factor in uremic-induced cachexia [64, 6974]. Other suggested actions in patients with end-stage renal disease which include leptin-induced reduction in erythropoiesis [75, 76], promotion of renal osteodystrophy [77, 78], and chronic inflammation [63, 78, 79].

7. Leptin and the Heart

It is now well recognized that the role of leptin in energy homeostasis extends into cardiac metabolism. The effects of leptin mediated by the LRb receptor include a reduction of insulin signaling with enhanced lipid oxidation and therefore inhibition of anabolic pathways [80]. Similar to the kidney, chronic hyperleptinemia may be indirectly important in the development of cardiac disease via sympathetic activation, pressor effects, enhancement of platelet aggregation, impairment of fibrinolysis as well as proangiogenic actions [12, 35, 81, 82] and systemic inflammation via leptin-induced expression of C-reactive protein [83, 84].

In addition, and although still controversial, leptin may be involved in the pathogenesis of myocyte hypertrophy and cardiac dysfunction [8587] through direct effects. Indeed, leptin can proliferate, differentiate, and functionally activate hemopoietic and embryonic cells to promote myocyte growth [8890]. Moreover, in rats with myocardial infarction, cardiac hypertrophy has been shown to be attenuated with the blockade of leptin receptors [91]. Among the suggested mechanisms of leptin-induced hypertrophy are the stimulation of endothelin-1, angiotensin II [92], and reactive oxygen species [93]. Additional studies in rats with myocardial infarction have also indicated that long-term continuous administration of leptin promoted the development of eccentric cardiac hypertrophy [94].

In contrast to these investigations, studies in leptin-deficient mice (ob/ob) with [94, 95] or without myocardial infarction [96] have suggested that leptin can exert protective cardiac effects with reversal of baseline myocyte hypertrophy during leptin supplementation [96]. Also, Tajmir et al. [97] have indicated that leptin can activate ERK 1/2 (extracellular signal-regulated kinase) and phosphoinositol-3 kinase-dependent signaling pathways in cardiomyocytes to promote physiological repair of myocardium. Presently, the reasons for the apparent discrepant effects of leptin on myocyte growth are unclear, but may be related to different experimental conditions, including the variable response of leptin in neonatal compared to adult cells [8297].

In addition to its potential actions on myocardial cell growth, leptin has been shown to exert direct negative inotropic effects on adult rat ventricular myocytes [98]. The suggested mechanisms involve activation of fatty acid oxidation leading to decreased triglyceride content or an altered adenylate cyclase function [96, 99]. Alternatively, Nickola et al. [98] reported that leptin may abnormally increase expression of Nitric Oxide Synthases in cardiac myocytes promoting oxidative stress and depressed cardiac function. However, similar to the controversy related to cardiac hypertrophy, more recent studies in ob/ob mice [95] or rats [94] with myocardial infarction have suggested that leptin may attenuate adverse cardiac remodeling by reducing apoptosis [95], which may improve left ventricular contractile function, and at least in part, increase survival [9496].

The relevance of these studies in humans is unclear. Although there is evidence to suggest a direct relationship between the hyperleptinemia of obesity with cardiac hypertrophy [96, 100], and possibly heart failure [101], these are not consistent findings [8, 11]. Additional in vitro and in vivo studies are needed to define and characterize the potential beneficial or deleterious effects of leptin in cardiac physiology and pathophysiology.

8. Summary and Conclusions

It is well established that cardiovascular and renal functions require the activation of multiple neuro hormonal mechanisms designed to maintain homeostasis. The hormone leptin has multiple actions that may be important not only for energy metabolism, but also in physiological and pathophysiological cardiovascular and renal regulation (Figure 1). Potentially prominent are its effects on renal sodium excretion, NO, sympathetic nervous system activation, and vascular tone. The interaction among the vasoconstricting, vasodilatory, and natriuretic effects of leptin to help achieve volume and pressure homeostasis in normal conditions may be disrupted during chronic hyperleptinemia, and this effect could likely contribute to hypertension and possible cardiac and renal dysfunction. Further research awaits the additional characterization of both 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 states, particularly obesity and related comorbidities.


This paper is supported in part by the Veteran Affairs Research Program (Merit Review), the Joseph C. Georg Research Award, and the Hendricks Research Award. The authors wish to acknowledge the expert technical assistance Jeffrey Montalbano.

