For this study we enrolled pregnant women, who were obese when entering pregnancy, and they were randomized to either placebo or 800 mg/day DHA. There were three study visits, at enrollment at 26 weeks gestation, the next visit at 32 weeks gestation, and finally near term at 36 weeks gestation. At delivery we collected the placentas for analysis. Company MARTEK (lif’s DHA). The placebo was a mixture of corn/soy bean oil. The DHA was of a non-fish source. Four tablets á 200 mg/day.
Maternal Obesity andPlacental FunctionTheresa Powell, PhDCenter for Pregnancy and Newborn ResearchDepartment of Obstetrics and GynecologyUniversity of Texas Health Science CenterSan Antonio, Texas
Obesity in PregnancyMaternal pregnancy risksmiscarriage/stillbirth, gestational hypertension, pre-eclampsia, gestational diabetesFetal risksincreased incidence of birth defects (folate insensitive)fetal overgrowth LGA (large for gestational age)birth trauma, increased surgical deliveriesLong term (programming) effects for the childobesityType 2 diabetesdyslipidemiahypertension
Obesity in Pregnancy:Hispanic Mothers in South TexasMaternal MetabolismWhat is the metabolic phenotype of the obese motherwithout gestational diabetes?Altered Placental FunctionHow does placental function change in cases ofmaternal obesity, what regulates those changes?Fetal OvergrowthWhat is the mechanism underlying fetal overgrowth inobese mothers?
Maternal Metabolism in HighBMI PregnancyNormal Glycemia with Insulin ResistanceHigh fasting InsulinHigh LeptinLow AdiponectinHyperlipidemia
Birth weight is correlated withpre-pregnancy BMIN=49r=0.42p<0.01Jansson, N et al 2008,Am J Clin Nutr 87:1743-1749.
Does the “Pedersen Hypothesis”apply to obese pregnancy?• 50 years ago Pedersen suggestedfetal overgrowth in diabetic pregnancies was related toincreased transplacental transfer of glucoseincreased release of insulin by the fetal beta cellstimulated growth and subsequently macrosomia.• True for obesity in pregnancy ?• Critical role of the placenta in determining fetalgrowth rates.Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic?Am J Obstet Gyn, 2011 204:479-487 Catalano and Hauguel-De Mouzon
Placental Function and FetalOvergrowthWe hypothesized that placental nutrient transportis increased in obese women leading to fetalovergrowth and its associated long term healthconsequences.
Is Placental Nutrient TransportAltered in Obese Mothers?Amino Acids• Multiple transport proteins are• responsible for uptake and transfer• of AAs• Non-Essential AA: System A• sodium dependent• SNAT 1, 2 and 4• Essential AA: System L• exchanger• LAT1 and LAT2, CD98Na+AALeucineAAMVM BM
System A Expression: MVMSNAT2 SNAT4n=10 n=12 n=10 n=12
System A activity correlates withbirth weight0204060801001201402700 3200 3700 4200MVMMeAIBuptakepmol/mgx30sBirth weight (g)N=21R=0.60P<0.001
Is Placental Nutrient TransportAltered in Obese Mothers?Fatty AcidsMulti-step process• Lipase activity to releasefatty acids from TGUptake by fatty acids transport proteins• Bound in the cytoplasm by• fatty acid binding proteins• Released to the fetal circulation.TGFATPMVM BMLPLFAsFATP
What regulates increased nutrienttransporter expression in obese mothers?• The placenta, uniquely juxtapositionedbetween the maternal and fetal bloodsupplies, must integrate both maternalsupply and fetal demand signals.• Metabolic signals are diverse and include:• macronutrients (glucose, amino acids, fatty acids)• hyperinsulinemia• elevated adipokines (leptin, TNF-a, IL1-b)• low levels of adiponectin
Insulin and Leptin stimulate amino aciduptake in villous explantsJansson N, et al. 2003J Clin Endocrinol Metab.88(3):1205-11.Nina Jansson
Mammalian Target of RapamycinA large number of upstream regulators of mTOR Complex 1mTORRaptorS6K1Thr 389PRPS6PTranslation4E-BP1PThr 37, 46 & 70Ser 235 & 236Insulin/IGF-I receptorPAKTIRS-1PI3KPp85hVps34TSC1/2GlucoseAmino acidsATPOxygenTyr 612PThr308FFALRbCortisolREDD1
