Valsartan restores inflammatory response by macrophages in adipose and hepatic tissues of LPS-infused mice.

2013·0.55 MB·English

by  Iwashita, Misaki

Adipocyte2:1,28–32;January/February/March2013;G2013LandesBioscience
Valsartan restores inflammatory response
by macrophages in adipose and hepatic tissues
of LPS-infused mice
Misaki Iwashita,1,2 Yusuke Nakatsu,1 Hideyuki Sakoda,3 Midori Fujishiro,3 Akifumi Kushiyama,4 Toshiaki Fukushima,1
Sonoko Kumamoto,2 Takanori Shinjo,1,2 Hideaki Kamata,1 Fusanori Nishimura2 and Tomoichiro Asano1,*
1DepartmentofMedicalChemistry;DivisionofMolecularMedicalScience;GraduateSchoolofBiomedicalSciences;HiroshimaUniversity;Hiroshima,Japan;
2DepartmentofDentalScienceforHealthPromotion;DivisionofCervico-Gnathostomatology;GraduateSchoolofBiomedicalSciences;HiroshimaUniversity;Hiroshima,Japan;
3DepartmentofInternalMedicine;GraduateSchoolofMedicine;UniversityofTokyo;Tokyo,Japan;4InstituteforAdultDiseases;AsahiLifeFoundation;Tokyo,Japan
Keywords: valsartan, adipocyte, macrophage, type 2 diabetes, ARB, inflammation
Inflammationinvolvingadiposetissueisregardedasoneofthemajormolecularmechanismsunderlyingobesity-related
insulin resistance. Recent studies have suggested a series of angiotensin II receptor blockers (ARBs) to improve insulin
resistance or protect against the development of diabetes mellitus. We previously demonstrated that valsartan
suppressestheinflammatoryresponseofmacrophages.Interestingly,however,thiseffectdidnotoccurviaperoxisome
proliferator-activated receptor (PPAR) c or the AT1a receptor. This suppression appears to secondarily lead to
ameliorationofinsulinresistanceandreductionsinabnormalgeneexpressionsinadipocytes.Inadditiontotheseinvitro
findings,wehereindemonstratetheinvivoeffectsofvalsartan,usingmiceconstitutivelyinfusedwithlipopolysaccharide
(LPS) for 4 weeks. Oral administration of valsartan to LPS-infused mice normalized the increased expressions of
inflammatorycytokinesinadiposeandlivertissues.Theseresultsraisethepossibilitythatvalsartannotonlycontributes
to normalization of obesity-related insulin resistance, but is also beneficial for the treatment of other diseases with
inflammationrelatedtothemetabolicsyndromesuchasatherosclerosisandnon-alcoholicsteatohepatitis.Furtherstudy
isnecessary to clarify these issues.
Introduction mechanism could be responsible for the high LPS in sera from
obese subjects, and might thus contribute to the pathogenesis
Therearenumerousfactorscausinginsulinresistanceleadingtype2 of HFD-induced or obesity-related insulin resistance.10,11
diabetesmellitus,butthemostcommonisobesity.1-4Recentstudies Furthermore, it is noteworthy that free fatty acids also bind to
suggest thatinfiltrating macrophagesinadipose tissue are involved TLR4 and exert activity similar to that of LPS. Based on these
in the pathogenesis of chronic inflammation and induce insulin previous findings, we speculated that reducing the response to
resistance in obese states.2,5-8 The interactions between enlarged LPSorfreefattyacidswouldnormalizethechronicinflammation
adipocytes and activated macrophages result in a vicious cycle observed in obese and diabetic patients.
causing chronic inflammation not only in adipose tissue but also Since the association of type 2 diabetes mellitus and
systemically,asshownbyelevatedserumC-reactiveprotein(CRP), hypertension is well known, considerableattention has been paid
increasedinflammatorycytokines,reducedadiponectinandsoon. to the insulin-sensitizing effects of many anti-hypertensive drugs.