1. Ogden CL,Carroll MD,Curtin LR,McDowell MA,Tabak CJ,Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004Journal of the American Medical AssociationYear: 2006295131549155516595758
2. Hall JE,Crook ED,Jones DW,Wofford MR,Dubbert PM. Mechanisms of obesity-associated cardiovascular and renal diseaseAmerican Journal of the Medical SciencesYear: 2002324312713712240710
3. Hajer GR,Van Haeften TW,Visseren FLJ. Adipose tissue dysfunction in obesity, diabetes, and vascular diseasesEuropean Heart JournalYear: 200829242959297118775919
4. Garrison RJ,Kannel WB,Stokes J,Castelli WP. Incidence and precursors of hypertension in young adults: the Framingham offspring studyPreventive MedicineYear: 19871622352513588564
5. Wofford MR,Hall JE. Pathophysiology and treatment of obesity hypertensionCurrent Pharmaceutical DesignYear: 200410293621363715579059
6. Hutley L,Prins JB. Fat as an endocrine organ: relationship to the metabolic syndromeAmerican Journal of the Medical SciencesYear: 2005330628028916355012
7. Guha PK,Villarreal D,Reams GP,Freeman RH. Role of leptin in the regulation of body fluid volume and pressuresAmerican Journal of TherapeuticsYear: 200310321121812756428
8. Sharma V,McNeill JH. The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiologyCurrent Vascular PharmacologyYear: 20053216918015853636
9. Misra A,Garg A. Leptin, its receptor and obesityJournal of Investigative MedicineYear: 19964495405489035607
10. Lönnqvist F. The obese (ob) gene and its product leptin—a new route toward obesity treatment in man?Monthly Journal of the Association of PhysiciansYear: 1996895327332
11. Bełtowski J. Role of leptin in blood pressure regulation and arterial hypertensionJournal of HypertensionYear: 200624578980116612235
12. Haynes WG,Morgan DA,Walsh SA,Mark AL,Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptinJournal of Clinical InvestigationYear: 199710022702789218503
13. Dunbar JC,Hu Y,Lu H. Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal ratsDiabetesYear: 19974612204020439392493
14. Villarreal D,Reams G,Freeman RH,Taraben A. Renal effects of leptin in normotensive, hypertensive, and obese ratsAmerican Journal of PhysiologyYear: 19982756R2056R20609843897
15. Chen H,Charlat O,Tartaglia LA,et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db miceCellYear: 19968434914958608603
16. Banks AS,Davis SM,Bates SH,Myers MG. Activation of downstream signals by the long form of the leptin receptorJournal of Biological ChemistryYear: 200027519145631457210799542
17. Münzberg H,Myers MG. Molecular and anatomical determinants of central leptin resistanceNature NeuroscienceYear: 200585566570
18. Tartaglia LA,Dembski M,Weng X,et al. Identification and expression cloning of a leptin receptor, OB-RCellYear: 1995837126312718548812
19. Wang MY,Zhou YT,Newgard CB,Unger RH. A novel leptin receptor isoform in ratFEBS LettersYear: 1996392287908772180
20. Hoggard N,Mercer JG,Rayner DV,Moar K,Trayhurn P,Williams LM. Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridizationBiochemical and Biophysical Research CommunicationsYear: 199723223833879125186
21. Anubhuti V,Arora S. Leptin and its metabolic interactions—an updateDiabetes, Obesity and MetabolismYear: 20081011973993
22. Mark AL,Agassandian K,Morgan DA,Liu X,Cassell MD,Rahmouni K. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidneyHypertensionYear: 200953237538019103999
23. Ozata M,Ozdemir IC,Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defectsJournal of Clinical Endocrinology and MetabolismYear: 199984103686369510523015
24. Bełtowski J,Jochem J,Wójcicka G,Zwirska-Korczala K. Influence of intravenously administered leptin on nitric oxide production, renal hemodynamics and renal function in the ratRegulatory PeptidesYear: 20041201–3596715177921
25. Lembo G,Vecchione C,Fratta L,et al. Leptin induces direct vasodilation through distinct endothelial mechanismsDiabetesYear: 200049229329710868946
26. Frühbeck G. Pivotal role of nitric oxide in the control of blood pressure after leptin administrationDiabetesYear: 199948490390810102710
27. Brook RD,Bard RL,Bodary PF,et al. Blood pressure and vascular effects of leptin in humansMetabolic Syndrome and Related DisordersYear: 20075327027418370781
28. Mitchell JL,Morgan DA,Correia MLG,Mark AL,Sivitz WI,Haynes WG. Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation?HypertensionYear: 20013851081108611711501