mTOR and placental amino acidtransportRosario FJ et alJ Physiol. 2013
Toll like Receptor 4SFA and MUFAPro-InflammatoryResponseLPS
Oleic acid stimulates amino aciduptake through a TLR4 mechanismLager S, et al .J Lipid Res. 2013Susanne Lager
01234560 0.002 0.02 0.2[TNF-a] ng/mlMeAIBuptakepmol/mg/minANOVA p=0.004 n = 6 for each concentration****Amino acid uptake is stimulated by TNF-ain primary cultured trophoblast cellsTNF-aJones et al, 2009Am J Physiol, Cell Physiol297:1228-1235.Helen Jones
Effects of SFA, MUFA and LCPUFA on trophoblastamino acid uptake
Study participants (n=35):• Obese (≥30 kg/m2) pre-pregnancy BMI.• Singleton pregnancies.• Exclusion criteria: concurrent inflammatory, vascular, or metabolic disease (such asdiabetes, pre-eclampsia), tobacco or street drug use, high usual intake of DHA.RecruitmentStudy visit 1:Enrollment/baseline26 weeks 32 weeksStudy visit 2:Compliance36 weeksStudy visit 3:CompliancePlacentacollection andanalysisTerm800 mg/day DHA or PlaceboDHA Supplementation in ObeseMothers: Study Design
DHA supplementation in obesepregnant women024681012PercentoftotalFASV1 SV3 SV1 SV3Placebo DHA*
DHA supplementation: effects onplacental function
Fatty Acids and Placental Function• We have demonstrated that saturated andmonounsaturated fatty acids stimulatetrophoblast System A amino acid uptake in aTLR4 dependent manner.• Omega3 long chain polyunsaturated fatty acidsinhibit amino acid uptake by System A.• DHA supplementation modulates placentalnutrient transport capacity in obese mothers.
Jansson N et al 2008, Am J Clin Nutr 87:1743-1749.r = -0.592, p<0.001Maternal adiponectin, placental function andfetal growthHypothesis: Maternal adiponectindown-regulates placental nutrienttransport and inhibit fetal growth.Jones HN et al., 2010, Diabetes 59:1161-1170N=6, ANOVA<0.0502468101214161820C I IAd AdSystemAactivitypmmo;/mg/min*
Chronic maternal infusion adiponectin inpregnant miceInfusion (mini-osmotic pump) of full length adiponectinGestational days 14.5-18.5 in miceDecreased pup weight ( -20%)Decreased placental amino acid transport04080120System ASystemAuptakepmol/mgprotein/15sec*00.10.20.30.40.50.6System LSystemLuptakepmol/mgprotein/15secC A*Rosario et al 2012 J Physiol 590:1495-1509
Adiponectin in PregnancyAdiponectin is insulin sensitizing in adult tissuesbut causes insulin resistance in placenta.Adiponectin is high in lean women and acts toinhibit placental insulin signaling. This would tendto decrease amino acid uptake in normal healthypregnancies.Obese women have low adiponectin which wouldpromote insulin stimulated amino acid transferacross the placenta.
High BMIHigher fasting insulin, leptin, cytokinesLow adiponectinHyperlipidemia –SFA and MUFALow omega3 LCPUFAMaternal metabolicfactors stimulate theplacenta to transportnutrientsIncreased nutrientdelivery to the fetusstimulates growththrough insulin releaseOmega3 LCPUFA
From Lager and PowellJ of Pregnancy 2013Integration of Signals: Mother Fetus PlacentaThe placenta integrates signalsfrom both the mother and fetus.Extrinsic signals such ashormones, cytokines, maternalnutrient and energy levelsIntrinsic placental signalingpathways for nutrientsensing, inflammation, andgrowth.
Obesity, Placenta and Developmental ProgrammingUnderstanding the complex placental signalingpathways that lead to alterations in fetal growth willallow for the development of strategies to preventshort- and long-term health consequences ofpathological fetal growth.
Thank you!to the mothers and babies University Hospital in San AntonioThomas JanssonPost Docs, Fellowsand studentsOur funding sources:Swedish Research CouncilNOVO NordiskaNIH NHLBI R21HL093532CTSA UL1RR025767Mike Hogg FundNIH NIDDK RO1 DK89989NIH NICHD R03 HD058030NIH NICHD R01 HD058045