Nutrition, Metabotism& Cardiovascutar Diseases(2012\22,300-306 a v a i l a b l e a t w w w . s c i e n c e d ir e c t . c o m Nutrition, ScienceDirect ELSEVIER Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd Hyperleptinemia is associated with hypertension, systemicinflammationand insulinresistance in overweightbut not in normalweightmen F. Galletti''_*,L. D'Elia", D. De Palmd',o. Russo ", G. Barbao, A. siani M.A.Miller', F.P.cappuccio',G. Rossi", G. Zampau,p. strazzullo' aDepartment of Clinical and ExperimentallAedicine, ESHExcellenceCenterfor Hypertension, Federicoll Universityof Naples(l), Via S. Ponsini,5, 80131Naples,ltaly " Institute of Food Sciences,CNR,Avellino (l), ttaly 'Clinicol Sciences Reseorchlnstitute, IJniversityof Warwick, IJK Received4 January2011; receivedin revisedform 26 Aprit 2011; accepted2g May 2011 KEYWORDS Leptin; Hypertension; Obesity; Insulinresistance; Adipocytokines Abstract Background and .Aim:Highteptin (LPI) is associated with highbtoodpressure(Bp), insulinresistance and systemicinflammationbut atsoexcessbodyweightand adiposity.To disentangte thesemultipteretations,we analyzedBP,HOMAandcircutatingC-reactiveprotein concentration (hs-CRP) in whitemaleadultswith differentLPTtevetsbut simitarage,bodymass index(BMl)andbodyfat distribution. Thenovelaspectis the differentstatistical approach used to investigatethe retationbetweenLPTand the other atterationspresentin obesity. tlethodsand Results:972OLivettiHeartStudyparticipantswere stratifiedaccordingto the medianLPTdistribution (2.97ng/mt)into towLpr (t-Lpr)andhighLpr (h-Lpr).Thetwo groups werethencarefutlymatchedfor ageandBMl.Weidentifiedtwo groupsof 207h-LpTand207tLPTindividuats with overlapping age,BMIandwaist/hipratio.Thetwo groupshaddifferentBp (132.9+ 16.2/85.7 * 9.0vs 128.7+ 18.2/82.8,1 9.8mmHg,p : 0.014for sBpandp : 0.002for DBP)and prevalence of hypertension (57%vs43%,p : O.OZ7\. Uponseparateevaluationof untreatedindividuals with BMI< 25or BMI> 25,withinthe tattersubgroup h-LPT compared with I-LPTparticipants (n : I 33eachgroup)hadhigherBp(p : 0.0001 ), HOIMindex(p : 0.013), hs_ CRP(p : 0.002)andheartrate (p : 0.008)despitesimitarageandBMt.Bycontrast,withinthe normaIweightsubgroup, h-LPTindividuats did not differ from t-Lpr (n : 37 each)for anyof thesevariabtes. Conclusions: HighLPT'is associated with higherBP,HR,hs-CRP andHOIMindexindependentty of BMIandfat distribution but onlyamongoverweight individuats. O 20'11 EtsevierB.V.Att riqhtsreserved. . Corresponding author. Tet./fax: +39 81 7464301. E-mail address:gatletti@unina.it(F. Gattetti). 0939-4753/S- see front matter @ 2011 EtsevierB.V.Att rishts reserved. d o i : 10 .10 16 / j . n u m e c d . 2 01.10 5 . 0 0 7 Hyperteptinerniaassociationwith hypertension,systemicinflammationand insulin resistance 301 Introduction Examinationprocedures Leptin (LPT) is produced by differentiated adipocytes in white adiposetissue, but also in other organswith a large contribution of brain and with greater LPTreleasein obese than in lean men [1]. lts main and better known physiotogicat effect, mediated by specific structures in the hypothatamus,is the suppressionof the desirefor food and the increment of energy expenditureby a sympatheticatty mediatedrise of thermogenesisin brown adiposetissue[2]. In addition, leptin exerts a beneficial effect on insulin sensitivity [3] but atso behaves as a proinflammatory substance [4] together with other molecules produced within the adipose tissue [5]. Obesity is associatedwith etevatedptasmaLPTtevets,the higherthe BMIor the waist circumferencethe higherthe serumLPTlevet [6]. However, the main metaboticactionsof LPTare targelyineffective in this disorder, a condition referred to as leptin resistance and resembtingthe conditionof insutinresistanceobserved in the