Besides the local events in adipose tissues, the serum First, it was reported that angiotensin converting enzyme (ACE)
concentration of lipopolysaccharide (LPS) is reportedly increased inhibitors enhance insulin sensitivity,12,13 by raising the concen-
in obese subjects, which would give rise to chronic inflammation tration of serum bradykinin. Although angiotensin II receptor
and insulin resistance, since LPS-infused mice reportedly showed blockers (ARBs) do not affect bradykinin metabolism, many
impaired glucose tolerance.9LPS is aligand forToll like receptor clinical studies have revealed ARBs to significantly reduce insulin
4 (TLR4), and activation of the TLR4 pathway reportedly resistance or protect against the development of type 2 diabetes
exacerbates inflammation and insulin resistance with increased mellitus.14-17 Some ARBs, such as telmisartan, have weak but
inflammatory cytokine expressions. In addition, interestingly, it significant peroxisome proliferator-activated receptor (PPAR) c
was shown that a high fat diet (HFD) weakens the barrier agonisticactivity, as they enhance adiposedifferentiationof3T3-
function of the gut epithelium and thereby increases the L1 cells.14,18-20 PPARc agonists also have an anti-inflammatory
absorption of LPS from the gut into the circulation. This role, as shown by their inhibitory effects on the production of
*Correspondenceto:TomoichiroAsano;Email:[email protected]
Submitted:05/01/12;Revised:08/13/12;Accepted:08/14/12
http://dx.doi.org/10.4161/adip.21837
28 Adipocyte Volume2Issue1
BRIEFREPORT
inflammatorycytokinessuchastumornecrosisfactor(TNF)-a,in Discussion
turn promoting the production of adiponectin and thereby
normalizing obesity-related insulin resistance.21-23 Thus, the As the association of type 2 diabetes mellitus is well recognized,
insulin-sensitizing effect of ARBs is considered to possibly be anti-hypertensive drugs are very frequently administered to
attributable to their PPARc agonist activity. However, valsartan, diabetic patients. Patients having both type 2 diabetes mellitus
one of the most widely used ARBs, also exhibits an insulin- and hypertension often have obesity and hyperlipidemia, which
sensitizing effect24 despite lacking PPARc activity.14 are features of the metabolic syndrome. Though not all of the
Inourpreviousinvitrostudy,weobtainedevidencesuggesting molecular mechanisms underlying the development of metabolic
that the main target of valsartan is not adipocytes but, rather, syndromeareasyetclear,recentreportssuggestanimportantrole
macrophages.25 LPS-induced insulin signaling impairment in ofadiposetissueinflammation.5,7,8Theenlargementofadipocytes
3T3-L1 adipocytes co-cultured with RAW264.7 cells showed and infiltration of macrophagesare criticalinthis process, but an
almost complete normalization with co-addition of valsartan. elevated serum LPS concentration is also likely to contribute to
Furthermore, valsartan strongly suppressed LPS-induced produc- this inflammation.
tions of cytokines, such as interleukin (IL)-1β, IL-6 and TNF-a In our previous studies using the co-culture system of macro-
with nuclear factor (NF) kB activation and c-jun N-terminal phages and adipocytes, valsartan, one of the widely-used ARBs,
kinase (JNK) phosphorylation, in RAW264.7 and primary was demonstrated to suppress the inflammatory response of
murine macrophages. Surprisingly, this effect of valsartan was macrophages and thereby restore impaired insulin signaling and
also observed in THP-1 cells treated with siRNA of AT1, the reduce abnormal gene expressions of adipocytes.25,26 Based on
human angiotensin II receptor gene, or a PPARc antagonist, as these previous in vitro studies, this study was performed to
wellasmacrophagesfromAT1areceptorknockoutmice.Herein, ascertaininvivoeffectsofvalsartanontheinflammationaffecting
we present evidence of the in vivo effects of valsartan on adipose adipose and liver tissues of mice continuously infused with LPS.
and liver tissues of LPS-infused mice and discuss the beneficial Although 300 mg/kg/d LPS-infused mice reportedly showed
aspects of valsartan-induced anti-inflammatory effects. significantincreasesintheexpressionsofTNF-aandIL-6mRNA
in adipose tissue, liver and muscle, as well as hepatic insulin
Results resistance,9 we employed physiologically low and high concentra-
tions of LPS as an in vivo model of inflammation, and obtained
Bodyweightsandplasmaglucoselevels.Bodyweightsofallmice essentiallythesameresults.LPS-inducedelevationsinTNF-aand
roseslightlyfor4weeks and thedifferences betweengroups were IL-6 expressions were observed in both adipose tissue and the
not significant (Fig.1A). While fasting plasma glucose levels liver.Inaddition,oraladministrationofvalsartanbluntedLPS-in-
differed slightly among the groups after 4 weeks of LPS or PBS ducedelevationsofTNF-aandIL-6inadiposetissues(Fig.1C),
infusion, the differences did not reach statistical significance observations in agreement with our previous in vitro findings.25
(Fig.1Bi). There were no significant differences in GTT results Similartothemacrophagesrecruitedintoadiposetissue,Kupffer
among the groups (Fig.1Bii). cells, resident hepatic macrophages, also play a pathogenic role in
mRNA levels of inflammatory factors in adipose tissue, liver hepaticinsulinresistanceinducedbyaHFD.27TNF-areleasedby
tissue and serum. We determined the expressions of the main Kupffer cells in response to physiological concentrations of LPS28
inflammatory factors involved in metabolic diseases after 4 weeks plays a central role in the insulin resistance of hepatocytes.29 This
oflow-doseLPS(1.0pg/g/h)infusion.TheexpressionsofTNF-a study also revealed that valsartan suppressed LPS-induced TNF-a
and IL-6 mRNA were increased in adipose tissue from LPS- expression in the liver, regardless of whether a high or a low
infused mice as compared with PBS-infused control mice. In concentrationofLPSwasused (Fig.1DandE).Recently,several
valsartan-administeredLPS-infused mice, however,expressions of ARBs have been shown to be effective for the treatment of non-
these inflammatory cytokines were significantly suppressed as alcoholic steatohepatitis (NASH),30 and LPS from the gut was
compared with mice receiving only LPS infusion (Fig.1C). foundtobeinvolvedinthepathogenesisofNASH.31Takingthese
Similarly, LPS-induced expression of TNF-a in the liver was reports together, it is reasonable to speculate that the anti-
significantly suppressed by valsartan (Fig.1D). inflammatory effect of valsartan contributes to notonlyimproved
Subsequently, the effect of a higher dose (1.0 ng/g/h) of LPS insulinactionormetabolismbutalsototherapyforNASHorother
for 4 weeks was also investigated. None of the groups showed inflammatory diseases, although the suppressive effect on serum
alterations in body weight or fasting glucose concentrations (data TNF-a concentrations exerted by valsartan was less marked than
not shown). Increased expressions of hepatic TNF-a and IL-6 that onhepaticTNF-a mRNAlevels.
