Pioglitazone therapy in mouse offspring exposed to maternal obesity

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Ttre ecosub g mmo r treinvasive microendoscopic fluorescence confocal imaging and intraperi-tesicalsuantriulinndm Pc chlict acs toop mmmmaternal obesity, mice, offspring, pioglitazoneCite201Adrooffolanepedingndrelative risk of childhood obesity associ-Fro ent,By ngiPa nchReThi cieTex nce(UL es,of H rdBu m thInstitute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of ChildHeTherepKeDirThePre6-1Re000Research www.AJOG.org30atedwithmaternal obesity in the first tri-mester of pregnancy was found to be in-creased by 2-fold at age 2-3 years and 2.3-fold at 4 years of age.3MetS was found to be more commonin adolescents who were born to obesemothers.5 Others have shown that themothers body mass index is one of thestrongest predictors of overweight/obe-alth and Human Development, and the Office of the Director, National Institutes of Health.views expressed herein are solely the responsibility of the authors and do not necessarilyresent the official views of the National Institute of Allergy and Infectious Diseases, the Eunicennedy Shriver National Institute of Child Health and Human Development, the Office of theector, or the National Institutes of Health.authors report no conflict of interest.sented at the 32nd annual meeting of the Society for Maternal-Fetal Medicine, Dallas, TX, Feb.1, 2012.prints not available from the authors.ccording to the International Dia-betes Federation, metabolic syn-me (MetS) is defined by the presencecentral obesity and at least 2 of thelowing components: hypertension,glucose intolerance,The MetS has reachedtions in many developsequently, understandpotential of obesity am the Departments of Obstetrics and Gynecology (Drs Kalanderian, Vinctautiene) and Internal Medicine (Dr Abate) and the Center for Biomedical Etrikeev, Wei, Vincent, and Motamedi), The University of Texas Medical Braceived Sept. 7, 2012; revised Dec. 7, 2012; accepted Jan. 9, 2013.s study was conducted with the support of the Institute for Translational Sas Medical Branch, supported in part by a Clinical and Translational Scie1TR000071) from the National Center for Advancing Translational Sciencealth. Dr Bytautiene is supported by a research career development awailding Interdisciplinary Research Careers in Womens Health Program) fro2-9378/$36.00 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/8.e1 American Journal of Obstetrics& Gynecology APRIL 2013d dyslipidemia.idemic propor-countries. Con-the detrimentalits unfavorableconsequences is vital to the developmentof preventative measures.1Traditionally, metabolic syndromeand obesity research has focused on life-style factors in childhood and adult-hood.More recently the role of pregnancyin the obesity epidemic is beginning to berecognized.The rate of obesity inpregnantwomen worldwide is between 18.5% and38.3%, and these rates continue to rise.2Epidemiological and experimental studiesdemonstrate that offspring from obesemothers are at an increased risk of obe-sity as well as other features and com-plications of MetS.3-7 For example, theSaade, andneering (Drs, Galveston, TX.nces, University ofAwardNational Institutes(K12HD052023:e Nationalthis article as: Kalanderian A, Abate N, Patrikeev I, et al. Pioglitazone therapy in mouse offspring exposed to maternal obesity. Am J Obstet Gynecol3;208:308.e1-7.BSTETRICSioglitazone therapy ixposed to maternalshag Kalanderian, MD; Nicola Abate, MDssoud Motamedi, PhD; George Robert SJECTIVE: Pioglitazone (PIO), an antidiabeticedione family, improves glucose and lipid mipose, and liver tissues via peroxisome proltor gamma activation. We hypothesize thatve the metabolic status of offspring exposea mouse model developmentally programdrome.UDY DESIGN: CD-1 female mice were fednths prior to breeding and throughout pregnans were weaned to a standard-fat diet. Offsprined to receive 40 mg/kg of PIO in 0.5% of methyl cellulose by daily oral gavage for 2 weekatment total body weights of the pups were rcutaneous adipose tissue were evaluated usingraphy. Serum analytes were measured. Aftemouse offspringesitygor Patrikeev, PhD; Jingna Wei, MD; Kae, MD; Egle Bytautiene, MD, PhDg of the thiazoli-bolism in muscle,ator-activated re-therapy will im-maternal obesityed for metabolicigh-fat diet for 3and lactation. Theere randomly as-cellulose or 0.5%he pre- and post-rded. Visceral andicrocomputed to-atment, minimallytoneal glucose toleranceusing appropriate statistRESULTS: PIO therapy receral adipose tissue gainPIO significantly loweredmodel assessment of insfemales. There was a treCONCLUSION: Short-terers attenuates metaboliprogramming of metabotential role for drugs thaceptor gamma receptoroffspring at risk to develKey words: fetal prograsitj.ajog.2013.01.013en Listiak Vincent, MD;ts were performed. The data were analyzedtests (significance, P .05).lted in lower total body weight and lower vis-d increased subcutaneous adipose tissue.glycerides, insulin levels, and homeostasisresistance in males and fasting glucose