29. Gardiner SM,Kemp PA,March JE,Bennett T. Regional haemodynamic effects of recombinant murine or human leptin in conscious ratsBritish Journal of PharmacologyYear: 2000130480581010864886
30. Bełtowski J,Wójcicka G,Jamroz-Wiśniewska A,Marciniak A. Resistance to acute NO-mimetic and EDHF-mimetic effects of leptin in the metabolic syndromeLife SciencesYear: 20098515-1655756719686764
31. Mark AL,Shaffer RA,Correia MLG,Morgan DA,Sigmund CD,Haynes WG. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese miceJournal of HypertensionYear: 199917121949195310703894
32. Correia MLG,Haynes WG,Rahmouni K,Morgan DA,Sivitz WI,Mark AL. The concept of selective leptin resistance: evidence from agouti yellow obese miceDiabetesYear: 200251243944211812752
33. Morgan DA,Thedens DR,Weiss R,Rahmouni K. Mechanisms mediating renal sympathetic activation to leptin in obesityAmerican Journal of PhysiologyYear: 20082956R1730R173618815209
34. Rahmouni K,Correia MLG,Haynes WG,Mark AL. Obesity-associated hypertension: New insights into mechanismsHypertensionYear: 200545191415583075
35. Tune JD,Considine RV. Effects of leptin on cardiovascular physiologyJournal of the American Society of HypertensionYear: 20071423124118670590
36. Bjorbaek C,Elmquist JK,Frantz JD,Shoelson SE,Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistanceMolecular CellYear: 1998146196259660946
37. Shek EW,Brands MW,Hall JE. Chronic leptin infusion increases arterial pressureHypertensionYear: 19983114094149453337
38. Huang F,Xiong X,Wang H,You S,Zeng H. Leptin-induced vascular smooth muscle cell proliferation via regulating cell cycle, activating ERK1/2 and NF-κBActa Biochimica et Biophysica SinicaYear: 201042532533120458445
39. Galletti F,D’Elia L,Barba G,et al. High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an eight-year follow-up studyJournal of Clinical Endocrinology and MetabolismYear: 200893103922392618682500
40. Ma D,Feitosa MF,Wilk JB,et al. Leptin is associated with blood pressure and hypertension in women from the National Heart, Lung, and Blood Institute family heart studyHypertensionYear: 200953347347919204185
41. Shankar A,Xiao J. Positive relationship between plasma leptin level and hypertensionHypertensionYear: 201056462362820713919
42. Fogari R,Derosa G,Zoppi A,et al. Comparison of the effects of valsartan and felodipine on plasma leptin and insulin sensitivity in hypertensive obese patientsHypertension ResearchYear: 200528320921416097363
43. Santos EL,de Picoli Souza K,da Silva ED,et al. Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in ratsBiochemical PharmacologyYear: 200978895195819549507
44. Haynes WG,Morgan DA,Djalali A,Sivitz WI,Mark AL. Interactions between the melanocortin system and leptin in control of sympathetic nerve trafficHypertensionYear: 1999331, part 25425479931162
45. Rahmouni K,Haynes WG,Morgan DA,Mark AL. Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulinJournal of NeuroscienceYear: 200323145998600412853417
46. Greenfield JR,Miller JW,Keogh JM,et al. Modulation of blood pressure by central melanocortinergic pathwaysNew England Journal of MedicineYear: 20093601445219092146
47. Serradeil-Le Gal C,Raufaste D,Brossard G,et al. Characterization and localization of leptin receptors in the rat kidneyFEBS LettersYear: 19974042-31851919119061
48. Jackson EK,Li P. Human leptin has natriuretic activity in the ratAmerican Journal of PhysiologyYear: 19972723F333F3389087676
49. Villarreal D,Reams G,Freeman RH. Effects of renal denervation on the sodium excretory actions of leptin in hypertensive ratsKidney InternationalYear: 200058398999410972663
50. DiBona GF. The kidney in the pathogenesis of hypertension: the role of renal nervesAmerican Journal of Kidney DiseasesYear: 198554A27A313993645
51. Patel S,Villarreal D,Kundra A,et al. Cardiovascular and renal actions of leptinCardiac HormonesYear: 2008111127
52. Bełtowski J,Wójcicka G,Górny D,Marciniak A. Human leptin administered intraperitoneally stimulates natriuresis and decreases renal medullary Na, K-ATPase activity in the rat—impaired effect in dietary-induced obesityMedical Science MonitorYear: 200286BR221BR22912070427
53. Villarreal D,Reams G,Samar H,Spear R,Freeman RH. Effects of chronic nitric oxide inhibition on the renal excretory response to leptinObesity ResearchYear: 20041261006101015229341