sameindividuats[2]. We have previouslyreported that circulatingptasmaLPT levels were directty associatedwith BP values in a crosssectionalsetting [7] and these data are been atsoconfirmed [8]. In addition were able to predict the risk to develop arterial hypertension[9] and metabolicsyndrome[10] in a prospective cohort investigation. These findings supported the hypothesis raised by the resutts of previous studiesin animal modetsof a pathogenicrole of hyperleptinemiaand/or leptin resistancein hypertension. Given the strong relationship of plasma teptin with excess body weight and adiposity, we decided to disentanglethese relations,analyzingBP,HOMAand circulating C-reactiveprotein concentration(hs-CRP)in white male adults with different LPT tevetsbut with overlappingage, body massindex (BMl)and bodyfat distribution.The novel aspect is the different statistical approachused to investigate the relation between LPTand the other alterations present in obesity. The opportunity was atso taken to evaluate the associationsof plasmaLPT tevetswith known indicatorsof insulinresistance(HOMAindex)and low grade systemicinflammation(hs-CRP) in the samesetting. Bodyweight and height were measuredon a standardbeam balance scale with an attached ruler. Body weight was measuredto the nearest 0.1 kg and body height was measuredto the nearest 1.0 cm, with subjectswearing tight indoor clothing without shoes. BMI was catcutated accordingto the standardformula. Overweightwas defined as a BMI > 25. The waist circumferencewas measuredat the umbiticus[eve[ with the subject standingerect with abdomenrelaxed,armsat the sides,and feet together;hip circumferencewas measured at the point where the buttocks extended the maximum, when viewed from the side. Measurements were performed at the nearest0.1 cm with a flexible inextensibleplastic tape. Systolic(SBP)and diastotic(DBP;phaseV) btood pressurewere taken three times 2 min apart with a randomzero sphygmomanometer (GetmanHawksleyLtd., Sussex,UK) after the subject had been sitting for at least 10 min. The averageof the second and third readingwas recorded. A subject was classifiedas hypertensiveif his BP was >140 and/or 90 mm Hg or if he was on current antihypertensive treatment,accordingto ESH/lSH guidelines.Restingsupine heart rate was measuredby standard 12-teadECG,recorded in att subjectsat 25 mm/s and 1 mV/cm catibration. Methods Population Simitarty to previous reports byourgroup[11],weusedthe databaseof the Otivetti Heart Study,an occupationalbased investigationof the genetic, nutritional and metabolic precursorsof cardiovasculardiseaseinvotving the whole male workforce of the Otivetti factories of Pozzuoli (Naptes) and Marcianise (Caserta). The local Ethics Committee approved the study protocol and the participantsgavetheir informed consentto participate. A totat of 972 individuatsin the age range 25-74 years (51.5 + 7.2 years), examined in 1994-5, for whom LPT ptasmalevets were available, were consideredfor the present analysis. The relevant demographicand anthropometricfeatures of this group were similar to those of the original OHS popuLation. Biochemical measurements A fasting venous btood sampte was taken in the seated position between 8:00 AM and 10:00 AM, after the BP measurements,for determinationof serum LPT, adiponectin, seruminsulin,glucoseand tipids. The blood specimenswere immediatelycentrifugedand stored at -70 "C until anatyzed.SerumLPTwas measured by an enzyme-tinkedimmunosorbentassay(R&D System GmbH, Wiesbaden-Nordenstadt, Germany). Intra- and inter-assaycoefficients of variation were 3.0% and 5.4%, respectively[12]. Serumadiponectinwas measuredby an enzyme-linked immunosorbent assay(BioVendor Laboratory Medicine,Inc.,Brno,CzechRepubtic).Intra-andinter-assay coefficientsof variation were 4.2%and 