intoward larger adipocyte size.IO therapy in the offspring of obese moth-anges associated with the developmentalsyndrome. These novel data suggest a po-tivate peroxisome proliferator-activated re-prevent metabolic syndrome in the adultetabolic alterations.ing, in vivo adipose tissue imaging,nob; IaaddruetaiferPIOd toma hcyy and percentage of body fat in herchersthoovonmaThdecorisMeemtotiotiocesancarincthainmofunclucreauhysomgamtivphlevancrianPPingactmopreincspristdin(TabtheveltheofoffthoIthaogprosprexpingpeMAllAnUnanatuwicycwaStuInmofeemonaofsigvatwhmoCDRivFewefedD1widuwe(mthe70stesontwanoilsubsuranMimiagidivgromefemtazMOlosPit(C4)(0.wa2 wTthefrowhasinwethetolmeanOntrelecsistheadidianInPrforceradrodpromaopmoistke5-1agenetiowe50timdeproweconwww.AJOG.org Obstetrics Researchildren.4,6 Adults born to obese moth-were more insulin resistant thanse born to nonobesemothers.8More-er, maternal prenatal fat intake wase of the strongest predictors of fatss in the offspring at 10 years of age.9us, there is strong accumulating evi-nce that offspring born of pregnanciesmplicated by obesity are at increasedk of obesity and other features oftS.Visceral adipose tissue dysfunction iserging as the primary defect leadingMetS.10,11 Pathological lipid accumula-n and adipocyte hypertrophy, in addi-n to hypoxia and a variety of other pro-ses, lead to adipose tissue dysfunctiond the development of metabolic and/ordiovascular disorders. Previous studies,luding our own, have demonstratedt adipose tissue dysfunction is presentfetal programmingmodels ofMetS.Thest notable examples of adipose dys-ction in fetal programmingmodels in-de elevated serum leptin levels, in-ased adipose tissue lipid accumulation,gmented expression of angiotensin,poxia-inducible factor-1 and peroxi-e proliferator-activated receptorma (PPAR) receptor, amplified ac-itiesof lipoprotein lipaseandglycerol-3-osphate dehydrogenase, and decreasedels of antioxidant enzymes.7,12-15PPAR is highly expressed in whited brown adipose tissue and plays atical role in adipocyte differentiationd mature adipocyte maintenance.AR regulates systemic insulin signal-via ligand-dependent transcriptionalivation of target genes. In animaldels, messenger ribonucleic acid ex-ssion of the PPAR is significantlyreased in the adipose tissue of the off-ing of obese dams.7,12 When admin-ered to pregnant animals, thiazoli-ediones (TZDs), PPAR agonistsZDs) improvematernal and fetal met-olic markers.16-20 However, none ofse studies followed up offspring de-opment into adulthood, nor werere studies that investigated the effectsTZDs if administered postnatally tospring at risk to developMetS, such asse born to obese mothers.n this study, we tested the hypothesist postnatal administration of the pi- samlitazone, a TZD class drug, will im-ve the metabolic status of adult off-ing at risk to developMetS because ofosure to amaternal high-fat diet dur-the prenatal and the early postnatalriods.ATERIALS AND METHODSprocedures were approved by theimal Care and Use Committee of theiversity of Texas Medical Branch. Theimalswerehoused separately in temper-re- and humidity-controlled quartersth constant 12 hour light, 12 hour darkles and were provided with food andter ad libitum.dy designour laboratory, we have established ause model of developmental MetS byding female mice a high-fat diet for 3nths before pregnancy, during preg-ncy, and until weaning. At 6 monthsage, offspring of these dams developnificant adiposity, hypertension, ele-ed fasting glycemia, and dyslipidemiaen compared with pups born tothers fed standard chow.21,22For the current study, female andmale-1 mice were obtained from Charlesers Laboratories (Wilmington, MA).male mice were approximately 4-5eks of age upon arrival. Females werehigh-fat rodent chow (34.9% fat;2492; ResearchDiets Inc, NewBruns-ck,NJ) for 3months prior to breeding,ring pregnancy, and until weaning (3eks postpartum), when all animalsothers and offspring) were placed onstandard chow diet (5.6% fat; Teklad12: Harlan Teklad LM-485 mouse/ratrilizable diet; Harlan Teklad, Madi-, WI). The fat source differed be-een diets: the high-fat diet used lard,d the standard-fat diet used soybean.At 8 weeks of age, the offspring werejected to fasting blood glucose mea-ements and blood collection for lateralysis of triglyceride and insulin levels.ce also underwent in vivowhole-bodycrocomputed tomography (CT) im-ng. At 10 weeks of age, the pups wereided into control and treatmentups to include animals born to thee mother in both groups. The treat- peAPRIL 2013 Americannt group (PIO group; males, n 6,ales, n 4) received 40mg/kg piogli-one (PIO; Sigma-Aldrich, St Louis,) dissolved in 0.5% of methyl cellu-e by oral gavage (Fisher Scientific,tsburgh, PA).23 The control groupTR group; males, n 6, females, nreceived a similar amount of vehicle5%methyl cellulose) only. Treatments given daily (except on weekends) foreeks, until 12 weeks of age.he selection of dosage and timing oftreatment was based on evidencem literature, in which db/db mice,ich are at risk to develop MetS (sameour animals), showed