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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.
[3] Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokinesand
.
insutinresistance.Mo[ Med2008:14:741-51
[4] LoffredaS, YangSQ Lin HZ, KarpCL, BrengmanML, WangDJ,
et a[. Leptin regutatesproinflammatoryimmune responses.
FASEBJ 1998;12:57-65.
[5] Rasouti N, Kern PA. Adipocytokines and the metabotic
1
compticationsof obesity. J Clin EndocrinolMetab 2008;93(1
Suppt.1):564-73.
[6] Considine RV, Sinha MK, Heiman ML, Kriauciunas A,
StephensTW, Nyce MR, et at. Serumimmunoreactive-teptin
Hyperteptinemiaassociationwith hypertension,systemicinflammationand insulin resistance
concentrationsin normat-weightand obesehumans.N EngtJ
Med 1996;34:297-5.
[7] BarbaG, RussoO, SianiA, lacone R, FarinaroE, GerardiMC,
et at. Ptasmaleptin and blood pressurein men: gradedassociation independentof body massand fat pattern. Obes Res
2003:11:160-6.
[8] ShankarA,XiaoJ. Positiveretationshipbetweenptasmaleptin
levet and hypertension.Hypertension2010;56:623-8.
[9] Galtetti F, D'EtiaL, BarbaG, SianiA, CappuccioFP,FarinaroE,
et al. High-circutating
leptin levelsare associatedwith greater
risk of hypertensionin men independenttyof body massand
insulin resistance:result of an eight-yearfottow-up study. J
Clin EndocrinolMetab 2008;93:3922-6.
[10] Gattetti F, BarbatoA, VersieroM, laconeR, RussoO, BarbaG,
et at. Circutatingleptin levets predict the devetopmentof
metaboticsyndromein middte-agedmen: an 8-yearfotlow-up
study. J. Hypertens 7007;25:1671-7 .
[11] Barbato A, lacone R, Tarantino G, RussoO, Sorrentino P,
Avaltone5, et a[. Olivetti heart study researchgroup. relationshipsof PAI-1[evelsto central obesity and liver steatosis
in a sampteof adult male poputationin southernltaly. Intern
EmergMed 2OO9;4:315-23.
[12] laconeR, RussoO, RussoP, VeneziaA, VarriateV, GerardiMC,
et at. Ptasmaleptin measurementsin epidemiotogicalinvestigation: comparisonof two commontyused assaysand estimate of regressionditution bias. Nutr Metab CardiovascDis
2002;12:71-9.
[13] MatthewsDR,HoskerJP, RudenskiAS,NaytorBA,TreacherDF,
insulin resistance
model assessment:
Turner RC. Homeostasis
and beta-cettfunction from fastingptasmagtucoseand insutin
concentrationsin man. Diabetotogia1985;28:412-9.
[14] HaffnerSM,MykkanenL, RainwaterDL, KarhapaaP, LaaksoM.
ls teptin concentrationassociatedwith the insulin resistance
syndromein nondiabeticmen?ObesRes1999;7:164-9.
[15] MattamaciF, Cuzola F, Tripepi G, Cutrupi S, Partongo5,
Tripepi R, et a[. Gender-dependentdifferences in ptasma
leptin in essential hypertension.Am J Hypertens2000;13:
914-20.
[16] KhokharKK,SidhuS, KaurG. Corretationbetween leptin tevel
and hypertension in normal and obese pre- and post'
2010;163(6):873-8.
menopausal
women.Eur J Endocrinot
[17] ltoh K, lmai K, MasudaT, Abe S, TanakaM, Koga R, et at.
Retationshipbetween changes in serum [eptin levets and
blood pressure after weight loss. Hypertens Res 2002;25:
881-6.
U8l Ma D, FeitosaMF, WiLkJB, Abe S, TanakaM, Koga R, et a[.
Leptin is associatedwith btood pressureand hypertensionin
women from the national heart, [ung, and btood institute
fami[y heart study. Hypertension2009;53:473-9.
[19] Aizawa-AbeM, Ogawa Y, MasuzakiH, Ebihara K, Satoh N,
rote of leptin in obesitylwai H, et at. Pathophysiological
related hypertension. J Ctin Invest 2000;105:1243-52.
[20] CorreiaMLG,RahmouniK. Ro[eof leptin in the cardiovascutar
and endocrinecompticationsof metabolicsyndromediabetes.
ObesMetab 2006:8:603-10.
[21] CartyteM, JonesOB, Kuo JJ, Hatt JE. Chroniccardiovascular
and rena[ actions of lept'in: role of adrenergic activity.
Hypertension2N7;39 : 496-501.
[22] CorreiaML, MorganDA,SivitzWl, MarkAL, HaynesWG. Leptin
acts in the central nervoussystemtoproducedosedependent
changes i n arterial pressure. Hypertension2001;37:936- 42.
G, TagliamonteMR,GatderisiM, Zito GA, PetrocetliA,
[23] Paotisso
CarellaC, et a[. Plasmaleptin is associatedwith myocardial
watl thicknessin hypertensiveinsutin-resistantmen. HyperO47-57.
tension 1999;34:.1
[24] Sciderberg5, Ahr6n B, Stegmayr B, Zito GA, PetrocettiA,
Caretla C, et al. Leptin is a risk marker for first-ever
305
hemorrhagicstroke in a population based cohort. Stroke
1999;30:.328-37.