5.17o,respectively. High-Sensitivity C-ReactiveProtein(hs-CRP) was measured by an immunoturbidimetricmethod using a RocheDiagnostics,Mitan, ltaly, automatedanalyzer.Serum glucose levets were measured with automated methods (CobasMira, Roche, ltaty). Serum insulin was determined by radioimmunoassay(lnsutin Lisophase; Technogenetics, Mitan, ltaly). The homeostaticassessment model (HOMA) index was usedto estimateinsulinresistanceand calcutated as fasting serum insulin (pU/mL) x fasting serum glucose ( m M ) / 2 2 . s[ 1 3 ] . Statistical analysis Statisticat analysis was performed using the Statistical. Packagefor the Socia[Sciences(SPSS-PC, version16; SPSS, Inc., Chicago,lL). The participantswere stratifiedaccord'ingto the median plasma of LPTdistribution of whole OHS population(7.97 ng/ml) into subjectswith low (t-LPT)and subjects with high LPT (h-LPT)levels. Thereafter, the two groups of subjects underwent a carefuI one-by-one F. Gattettiet at. 302 matchingfor age and BMl,with a first decimaldigit preciTable 2 Logistic regressionanaly-sis:Rol€,of LPT on sion. We thus identified 207 subjectswith [-LPTand 207 Hypertension. with h-LPT,who had the sameage and BMl.As the distriOverweightsubjects butions of ptasma LPT tevels deviated significantly from normality, they were normatizedby tog transformation; oR{e5%cl) I n d e p e n d e n t v a r i a bFt eI S E log-transformedvatues were used in the analysis, as ' 1 . 1 0 + 0 . 2 93 . 0 1 . r r i : 0 . 0 @ 1 h-LPT, , appropriate. Analysis of variance (ANOVA)was used to (1,70;5.34) assessdifferencesbetweengroup means.Cross-tabulation subjects Normatweight analysis was used to analyze the frequency of a given -0.35 - 0.59 0.70'. ' 0.55 h-LPT conditionacrossdifferent studygroups.The genera[[inear (0.22:2:,24\ modelwas adootedto evaluatethe interrelationsbetween Modetsadjustedfor smoking,physicalactiv,ily[eve[s,alcohol selected variabtes adjusting for confounders. Logistic HiehLeotin. intake.h-LPT: regressionanatysiswas carried out to estimate the rote of LPT on hypertensionin overweight and normat weight participants,separatety.Resuttsare expressedas means of participantshavingnormal BMIand of those with overand standarddeviation untessotherwise indicated. Two sidedP valueslessthan 0.05 were consideredstatisticallv weight or obesity. To rule out the possibleinfluenceof antihypertensivedrug treatment, in this anatysiswe significant. therapy.We identiexcludedsubjectson pharmacological fied 133 pairs of h-LPTand [-LPTuntreatedsubjectswith BMI> 25 and 37 pairsof subjectswith BMI< 25.Tabtes2 and Results Within 3 reportthe retevantfeaturesof the two subgroups. the averageageand BMIof h-LPTand t-LPT both subgroups, The two groups(n : 207 each) identified by the one-toindividualswere again exactty comparable.Among overone matching procedure had, by setection, similar age participants,the differencein plasmaLPTconcenweight and BMI but significantlydifferent ptasma LPT levets with significantdifferencesin tration was againassociated (Tabte1). The high-and low-teptingroupshad also similar BP. Further more, significant differenceswere detectedin body fat distribution (waistihip: 0.98 + 0.04 vs index heart rate (Tabte3). Conversety, hs-CRP, HOMA and 0.98 + 0.04) but were found to differ with regard to individuals, no differencebetweenhnormal weight among : : prevatenceof hypertension ([-LPT 43%,h-LPT 57%; LPT and [-LPTparticipantswas detected in any of these : 5 . 3 1 ; p : 0 . 0 2 7 ) ( T a b t e B P t e v e t s 1 ) . l n a d d i t i o n a n d x' togisticregressionanatysisshowedthat h-LPTwas associ- variabtes(Tabte4). GFRand plasmaadiponectinlevetsof h-LPTand [-LPT ated with hypertension,atsoadjustingfor smokingstatus, individuals did not differ either in the normalweieht or in physicatactivity tevels and alcohol intake, but only in subgroups. the overweight participants (O.R. Cl]: 3.01 overweigh [95% 11.70-5.341; p : 0 . 