improvementstheir metabolic parameters after 2-3eks of PIO treatment.23,24 Followingtreatment, intraperitoneal glucoseerance tests (IGTT), fasting glucoseasurements, and in vivo micro-CTd confocal imaging were performed.e male per group died during post-atmentmanipulations. Bloodwas col-ted for insulin and triglyceride analy-from the remaining animals, and thenoffspring were euthanized. Visceralipose tissue, includingmesenteric, ep-dymal, and perirenal fat, was excisedd weighed.vivo imagingeviously validated imaging methodsthe quantitative assessment of vis-al (VAT) and subcutaneous (SAT)ipose tissue and liver fat infiltration inents were used.25-27 Experimentaltocols for noninvasive CT and mini-lly invasive confocal imaging weretimized in our laboratory over severalnths prior to the study. After admin-ering anesthesia intraperitoneally withtamine/xylazine (80-100 mg/kg and0mg/kg, respectively), mice were im-d with a small animal micro-CT scan-r (Inveon; Siemens Preclinical Solu-ns,Knoxville, TN). Imagingparametersre set as follows: voltage 70 kV, current0 A, resolution 0.107 mm, exposuree 1000 milliseconds, 520 steps and 360grees of rotations. Scan time was ap-ximately 15 minutes per mouse. Micere given supplemental oxygen via nosee during scanning.The transverse views of CT images (1r animal) at the level of the fifth lum-Journal of Obstetrics& Gynecology 308.e2baVAlevfortioareseacen(%sectiomibyPforathoexpanradthesplinfimeoffimcen48Keres(0.themmdomepoInsthetrawianeacuselivsiztroIntIGweMhog/ktiopri60tiodostubloprisulmewasaySeBlineS(1fromusstrtritemtalDaDafronuasIGusmeresbydeunnifipatesuteingofAsigTB onaV NoB 3. .........V 2. .........S. .........L. .........T. .........F 17. .........F. .........H. .........DC ssesssa .K of mResearch Obstetrics www.AJOG.org30r vertebra were selected for analysis ofT, whereas transverse images at theel of sixth lumbar vertebra were usedanalysis of SAT.25,26 The cross-sec-nal total body area and adipose tissuea were measured using Inveon Re-rch Workplace software. The per-tage of VAT (%VAT) and SATSAT) was calculated from the cross-tional total body area. The correla-ns between the weight of VAT deter-ned after extraction and determinedCTwere significant (Pearson r 0.82,.003 for males and r 0.82, P .01females).Liver and spleen radiodensity values intransverse section between the 13thracic and first lumbar vertebrae wereressed as liver to spleen density ratiod compared between the groups. Theiodensity of the liver normalized toradiodensity of the spleen (liver toeen radiodensity ratio) indicated fatltration in the liver.25,26,28,29To quantitatively assess PIO treat-nt-induced changes in adipocyte size,springunderwent high-resolutionmin-ally invasive microendoscopic fluores-ce confocal imagingusing aCell-Vizio-8 confocal microendoscope (Maunaa Technologies, Paris, France). A fluo-cent 1% fluorescein sodium solution2-0.3 mL per animal) was injected viatail vein or intraperitoneally. A 1.8probe was inserted through an ab-minal incision. Confocal images ofsenteric adipocytes in VAT were ex-rted into Image J software (Nationaltitutes of Health, Bethesda,MD), andcell area was measured by manuallycing the cell borders.30 Every cellthin 5 imaging fields was measured,d the mean cell area was calculated forh animal. The mean area values wered to compare the 2 groups.Individuals interpreting VAT, SATer/spleen radiodensity, and adipocytee were blinded to the treatment/con-l group allocation.raperitoneal glucose tolerance testTTs were performed following 2eks of PIO or vehicle administration.ice were fasted overnight (16-18urs) prior to a 20 % glucose bolus (1gpermouse) by intraperitoneal injec-Pasen8.e3 American Journal of Obstetrics& Gynecologyn. Blood glucose levels were recordedor to glucose injection and at 15, 30,, 90, and 120 minutes after the injec-n. Overnight fasting and the glucosese were selected based on our pilotdies inCD-1mice. Sixtymicroliters ofod were collected via the tail veinor to glucose injection for fasting in-in measurements. The blood was im-diately centrifuged, and the serums stored at80C until the insulin as-was performed.rologic analysisod glucose levels were measured us-an OneTouch Ultra glucometer (Lif-an, Milpitas, CA) after an overnight-18 hours) fast. Blood was collectedm the offspring before and after treat-nt. Commercially available kits wered according to themanufacturers in-uctions to determine serum levels ofglycerides, cholesterol (BioAssay Sys-s, Hayward, CA), and insulin (Crys-Chem, Downers Grove, IL).ta analysista were analyzed as the differencem baseline (posttreatment value mi-s pretreatment value) and expressedthe mean SEM. The area under theTT curve for glucose was calculatedngGraphPad Prism software (Graph-d Software, Inc, La Jolla, CA). InsulinABLE 1aseline values before treatment in nnd pioglitazone-treated malesariableody weight, g.........................................................................................................................AT as determined by CT (% from total