[25] SciderbergS, Ahr6n B, JanssonJH, JohnsonO, HaltmansG,
AsptundK, et a[. Leptin is associatedwith increasedrisk of
myocardialinfarction. J Intern Med 1999;246:409-18.
[26] EiketisN, SchlaichM, AggarwatA, KayeD, EslerM. Interactions
between leptin and the human sympatheticnervoussystem.
Hypertension2003;41: 1072-9.
[27] lhara S, ShimamotoK, WatanabeH, Sakai R, KawanaM. An
atphal-receptor blocker reduces plasma leptin [evets in
hypertensive patients with obesity and hyperteptinemia.
HypertensRes2006;29:805-l1.
[28] MorganDA, ThedensDR, WeissR, RahmouniK. Mechanisms
mediating renal sympatheticactivation to teptin in obesity.
Am J PhysiotRegulIntegrCompPhysiol2008;295:R1730-6.
[29] Ester M, Straznicky N, Eikelis N, Masuo K, Lambert G,
Lambert E. Mechanismsof sympatheticactivation in obesityretated hypertension.Hypertension2006;48:787-96.
[30] Martin SS, QasimA, Reitty MP. Leptin resistancea possibte
interface of inflammationand metabotismin obesity-related
cardiovascutardisease.J Am CottCardiot2008;52:1201-10.
[31] SinghP, HoffmannM, Wotk R, ShamsuzamanAS, SomersVK.
Leptin inducesC-reactiveprotein expressionin vascularendothetiat cetls. ArteriosclerThrombVascBio[2007;27:e302-7.
[32] ShamsuzzamanA5, Winnicki M, Wotk R, Svatikova A,
Phittips BG, DavisonDE, et at. Independentassociation
between plasma leptin and C-reactive protein in heatthy
-5.
humans.Circulation2O04;109:2181
RM,
Hirsch
The
effects
of leptin administration
Mackintosh
J.
[33]
humansubjects.ObesRes2001;9:462-9.
in non-obese
[34] Hukshorn CJ, van Dieten FM, Buurman WA, WesterterpPlantengaMS, CampfietdLA, SarisWH. The effect of pegylated recombinanthuman teptin (PEG-OB)
on weight lossand
inflammatorystatusin obesesubjects.Int J ObesRelatMetab
Disord2002;26:504-9.
[35] YamagishiSl, Edetstein D, Du XL, Kaneda Y, Guzman M,
Browntee M. LeDtin induces mitochondriaI superoxide
productionand monocytechemoattractantprotein-1 expression in aortic endothe[ia[ cetts by increasing fatty acid
oxidation via protein kinase A. J Bio[ Chem 2001;276:
25096-100.
[36] O'RourkeL, GronningLM, YeamanSJ, ShepherdPR. Gtucose
dependent regulation of cholesterol ester metabotism in
macrophagesby insutin and teptin. J Bio[ Chem 2002;277:
42557-62.
[37] Lam QL, Lu L. Roteof leptin in immunity. Cett Mot lmmunol
2007;4:1-13.
[38] ChenK, Li F, Li J, Cai H, Strom5, BisettoA, et at. Inductionof
leptin resistance through direct interaction of C-reactive
protein with leptin. Nat Med2006;12:425-32.
[39] PignattiP,CiapponiL, GatteP, HansenMB,MassaM, MeazzaC,
et at. Highcirculating[evelsof biotogicattyinactive lL-6lSlL-6
receptor complexesin systemicjuvenile idiopathic arthritis:
evidence for serum factors interfering with the binding to
g p 1 3 0C
. t i nE x pl m m u n o2l 0 0 3 ; 1 3 1 : 3 5 5 - 6 3 .
[40] SeufertJ, Kieffer TJ, LeechCA, Holz GG,Moritz W, RicordiC,
et at. Leptin suppressionof insutin secretion and gene
expressionin human pancreatic istets: impticationsfor the
devetopmentof adipogenicdiabetes meltitus. J C[in Endocrinot Metab 1999;84:670-6.
N, Scutty5, QrM, ShiZQ. Differentiat
[41] WangJL, Chinookoswong
effects of leptin in regulation of tissue glucose utilization
1999;140:2117-24.
in vivo. Endocrinotogy
[42] Rossetti L, Massitlon D, Barzilai N, Vuguin P, Chen W,
HawkinsM, et at. Short term effects of leptin on hepatic
'1997;
gluconeogenesis
and in vivo insutinaction. J Biot Chem
272:27758-63.
306
[43] Sonnenberg GE, Krakower GR, Hoffmann RG, Maas DL,
HennesMM, KissebahAH. Plasmaleptin concentrationsduring
extended fasting and graded gtucose infusions: relationships
with changesin glucose,insulin, and FFA.J Ctin Endocrinol
Metab 2001:86:4895-900.
[44] Pecoits-FithoR, Nordfors L, Heimbi.irgerO, Lindhotm B,
Anderstam B, MarchlewskaA, et al. Soluble leptin receptors
and serumteptin in end-stagerenal disease:relationshipwith
F. Gatlettiet at,
inflammation and body composition. Eur J Clin Invest 2002;
32(111:811-7.
[45] Risch L, Saety C, Hoefle G, Rein P, Langer P, Gouya G,
et al. Relationship between glomerular filtration rate
and the adipokines adiponectin, resistin and leptin in
coronary patients with predominantly normat or mitdty
impaired renal function. Ctin Chim Acta 2007 Feb:
376(1-2):108-1 3.
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