0 0 0 1 )( T a b t e2 ) . In the h-LPTcomparedwith the [-LPTgrouptrendswere Discussion and HOMAindex levets observedtoward higherHR, hs-CRP ptasma adiponectinconcentration: as well as toward lower This is to our knowledge the first case-controlstudy of however, none of these difference attained statistical (Tabte1). individuatswith high versus others with low ptasma LPT significance of plasmaLPTwithBPwe concentration,derivedfrom an unsetectedsampleof adult With respectto the retationship generalpoputationand carefuttymatchedfor sex, age, body detected a significantinteractionbetween LPT and BMl, a n d t h e h - L P Tg r o u p massand fat distribution.lts main findingsare threefold: b o t h i n t h e [ - L P T( p : 0 . 0 3 1 ) (p : 0.039).Therefore,we carriedout separateevaluations i) for a comparabtebody massand adiposityindex, high Tabte1 matchedfor ageand BMl. of low LPTandhighLPTparticipants Characteristics h . L P T( n : 2 0 7 ) [ - L P T( n : 2 0 7 ) Age (years) i, ::l ':' ' :" AMt$g/'mzi: L P T( n g l m L ) S B P( m mH g ) D:BF(mm Hg; : - : Ecc'nn(blmin) nlrCnF {mg,ll-) HOMAjndex, Adiponettin,(pg/mL) G F R { m L l m i n )I"' 51.37'+ 7.44 ii.as *z.qq 1,80+ 0.83 118.7+ 18-2 8 2 . 8+ 9 . 8 6 1 . 4 0+ 9 . 7 3 1 . 5 7+ 2 . 1 3 2;32+ 1.50 4 . 8 3+ 2 . 5 3 88:7+ 16.2 5 1 . 8 2+ 27.Q9X 5 . 9 7+ 132.9+ 8 5 . 7+ 6 3 . 0 2+ 1 . 9 4+ 2 . 5 9+ 4.58+ 90.8+ 8.33 7;43 2.10 16.2 9.0 8.59 1.93 1.54 2.44 '17.5 0.557 0.983 0,000 a.ou 01002 O.;Q72 0,067 o.0s2 0,309 0.190 heart rate by ECG,GFR:gtomerutalfiltt"ation M + SD;LPT:!ep!!n, SBP:sy9!ot!cblood pressure,DBP:diastoticbtood pr:essuie,ECG-HR: rate, [-LPT:Low Leptin,h-LPT:HighLeptin. Hyperleptinemia association with hypertension,systemicinflammationand insulinresistance Table3 303 subjectsmatchedfor age and BMIin overweightsubjects. Characteristics of.i,untieated I-LPT(n : 133) h - L P T( n : 1 3 3 ) Age(years) BMI(kglmz) LP:I(nglmL) SBP(mm Hg) Hg) DBPI(mm ECG'HR(b/min) hICRP(mg/L) HOA{A'index Adiponectin{pglmL) GFR,rlmtlminl 50.24+ 6.51 27.69+ 1.77 1 . 8 5* 0 . 8 1 124.5+ 13.9 80.8+ 8.4 6 0 . 1 3+ 9 . 3 2 1 . 3 3+ 1 . 4 2 2 , 1 9+ 1 . 2 2 :4;59:*2:16 -'911 ,9'*'15''6 ,5:!'',57 -+]sr;,1t11 :77..731,'.*..'::1:,,,87 .'5I84,:+,'.2:46 ,{,ff;t-: *:l$;:l r:tg,,9 r*:,7,9:, fi;'Ot,,*'8:26 :"2lA5',,&:,,,7',1,5 ,164'*.i,;'65 a-:'+idi'!:1:,'ta ,'92.1 }r15:4 01;11'{1 0,,,S69 0.:1001 or,]o01 0,:00r 0:008 0.,002 0.101.3 o,',:aip1a A,;,940 M - SD;LPT:teptin, sBP:systoticblood pressure,DBP:diastoticbtood pressure,ECG-HR: heart rate by ECG,GFR:gtomerutarfittration rate, t-LPT:Low Leptin,h-LPT:HighLeptin. plasma LPT is associatedwith higher btood pressureand greater prevalenceof hypertension;ii) besidesblood presinsulinresistanceand heart rate tend to sure,atsohs-CRP, be etevatedin individualswith higherLPTlevelsbut similar BMIand fat distribution; iii) excessbody weight is a condition necessaryfor the detection of these muttiple associations. Altogether,these resuttsare in keepingwith previous cross-sectional reportsby our group[10] and others[14*18] of a significantassociationof plasmaLPTconcentrationwith BPand metabolicsyndrome.Particulartyimpressivein this respectis the paperby ltoh and co-workersin which LPTwas correlated with BP also after weight [oss,in obese hyperresuttsare in tensivewomen [17]. Finatty,cross-sectional tine with our further reports [9,10] that plasma LPT is a predictor of the devetopmentof HPT and metabolic syndrome. men with various body size, plasma LPT concentration correlated with the degree of adiposity and with renal sympathetic nerve activity determined through the renal -receptorblockade spilloverof norepinephrine [26].Atpha-1 by bunazosinhydrochtoride improvesinsulinresistanceand