area).........................................................................................................................AT as determined by CT (% from total area).........................................................................................................................iver/spleen radiodensity, HU.........................................................................................................................riglyceride, mmol/L.........................................................................................................................asting glucose, mg/dL.........................................................................................................................asting insulin, ng/mL.........................................................................................................................OMA-IR.........................................................................................................................ata are means SEM.T, microcomputed tomography; HOMA-IR, homeostasis model aubcutaneous; SEM, standard error of the mean; VAT, visceral.Statistically significant difference between the groups (P .05)alanderian. Pioglitazone and developmental programmingsitivity was determined using the ho- wiAPRIL 2013ostasis model assessment of insulinistance (HOMA-IR) and calculated(fasting glucose level [milligrams perciliter] fasting insulin level [milli-its per liter])/405.31,32 Statistical sig-cance was determined using an un-ired Student t test or aMann-Whitneyt if the data were not normally distrib-d. The IGTT results were analyzed us-a 2-way repeated-measures analysisvariance with Bonferonni correction.P .05 was considered statisticallynificant.SULTSere were no differences in total bodyight, VAT and SAT area, or fastingod glucose and insulin levels between2 groups of mice at the start of thedy (Tables 1 and 2). Triglycerides lev-were significantly higher inmalemiceigned to PIO group (Table 2,P .01).ffects of PIO treatment on outcomeasures are presented inTables 3 and 4:PIO-treatedmales and females groupned less total body weight. Treatedles acquired less VAT than animals inCTR group. Females in both groupst VAT with the PIO group losing lessn CTR mice. The area of SAT in-ased in PIO-treated animals. Theer to spleen radiodensity ratio in-ased in males and females treatedtreatedntreatedPioglitazonetreatedPvalue8.4 3.5 39.8 4.7 .6...........................................................................................................8.7 5.7 34.5 2.9 .4...........................................................................................................8.3 1.3 8.9 1.8 .7...........................................................................................................0.7 0.04 0.6 0.02 .6...........................................................................................................2.3 0.2 3.1 0.2a .01...........................................................................................................8 11.5 164 11.0 .4...........................................................................................................0.8 .02 1.3 0.2 .1...........................................................................................................5.8 2.0 12 3.2 .2...........................................................................................................ment of insulin resistance; HU, Haunsfield units; SAT,etabolic syndrome. Am J Obstet Gynecol 2013.ogc6eeiREThweblothestuelsassEmethegaimathelosthacrelivcreth PIO, suggesting that fat infiltra-tioPItivetetwSdecre.02betriInelstisdelippolevvehstaglufaslarcochlowPIOsiggluaftbloanimdebeaftPun.04frotivproingtrecre.03inswhthodifsisproPwaPIOwelarwialtbeCOIneffspranthetrilinsmweprsenexchmainvBBKwww.AJOG.org Obstetrics Researchn in the liver decreased as a result ofO exposure (Tables 3 and 4, respec-ely). None of these changes/param-rs were statistically significant be-een the groups.erum triglyceride levels significantlycreased in PIO-treatedmales while in-asing in control animals (Table 3, P). This change is especially significantcause PIO-assigned males had higherglyceride levels before the treatment.females, a decrease in triglyceride lev-was also observed, although not sta-tically significant (Table 4).TABLE 2Baseline values before treatment in nand pioglitazone-treated femalesVariableody weight, g..........................................................................................................................VAT as determined by CT (% from total area)..........................................................................................................................SAT as determined by CT (% from total area)..........................................................................................................................Liver/spleen radiodensity, HU..........................................................................................................................Triglyceride, mmol/L..........................................................................................................................Fasting