54. Lin L,Martin R,Schaffhauser AO,York DA. Acute changes in the response to peripheral leptin with alteration in the diet compositionAmerican Journal of PhysiologyYear: 20012802R504R50911208581
55. Bouloumié A,Marumo T,Lafontan M,Busse R. Leptin induces oxidative stress in human endothelial cellsFASEB JournalYear: 199913101231123810385613
56. Dobrian AD,Schriver SD,Lynch T,Prewitt RL. Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesityAmerican Journal of PhysiologyYear: 20032854F619F62812799306
57. Adamczak M,Kokot F,Chudek J,Wiecek A. Effect of renin-angiotensin system activation by dietary sodium restriction and upright position on plasma leptin concentration in patients with essential hypertensionMedical Science MonitorYear: 200287CR473CR47712118193
58. Wolf G,Ziyadeh FN. Leptin and renal fibrosisContributions to NephrologyYear: 200615117518316929141
59. Wolf G,Chen S,Han DC,Ziyadeh FN. Leptin and renal diseaseAmerican Journal of Kidney DiseasesYear: 200239111111774095
60. Deji N,Kume S,Araki SI,et al. Structural and functional changes in the kidneys of high-fat diet-induced obese miceAmerican Journal of PhysiologyYear: 20092961F118F12618971213
61. Gannagé-Yared MH,Khalife S,Semaan M,Fares F,Jambart S,Halaby G. Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly menEuropean Journal of EndocrinologyYear: 2006155116717616793964
62. Sharma K,Considine RV,Michael B,et al. Plasma leptin is partly cleared by the kidney and is elevated in hemodialysis patientsKidney InternationalYear: 1997516198019859186891
63. Nordfors L,Lönnqvist F,Heimbürger O,Danielsson A,Schalling M,Stenvinkel P. Low leptin gene expression and hyperleptinemia in chronic renal failureKidney InternationalYear: 1998544126712759767543
64. Stenvinkel P,Lönnqvist F,Schalling M. Molecular studies of leptin: implications for renal diseaseNephrology Dialysis TransplantationYear: 199914511031112
65. Heimbürger O,Lönnqvist F,Danielsson A,Nordenström J,Stenvinkel P. Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failureJournal of the American Society of NephrologyYear: 199789142314309294834
66. Cumin F,Baum H-P,De Gasparo M,Levens N. Removal of endogenous leptin from the circulation by the kidneyInternational Journal of ObesityYear: 19972164955049192234
67. Johansen KL,Mulligan K,Tai V,Schambelan M. Leptin, body composition, and indices of malnutrition in patients on dialysisJournal of the American Society of NephrologyYear: 199896108010849621292
68. Stenvinkel P,Heimbürger O,Lönnqvist F. Serum leptin concentrations correlate to plasma insulin concentrations independent of body fat content in chronic renal failureNephrology Dialysis TransplantationYear: 199712713211325
69. Fontan MP,Rodriguez-Carmona A,Cordido F,Garcia-Buela J. Hyperleptinemia in uremic patients undergoing conservative management, peritoneal dialysis, and hemodialysis: a comparative analysisAmerican Journal of Kidney DiseasesYear: 199934582483110561137
70. Bossola M,Tazza L,Giungi S,Luciani G. Anorexia in hemodialysis patients: an updateKidney InternationalYear: 200670341742216775598
71. Stenvinkel P,Lindholm B,Lönnqvist F,Katzarski K,Heimbürger O. Increases in serum leptin levels during peritoneal dialysis are associated with inflammation and a decrease in lean body massJournal of the American Society of NephrologyYear: 20001171303130910864587
72. Odamaki M,Furuya R,Yoneyama T,et al. Association of the serum leptin concentration with weight loss in chronic hemodialysis patientsAmerican Journal of Kidney DiseasesYear: 199933236136810023651
73. Mak RH,Cheung W,Cone RD,Marks DL. Leptin and inflammation-associated cachexia in chronic kidney diseaseKidney InternationalYear: 200669579479716518340
74. Cheung W,Yu PX,Little BM,Cone RD,Marks DL,Mak RH. Role of leptin and melanocortin signaling in uremia-associated cachexiaJournal of Clinical InvestigationYear: 200511561659166515931394
75. Axelsson J,Qureshi AR,Heimbürger O,Lindholm B,Stenvinkel P,Bárány P. Body fat mass and serum leptin levels influence epoetin sensitivity in patients with ESRDAmerican Journal of Kidney DiseasesYear: 200546462863416183417
76. Hung SC,Tung TY,Yang CS,Tarng DC. High-calorie supplementation increases serum leptin levels and improves response to rHuEPO in long-term hemodialysis patientsAmerican Journal of Kidney DiseasesYear: 20054561073108315957137
77. Coen G,Ballanti P,Fischer MS,et al. Serum leptin in dialysis renal osteodystrophyAmerican Journal of Kidney DiseasesYear: 20034251036104214582047