decreasesptasmaLPT levels in hypertensivepatients with hyperleptinemia.These findingssuggestthat excessLPT causessympatheticactivation in human obesity 127,281. The sma[[but significantdifference'in heart rate found in our study between subjects with different ptasma LPT levets is in accordancewith this hypothesis.Central sympatheticactivation by high LPTlevetsis translatedinto increasedsympatheticdischargeto brown adiposetissue but also to other organsand, in particutar,to the kidney [29]. The leptin-mediatedrenal sympatheticstimulation may be fotlowed by increasedsodiumand water retention and by stimulationof renin secretion. Leptin and BP Leptin and CRP Aside to the epidemiotogicaIevidence, the resutts of severalexperimentalstudiessupportthe contentionthat teptin ptaysa significantrote in BP modulation 119*221.A number of ctinical studies shed tight on the possibLe mechanismswhereby hyperleptinemiaand the attendant LPTresistancemay contributeto developmentand maintenanceof hypertensionand eventuallyof cardiovascular disease123-251.Thus, Eiketiset at. demonstratedthat in Table 4 The relationshipbetween ptasmaleptin and CRPhas been previouslyreported.LeptininducesCRPexpressionin vitro in humanprimaryhepatocytes[30] aswett asin humancoronary artery endothelialcetls [31]. Accordingly,studiesin heatthy humans show a direct indeoendent associationbetween leptin and plasmaCRPconcentrations [32]. Leptinadministration in vivo increasesCRPconcentrationin non-obese Characteristics of untreatedsubjectsmatchedfor age and BMIin normalweightsubjects. I-LPT(n : 37) h-LPT(n : 37) :age&eais) ,,Bll!lllikgl'mat ,r'tPT,,]{nglmL) Hc) :'.S.BPi:(mm I,bitF.,l!mA''1tgI ,.ECG:HR l{blmin) .'rh!::CRPr,.1(mg/L) i'rHol!i|A',ind,bi l,Aoipontclin, (pgimL) ,6FR{mLl:mtn) 5,1';,10,,*,8;'172 49';'59 *9:27 ii,gi *,,o,bg 2l.gz* o.s+ ..,, 1,,, ;87',*,' A;17:4 L:177;',9;::1;.;lt:6;'5 '.:,,81,,;, 9:,'*'9,;1.,, 6L;r/,L,.,,'.',9.;,42 ,:1',il8':,$,rtit:,9! ,,.21091+:,:!,,se ,4t,.57 I:7'42 , 80.3+ 15,,3 .5.A1* 3.22 1,74;1 + 17)4 AOt +.,9.0,, 't,.'8t49 61',;:1:'1 ,.,:1ir:,?.1:.r:$..:0;97 ,i']l89,:*.'i0i72 'i4:.'3.5r',+ r1r,:79 ,,,88:6,,'},,i:,:a 0,,474 O;'8S4 :0;.001 :0i,458 '0,tcc ':A;597 'Ard,u r01'500 ,0q.659 A':47:', heart rate by ECG,GFR:gtomerutarfiltration M r 5D: LPT:leptin, SBP:systoticblood pressure,DBP:diastoticblood pressure,ECG-HR: rate, [-LPT:Low Leptin,h-LPT:HighLeptin. 304 individuats[33] atthoughit doesnot so in obesesubjects[34], perhapsas a consequenceof leptin resistance.Besidesto raiseCRPproduction,leptin atsopromotesintimal monocyte recruitment [35], eticits macrophagefoam cell formation [36]and inducessecretionof proinflammatorycytokines[37]. a rote of CRPin the inductionof teptin resistance Conversety, hasbeen proposed.CRPwas identified as SLIP-1,one of the circutatingfactorsknownto bind ptasmaleptin and to reduce its circutating active form [38]. Moreover,the abitity of humanCRPto inhibit teptin bindingto its receptorand the ensuingcetl signatingprocesswas shownin HEK293celtsand hypothatamic neuronsin vitro [39]. F. Galletti et at. Neverthelessthis relationship there was not evident in "norma[" renal function [45], as wetl as for our results where GFR was not different between [-LPT and h-LPT groups,atso after stratification for overweight and normal weight participants. In this respect,a limitationof our studywas the lack of measurementof the Serum Leptin Interacting Proteins (SLlPs)and of the circutat'ingleptin-receptor, atl factors able to bind circulatingLPTand to atter the active free LPT concentrationin the blood. Another limitation is the recruitment of white mate participants onty, so that its resutts may be generalized only to a comparablewhite male poputation. Leptin and insulin sensitivity Conclusions and perspectives Leptin