glucose, mg/dL..........................................................................................................................Fasting insulin, ng/mL..........................................................................................................................HOMA-IR..........................................................................................................................Data are means SEM.CT, microcomputed tomography; HOMA-IR, homeostasis model asubcutaneous; SEM, standard error of the mean; VAT, visceral.Kalanderian. Pioglitazone and developmental programmingTABLE 3Effects of pioglitazone (change fromin malesVariableody weight, g..........................................................................................................................VAT as determined by CT (% from total area)..........................................................................................................................SAT as determined by CT (% from total area)..........................................................................................................................Liver/spleen radiodensity, HU..........................................................................................................................Triglyceride, mmol/L..........................................................................................................................Fasting glucose, mg/dL..........................................................................................................................Fasting insulin, ng/mL..........................................................................................................................HOMA-IR..........................................................................................................................Data are means SEM.CT, microcomputed tomography; HOMA-IR, homeostasis model asubcutaneous; SEM, standard error of the mean; VAT, visceral.a Statistically significant difference between the groups (P .05.alanderian. Pioglitazone and developmental programming of mThere was no change in serum high-nsity lipoprotein (HDL), low-densityoprotein (LDL)/very low-density li-protein (VLDL), and total cholesterolels following treatment with PIO oricle (data not shown).Both groups ofmales had reduced, buttistically not significant, fasting bloodcose levels, although the change inting glycemia of PIO-treatedmicewasger (Table 3). In females fasting glu-se levels increased; however, theange from baseline was significantlyer in mice that were administeredtreatedontreatedPioglitazonetreatedPvalue9.6 2.4 32.2 2.3 .2...........................................................................................................2.8 3.5 37.5 5.5 .7...........................................................................................................0.8 2.5 10.9 2.4 1.0...........................................................................................................0.7 0.02 0.7 0.03 .9...........................................................................................................1.9 0.3 2.4 0.4 .5...........................................................................................................0 5.7 79 7.4 .6...........................................................................................................0.4 0.07 0.5 0.1 .7...........................................................................................................2.5 0.5 2.2 0.6 .9...........................................................................................................ment of insulin resistance; HU, Haunsfield units; SAT,etabolic syndrome. Am J Obstet Gynecol 2013.seline) on outcome measurestreatedPioglitazonetreatedPvalue4.2 1.0 0.3 2.0 .3...........................................................................................................0.5 5.0 6.2 3.1 .4...........................................................................................................1.2 1.4 5.2 1.8 .2...........................................................................................................0.01 0.04 0.08 0.04 .2...........................................................................................................0.8 0.2 0.9 0.04a .02...........................................................................................................2.4 11.9 55.8 7.6 .1...........................................................................................................0.58 0.2 0.6 0.3a .03...........................................................................................................3.7 1.8 7.3 2.6a .03...........................................................................................................ment of insulin resistance; HU, Haunsfield units; SAT,offetabolic syndrome. Am J Obstet Gynecol 2013.APRIL 2013 American(Table 4, P .04). There were nonificant differences in the IGTT bloodcose levels between the 2male groupser treatment, although the PIO groupod