78. Mallamaci F,Tripepi G,Zoccali C. Leptin in end stage renal disease (ESRD): a link between fat mass, bone and the cardiovascular systemJournal of NephrologyYear: 200518446446816245256
79. Zoccali C,Mallamaci F,Tripepi G. Adipose tissue as a source of inflammatory cytokines in health and disease: focus on end-stage renal diseaseKidney International, SupplementYear: 20036384S65S6812694312
80. Emilsson V,Liu YL,Cawthorne MA,Morton NM,Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretionDiabetesYear: 19974623133169000710
81. Konstantinides S,Schäfer K,Koschnick S,Loskutoff DJ. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesityJournal of Clinical InvestigationYear: 2001108101533154011714745
82. Sierra-Honigmann MR,Nath AK,Murakami C,et al. Biological action of leptin as an angiogenic factorScienceYear: 19982815383168316869733517
83. Singh P,Hoffmann M,Wolk R,Shamsuzzaman ASM,Somers VK. Leptin induces C-reactive protein expression in vascular endothelial cellsArteriosclerosis, Thrombosis, and Vascular BiologyYear: 2007279e302e307
84. Romero-Corral A,Sierra-Johnson J,Lopez-Jimenez F,et al. Relationships between leptin and C-reactive protein with cardiovascular disease in the adult general populationNature Clinical Practice Cardiovascular MedicineYear: 200857418425
85. Karmazyn M,Purdham DM,Rajapurohitam V,Zeidan A. Leptin as a cardiac hypertrophic factor: a potential target for therapeuticsTrends in Cardiovascular MedicineYear: 200717620621117662916
86. Rajapurohitam V,Gan XT,Kirshenbaum LA,Karmazyn M. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytesCirculation ResearchYear: 200393427727912893740
87. Selthofer-Relatić K,Radić R,Vizjak V,et al. Hyperleptinemia—non-haemodynamic risk factor for the left ventricular hypertrophy development in hypertensive overweight femalesCollegium AntropologicumYear: 200832368168518982737
88. Umemoto Y,Tsuji K,Yang FC,et al. Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cellsBloodYear: 1997909343834439345027
89. Paolisso G,Tagliamonte MR,Galderisi M,et al. Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant menHypertensionYear: 19993451047105210567180
90. Leyva F,Anker SD,Egerer K,Stevenson JC,Kox WJ,Coats AJS. Hyperleptinaemia in chronic heart failure. Relationships with insulinEuropean Heart JournalYear: 19981910154715519820994
91. Purdham DM,Rajapurohitam V,Zeidan A,Huang C,Gross GJ,Karmazyn M. A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heartAmerican Journal of PhysiologyYear: 20082951H441H44618469142
92. Rajapurohitam V,Javadov S,Purdham DM,Kirshenbaum LA,Karmazyn M. An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1Journal of Molecular and Cellular CardiologyYear: 200641226527416806260
93. Nagae AI,Fujita M,Kawarazaki H,Matsui H,Ando K,Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertensionCirculationYear: 2009119797898619204299
94. Abe Y,Ono K,Kawamura T,et al. Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensationAmerican Journal of PhysiologyYear: 20072925H2387H239617220191
95. Mcgaffin KR,Zou B,Mctiernan CF,O’donnell CP. Leptin attenuates cardiac apoptosis after chronic ischaemic injuryCardiovascular ResearchYear: 200983231332419233863
96. Barouch LA,Berkowitz DE,Harrison RW,O’Donnell CP,Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in miceCirculationYear: 2003108675475912885755
97. Tajmir P,Ceddia RB,Li RK,Coe IR,Sweeney G. Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathwaysEndocrinologyYear: 200414541550155514715711
98. Nickola MW,Wold LE,Colligan PB,Wang GJ,Samson WK,Ren J. Leptin attenuates cardiac contraction in rat ventricular myocytes role of NOHypertensionYear: 200036450150511040226
99. Luo JD,Zhang GS,Chen MS. Leptin and cardiovascular diseasesDrug News and PerspectivesYear: 200518742743116362081
100. Tritos NA,Manning WJ,Danias PG. Role of leptin in the development of cardiac hypertrophy in experimental animals and humansCirculationYear: 20041097p. e67
101. Schulze PC,Kratzsch J,Linke A,et al. Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failureEuropean Journal of Heart FailureYear: 200351334012559213

Article Categories:
  • Review Article

Previous Document:  The natural history of globus pharyngeus.
Next Document:  Role of the rostral ventrolateral medulla in the arterial hypertension in chronic renal failure.