with high-dose LPS were significantly suppressed by valsartan Several other ARBs have already been reported to have anti-
(Fig.1E),resultsverysimilartothoseobtainedwithinfusionofa inflammatory effects. These effects are believed to be exerted
lowerdose(1.0pg/g/h)ofLPS.Whiletheserumconcentrationof through their PPARc agonist actions on macrophages. However,
TNF-a in mice infused with LPS (1.0 ng/g/h) for 4 weeks was surprisingly, at least in the case of valsartan, which has already
markedlyelevatedascomparedwiththatofthecontrolmice,oral been reported to have no PPARc agonist activity,9,14 the anti-
administration of valsartan tended to normalize LPS-induced inflammatory effect on macrophages was shown to be independ-
TNF-a elevations, but the difference between the two doses was ent of either PPARc or the AT1 receptor, based on findings
not significant (Fig.1F). obtained in AT1 KO mice and cells treated with PPARc or
www.landesbioscience.com Adipocyte 29
Figure1.EffectsofcontinuousLPS-infusionandvalsartan(Val)-administration.Six-week-oldLDL-RKOmicefedaHFDwereinjectedwithlose-dose
(1.0pg/kg/h)LPScontinuouslyusingosmicminipumps,withorwithoutoraladministrationofvalsartan,for4weeks.Eachgroupconsistsof6mice.
(A)Bodyweights.“Time-0”meansbeforetreatment.(Bi)Fastingplasmaglucoselevels.GTTs(ii)of10-week-oldmicekeptontheHFDfor4weeks.
(CandD)TotalmRNAwaspreparedfromepididymaladiposeandlivertissues.TNF-aandIL-6mRNAlevelswereexaminedusingreal-timePCR.
(EandF)LDL-RKOmicefedaHFDwereinjectedwithhigh-dose(1.0ng/kg/h)LPS,withorwithoutoraladministrationofvalsartan,for4weeks,and
hepaticTNF-aandIL-6mRNAlevelsandserumconcentrationsofTNF-aweremeasured.Dataaremeans±s.e.m.*p#0.05,**p#0.01,Student’st-test.
AT1 siRNA or PPARc antagonist.25 This suggests the presence macrophages, from two viewpoints; altered gene expression
of another target molecule on which valsartan exerts an patterns and insulin signaling.25,26 Regarding the gene expression
anti-inflammatory effect, although further study is necessary to pattern of adipocytes co-cultured with macrophages, DNA
clarify this issue. The relationship between macrophages and microarray analysis revealed that the profiles of gene expressions
adipocytesplaysimportantrolesinobesity-inducedinflammatory localized downstream from NFkB, thyroid receptor and activator
changes and insulin resistance.2,5-8 We have reported the effects protein(AP)inadipocyteswerealteredbyco-incubationwithLPS-
of valsartan using adipocytes co-cultured with LPS-treated stimulated macrophages, and that these alterations were generally
30 Adipocyte Volume2Issue1
normalized by co-incubation with valsartan. In particular, the
expression patterns of caspases, integrins, matrix metallopeptidases
and adipogenic genes, altered by co-culture with LPS-treated
macrophages,weregenerallynormalizedbyvalsartantreatment.In
lightofthesedata,itisreasonabletoconsidervalsartantoameliorate
inflammation,apoptosisandfibroticchangesofadiposetissue.