glucose trended lower (Figure 1, AdB). In females, therewas a significantprovement in glucose IGTT as evi-nced in Figure 2, with glucose levelsing prominently lower at 30 minuteser the glucose challenge (Figure 2, A;.05) andwith significantly lower areader the IGTT curve (Figure 2, B; P ). The area under the curve calculatedm IGTT is one index of insulin sensi-ity; thus, insulin sensitivity was im-ved in mice treated with PIO, reach-statistical significance in females.Fasting insulin decreased after theatment with PIO in males while in-asing in control animals (Table 3, P). In females, the opposite occurred:ulin increased in treated and some-at decreased in control mice, al-ugh changes were not significantlyferent (Table 4). Similarly, insulin re-tance assessed by HOMA-IR was im-ved in PIO-treated males (Table 3,.03). In females, again, the opposites observed:HOMA-IRwas elevated in-treated mice (Table 4).Confocal imaging revealed that therere fewer adipocytes and they wereger in the PIO-treatedmice comparedth the nontreated controls (Table 5),hough it did not differ significantlytween the groups.MMENTthis study, we examined themetabolicects of a 2 week PIO treatment in off-ing exposed to a maternal prenatald early postnatal high-fat diet. PIOrapy significantly reduced serumglyceride, fasting glucose, and insu-levels. There was a trend toward aaller increase in VAT and bodyight, a larger increase in SAT, im-oved glucose tolerance and insulinsitivity, and larger adipocytes afterposure to PIO. Some of theseanges were different in males and fe-les. In addition to being the first toestigate postnatal treatment in thebaNon.........1....................................3...........................ssess)onN2.........3.........1...........................7...........................ssessof mspring of obese mothers, we are theJournal of Obstetrics& Gynecology 308.e4alsco mimoadapmitaltherisPIOofamgenfatfatclecofatleaadcirprodushosufgluthadiehuceihigtrebaNonB.........1....................................4...........................ssess.K of mA, IwitmaclepreIGTTof thKalpro201A, Iwittern(CTmenifiIGTTof thKalpro201Research Obstetrics www.AJOG.org30o first to demonstrate that PIOuld be used to treat MetS overall.TABLE 4Effects of pioglitazone (change fromin femalesVariableody weight, g..........................................................................................................................VAT as determined by CT (% from total area)..........................................................................................................................SAT as determined by CT (% from total area)..........................................................................................................................Liver/spleen radiodensity, HU..........................................................................................................................Triglyceride, mmol/L..........................................................................................................................Fasting glucose, mg/dL..........................................................................................................................Fasting insulin, ng/mL..........................................................................................................................HOMA-IR..........................................................................................................................Data are means SEM.CT, microcomputed tomography; HOMA-IR, homeostasis model asubcutaneous; SEM, standard error of the mean; VAT, visceral.a Statistically significant difference between the groups (P .05)alanderian. Pioglitazone and developmental programmingFIGURE 1Results of IGTT in male offspringGTT;B, area under the curve inmale offspringh prenatal and early postnatal exposure toternal high-fat diet after treatment with vehi-(CTR) or pioglitazone (PIO). Data are ex-ssed as mean SEM., intraperitoneal glucose tolerance test; SEM, standard errore mean.anderian. Pioglitazone and developmentalgramming of metabolic syndrome. Am J Obstet Gynecol3.ity8.e5 American Journal of Obstetrics& GynecologyA monthly quantitative noninvasivecro-CT scan of mice between 1 and 6nths of age determined that visceraliposity and fat deposition in the liverpears in 3 month old animals if thece were exposed to a maternal prena-and early postnatal high-fat diet;refore, the mice in our study were atk to develop metabolic syndrome.22was first administered at 2.5monthsage, before a significant increase in theount of VAT and hepatic fat infiltra-n was observed. Our demonstrationt PIO can be administered to mice atk to develop MetS and that this treat-nt can improve their metabolic statusmpared with their nontreated coun-parts is significant.Some of the PIO effects (fasting glu-se, triglyceride levels) were different inles and females. To our knowledge,re are no definitive data on sex differ-ces on the effects of TZDs, althoughe studies report a favorable effects ofon blood glucose control, especiallyfemale patients.33 We are