decreasesinsulin secretion via direct action on leptin receptorsin pancreaticbeta-cetts[40], enhances skeletal muscle glucose uptake and oxidation [41] and gluconeogenesis suppresses [42]. Conversety,insutin and gtucoseappear to stimulate leptin secretionby adipocytes [43]. Taken together, these resutts suggest that teptin resistancemay favour insutinresistanceand diabetes.Our data confirm previous reports that increased leptin is associatedwith hyperinsutinemia and insulin resistance independenttyof BMI[3]. Leptin and related variables in overweight and normal weight subjects The most intriguingresult of our study was the findingof a significant interaction between plasma LPT and BMI in their associationwith BP and the consequentobservation that the statistical associationof olasma LPTwith BP was undetectable in the absence of overweight. A similar pattern was alsoobservedfor the relationshipof plasmaLPT to hs-CRP, HOMAindexand heart rate. This impliesthat the relationship between leptin and retated variables is different in the presenceor absenceof excessbodyweight. The explanation(s)of this finding is (are) not at hand. However, this finding might be related to the para[tel questionsof why plasmaleptin concentrationwas 'increased in a substantialgroup of normalweight individualsin our study poputationand where the excessLPTwasproducedin these subjects. The answer to these questionscoutd hetp understandwhy in these subjectsan elevated LPTconcentration was not associatedwith the unfavourableeffects otherwiseobservedin overweightindividuals. LPT is physiotogicattyexpressedin several other cells besidesthe adipocyteand one possibitityis that the surplus of LPT production occurring in subjects without excess adipositytakes place in one or more sitesdifferent from the adiposetissue. Accordingto Eiketiset at., the brain is a substantialsource of circulatingleptin in humansbut probabtymore so in the obesethan in the lean subject [1]. Hyperteptinemiais generatty expressionof leptin resistance, atbeit not a very accurateone: thus, for similarly elevated plasmaLPT tevetsdifferent degreesof LPTresistance may occur, possibtyexptaining differences in the pteiotropiceffects of the motecute.A different exptanation could be related to GFR. lt is wett known that high LPT levets are associatedwith a impaired renal function (al. In conctusion,our studyprovidesthe direct demonstration, in a case-controlstudy of high LPTvs low LPTadutt men carefulty matched for age, BMI and body fat distribution, that elevated ptasmaLPTis independentlyassociatedwith and insulin high BPand higherlevelsof heart rate, hs-CRP resistance.Moreover,it showedthat these associationscan be observedin overweight and obese subjects but not in subjects with normal weight. Atthoughthe mechanistic interpretation of our findingsis only speculative,these resutts support the hypothesis of a pathogenic role of hyperteptinemia and leptin resistancein the devetopment of obesity hypertensionand, as a consequence,also strengthenthe potential benefits deriving from correction of overweightand obesityin the preventionof hypertension disease. and cardiovascular Disclosure statement GattettiF., D'EliaL., De PatmaD., RussoO., BarbaG., Siani A., Miller M.A., CappuccioF.P., RossiG., Zampa G. and StrazzulloP. have nothine to dectare. Acknowledgments This study was partly funded by the ltalian Ministry of Universityand Research(PRIN2004-2004069989). References [1] EiketisN, LambertG, WiesnerG, KayeD, SchtaichM, MorrisM, et at. Extra-adipocyteleptin reteasein humanobesityand its function. Am J PhysiotEndocrinol relationto sympathoadrenat (5):E744-52. Metab 2004;286 [2] HaynesWG. Rote of leptin in obesity-retatedhypertension. Exp Physiot2005;90:683-8. 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