In addition, while valsartan does not improve insulin signaling
in 3T3-L1 adipocytes treated with TNF-a or conditioned
medium from activated RAW 264.7 macrophages, it was
demonstrated to markedly enhance signaling in adipocytes co-
culturedwithRAW264.7macrophages.Thus,wespeculatedthat
the principle action of valsartan is suppression of the inflammat-
ory responses ofmacrophages, since valsartan inhibitsinflammat-
ory cytokine production, thereby suppressing the NF-kB
activation associated with p65 phosphorylation and reducing c-
Jun NH -terminal kinase/AP-1 activation in macrophages.25
2
Taking our results and those of previous studies together, it is
reasonable to assume that valsartan has mechanisms of action
different from those of thiazolidinediones (TZDs) or telmisartan
with PPARc activity, and that these actions improve the insulin
sensitivityofadiposetissues.20,25,32AlthoughTZDsactdirectlyon Figure2.Valsartanimprovesinsulinresistancebysuppressinginflam-
mationindependentlyofPPARc.
adipocytes and suppress pro-inflammatory cytokine secretion
from these cells, TZDs induce adipose tissue enlargement and
obesity as well. There is also concern that long-term TZD (2 g/kgglucose,10% glucose solution)into theperitonealcavity.
administrationmightleadtoosteoporosis,3,33,34sinceTZDsinduce Bloodglucosewasdeterminedwithaglucosemeter(Roche)using
thedifferentiationofbonemarrowstemcellsintoadipocytesrather 3.5 ml of blood collected from the tip of the tail vein.
than bone cells. In contrast, although valsartan improves the Measurement of mRNA expression by real-time PCR.
functions of adipose tissues, this effect is mediated by co-existing Epididymal adipose and liver tissues were collected and frozen
macrophages. It appears that the insulin-sensitizing effect of at −80°C. Total RNA was extracted from these tissues using
valsartanonadipocytesisverylikelynotadirectaction,butrather Sepazol-RNA I (NakaLai Tesque), and 1 mg of RNA was reverse
one which occurs via altered functions of macrophages infiltrating transcribedwithTranscriptorReverseTranscriptase(Roche).The
adiposetissues.Theunknowntargetofvalsartanmightbeakeyto amplification reaction assay was performed using SYBR Premix
establishingnoveltreatmentsforinsulinresistance(Fig.2). EX Taq (Takara) according to the manufacturer’s protocol. The
primers were as follows: mouse TNF-a forward, 5'-GCCACC
Materials and Methods ACGCTCTTCTGTCT-3',mouseTNF-areverse,5'-GTCTGG
GCCATAGAACTGAT-3', mouse IL-6 forward, 5'-GATGCT
Animals. Six-week-old low density lipoprotein receptor (LDL-R) ACCAAACTGGATATAATC-3', mouse IL-6 reverse, 5'- GGT
knockout (KO) mice (obtained from Jackson Laboratory) were CCTTAGCCACTCCTTCTGTG-3', mouse GAPDH forward,
used. The animals were housed under climate-controlled con- 5'-TGACGTGCCGCCTGGAGAAA-3', mouse GAPDH re-
ditions with a 12-h light/dark cycle and were provided a HFD verse, 5'-AGTGTAGCCCAAGATGCCCTTCAG-3'. Post-PCR
(7.5%carbohydrate,24.5%proteinand60%fat)purchasedfrom melting curves confirmed the specificity of single-target amp-
Oriental Yeast Co. Ltd. and water ad libitum. All protocols were lification. Fold changes in the expressions of TNF-a and IL-6
approved by the institutional review board of Hiroshima relative to GAPDH were determined in triplicate.
University. Enzymelinkedimmunosorbentassay(ELISA).SerumTNF-a
Pumps delivering either PBS or LPS. Osmic minipumps levelsweremeasuredusingELISAkits(eBioscience),accordingto
(AlzetModel1004;Alzet)wereimplantedintraperitoneallyunder the manufacturer’s instructions. Absorbances at 450 nm were
Somnopentyl (pentobarbital sodium, 25 mg/kg body weight, determined using a microplate reader (Biorad Laboratories).
KyoritsuShojiCo.)anesthesia.Thepumpswerefilledeitherwith Statisticalanalysis.Dataareexpressedasmeans±SE.Statistical
phosphate buffered saline (PBS) or LPS (Escherichia coli 055:B5; analyseswereperformedusingStudent’st-test.Valuesofp,0.05
Sigma)toinfuse1.0pgor1.0ng/kg/hfor4weeks.Bodyweights wereconsideredsignificant.
were monitored every other week.
Glucose tolerance test. Glucose tolerance tests (GTTs) were Disclosure of Potential Conflicts ofInterest
performedasfollows:10h-fastedmicewereinjectedwithglucose No potential conflicts of interest were disclosed.
www.landesbioscience.com Adipocyte 31
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32 Adipocyte Volume2Issue1