inclined toribute sex differences observed in ourdel to a short duration of PIOatment.ZDs are high-affinity ligands forAR, and TZD activation of PPARadipose tissue alters glucose and lipidtabolism to improve insulin sensitiv-seline) on outcome measurestreatedPioglitazonetreatedPvalue2.3 0.2 0.3 0.9 .34...........................................................................................................0.5 5.1 4.8 2.7 .5...........................................................................................................0.7 2.9 1.2 1.5 .8...........................................................................................................0.0006 0.04 0.08 0.02 .3...........................................................................................................0.3 0.1 0.7 0.6 .7...........................................................................................................1.0 8.1 5.5 4.3a .04...........................................................................................................0.15 0.07 0.2 0.3 .4...........................................................................................................0.7 0.4 1.4 1.3 .4...........................................................................................................ment of insulin resistance; HU, Haunsfield units; SAT,etabolic syndrome. Am J Obstet Gynecol 2013.. Activated PPAR promotes adipo- dbAPRIL 2013esis and enhances the ability of whiteto store dietary fatty acids. As a result,ty acids are not stored in skeletal mus-or liver in which their accumulationuld impair insulin action; instead,ty acids are retained in adipose tissue,ding to increases in body weight andiposity. Consequently, TZDs reduceculating free fatty acid levels and im-ve glycemic control as a result of re-ced insulin resistance.34,35In our study, we determined that art, 2 week treatment with PIO wasficient to lower triglyceride, fastingcose, and insulin levels in offspringt were born to mothers on high-fatts. Similar results have been shown inmans with type 2 diabetes who re-ved PIO for 24 weeks, in mice fed ah-fat diet for 6 months and thenated with PIO for 2-3 months, and inFIGURE 2Results of IGTT in female offspringGTT;B, area under the curve in female offspringh prenatal and early postnatal exposure to ma-al high-fat diet after treatment with vehicleR) or pioglitazone (PIO). Data are expressed asan SEM. The asterisk indicates statistical sig-cance (P .05)., intraperitoneal glucose tolerance test; SEM, standard errore mean.anderian. Pioglitazone and developmentalgramming of metabolic syndrome. Am J Obstet Gynecol3.tiotharismecotercomatheensomPIOinattmotreTPPinme/db mice after 4 weeks of PIO treat-mewimodidwePIOCTfinmemowemearedafettradufintreannomithefatlatcifihuFupreincCTcoCheTZdiotrelivPTZsivstaadwhreptiddedecreaffelsdetrefecdismecanelsdyglyregthesocmiOuteninsprnoACWetanREF1. EamageUnpo2. GObcos3. Watpre4. Clonthe1135. BMewittione296. Kteryea73-7. Set atosiomoten8. Mal.siti2009. BmaandcomNu10.ob11711.Adand29512.anr vA.........6.5.........2.9..................1.9.........2.1.........of mwww.AJOG.org Obstetrics Researchnt.34,36-38 TZD therapy is associatedth weight gain in some patients and inuse models.34,36,38,39 PIO treatmentnot significantly increase total bodyight in our mice. On the contrary, thegroup gained less weight than theR animals.There are several explanations for ourdings. First, an increase in the treat-nt duration from 2 weeks to severalnths may have resulted in similaright gain as that observed in the afore-ntioned studies. Second, when TZDsgiven to pregnant animals on stan-rd chow for a few days to a few weeks,al weight does not increase. In con-st, embryonic and neonatal weight re-ctions have been reported.16-19 Ourdings confirm that short-durationatment has no effect on weight gaind raises the possibility that TZDs dot affect body weight in fetal program-ng models.Weight gain associated with TZDrapy is attributable to an increase inmass and fluid retention.39 TZD-re-ed increase in fat mass is depot spe-c: CT scans indicate PIO treatment inmans increase SAT but not VAT.37rthermore, when administered tognant animals, TZD does not lead toreased fetal visceral adiposity.16 Ourimaging results of VAT and SAT arensistent with these findings.linical studies have reported reducedpatic fat following administration ofDs.40 Similarly, the liver to spleen ra-density ratio increased in our PIO-ated mice, which reflects a decrease inTABLE 5Adipocyte size and numbers in maleafter administration of pioglitazone oVariable Nontreatedverage adipocyte size, m2.................................................................................................................Males 5740 54.................................................................................................................Females 3737 41..........................................................................................................................Average number of adipocytes.................................................................................................................Males 105.5 1.................................................................................................................Females 169.5 2..........................................................................................................................Kalanderian. Pioglitazone and developmental programminger fat infiltration. trerevious studies regarding the effect ofDs on adipocyte size were inconclu-e.34,38,41 In our study, although nottistically significant, we found largeripocytes after the PIO treatment,ich are in line with several earlierorts.38TZDs, especially PIO, are the only an-iabetic drug class that affects dyslipi-mia, one of the markers of MetS. PIOcreases triglyceride levels and in-ases HDL cholesterol levels withoutecting LDL and total cholesterol lev-.36 Although we observed a significantcrease in triglyceride levels after PIOatment, no other lipid-lowering ef-ts were determined. We attribute thiscrepancy to short-duration treat-nt, which was sufficient to signifi-tly change fasting blood glucose lev-but not long enough to improveslipidemia other than circulating tri-ceride levels. A longer treatmentimen may be required to observeanges in total cholesterol, HDL cho-terol, and LDL/VLDL cholesterolels.Themain limitation of our study is thert duration of treatment with PIO.e hypothesize that administeringatment for a longer period of time, upseveral months, may lead to a signifi-t improvement in the metabolic sta-of offspring born to obese mothers.addition, posttreatment monitoringuld determine whether improve-nts in metabolic parameters in thespring continue or diminish after thed female offspringehiclePioglitazone-treated P value...........................................................................................................6460 575.7 .4...........................................................................................................4901 711.4 .2......................................................................................................................................................................................................................102.2 9.5 .9...........................................................................................................113.8 15.6 .08...........................................................................................................etabolic syndrome. Am J Obstet Gynecol 2013.atment is discontinued.IncsomAPRIL 2013 AmericanIn summary, postnatal pioglitazonerapy attenuatesmetabolic changes as-iated with developmental program-ng in the offspring of obese mothers.r data are novel and we propose a po-tial role for PPAR ligands not onlythe prevention of MetS in adult off-ing of obese mothers but also as avel treatment for MetS. fKNOWLEDGMENTthank Ms Fernanda Vergara for her assis-ce with imaging studies.ERENCESrvin RB. Prevalence of metabolic syndromeong adults 20 years of age and over, by sex,, race and ethnicity, and body mass index:ited States, 2003-2006. Natl Health Stat Re-rt 2009:17.altier-Dereure F, Boegner C, Bringer J.esity and pregnancy: complications andt. Am J Clin Nutr 2000;71:1242S-8.hitaker RC. Predicting preschooler obesitybirth: the role of maternal obesity in earlygnancy. Pediatrics 2004;114:e29-36.atalano PM, Ehrenberg HM. The short- andg-term implications of maternal obesity onmother and her offspring. 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AJR Am J Roentgenol 2007;:1307-12.Speliotes EK, Massaro JM, Hoffmann U, etFatty liver is associated with dyslipidemia andglycemia independent of visceral fat: Themingham heart study. Hepatology 2010;51:9-87.Nishimura S, Manabe I, Nagasaki M, et al. Inimaging in mice reveals local cell dynamicsinflammation in obese adipose tissue. J Clinest 2008;118:710-21.APRIL 2013Goldberg RB, Kendall DM, Deeg MA, et al.omparison of lipid and glycemic effects ofglitazone and rosiglitazone in patients withe 2 diabetes and dyslipidemia. Diabetesre 2005;28:1547-54.Smith SR, de Jonge L, Volaufova J, Li Y,H, Bray GA. Effect of pioglitazone on bodyposition and energy expenditure: a ran-mized controlled trial. Metabolism 2005;:24-32.Yang KJ, Noh JR, Kim YH, et al. Differentialdulatory effects of rosiglitazone and pioglita-e on white adipose tissue in db/db mice. Lifei 2010;87:405-10.Wilding J. Thiazolidinediones, insulin resis-ce and obesity: finding a balance. Int J Clinct 2006;60:1272-80.Bajaj M, Suraamornkul S, Pratipanawatr T,al. Pioglitazone reduces hepatic fat contentaugments splanchnic glucose uptake inients with type 2 diabetes. Diabetes 2003;1364-70.Okuno A, Tamemoto H, Tobe K, et al. Tro-azone increases the number of small adi-cytes without the change of white adiposeue mass in obese Zucker rats. J Clin Invest8;101:1354-61.Pioglitazone therapy in mouse offspring exposed to maternal obesityMaterials and MethodsStudy designIn vivo imagingIntraperitoneal glucose tolerance testSerologic analysisData analysisResultsCommentAcknowledgmentReferences

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