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Freeman o&p2013


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  • The anti-lipolytic alpha2 and the pro-lipolyic beta2 are more highly expressed in the subcutaneous depot.The beta-3 adrenoceptor is more highly expressed in the subcutaneous depot however, it’s physiological role is still debated as it isn’t thought to contribute to catecholamine-induced lipolysis in human adipocytes.B1 and B2 shown to be higher in visceral in non-pregnant – thought to be responsible for differences in catecholamine responses
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    • 1. The impact of obesity on the maternal metabolicadaptation to pregnancyDilys J FreemanInstitute for Cardiovascular and Medical SciencesUniversity of Glasgow
    • 2. Dilys J FreemanDisclosed no conflict of interestPresenter Disclosure Information
    • 3. • Healthy pregnancy• Obese pregancy• Complicated pregnancy (preeclampsia)
    • 4. HealthyHHealthy Pregnancy
    • 5. Gestational hormonal changesPaulev and Zubieta-Calleja, Textbook in MedicalPhysiology and Pathophysiology, 2nd Ed
    • 6. Taggart (1967) Br J Nutr 21;439Fat acquisition during pregnancy
    • 7. Adipose tissue adaptation to pregnancyFirst trimester gain ininsulin sensitivityGain in fatMid-trimester loss ofinsulinsensitivityIncreased adiposeturnoverFetal growthNon-pregnant Mid gestation TermHuda et al Clinical Lipidology 2009NEFA
    • 8. Plasma NEFA flux vs concentrationTG NEFAAdiposeTissuePlasmacompartmentLiver/PlacentaUtilisationTG NEFA UtilisationNon-pregnantPregnant
    • 9. SAT physiological storage depot inpregnancy↑ NEFA releasepregnancy hormonesinsulin resistance+VLDL
    • 10. Adipose tissue depots – relativecontributionVisceral(VAT)SubcutaneousUpper body(USAT)Lower body(LSAT) lipolysis net lipolysismmol/L/ugDNAglycerolorNEFAUSATVATHuda et al submittedP=0.005*P=0.026*USAT is more lipolytic than VAT inthe third trimester of pregnancyEx-vivo basal adipocyte lipolysis experiments
    • 11. Effect onlipolysis: + +- + + + -/?-+/?Forrest et al unpublishedSAT and VAT lipolysis regulated differentlyReceptor profile suggests:- in VAT pregnancy hormones reduce lipolysis- in SAT pregnancy hormones promote lipolysis andadrenergic-driven lipolysis is reduced
    • 12. SAT as a reservoir of fatty acids in health• Based on the functionality and size of the SAT depot, wewould suggest that in healthy pregnancy plasma NEFA arederived from this depot• In the non-pregnant (Jensen et al JCEM 2008), USAT isestimated to be the source of 60% of circulating NEFA, LSAT15-20% and VAT 6-17%• SAT provides a “safer” depot for gestationally-acquired fat asVAT releases NEFA into the portal circulation and hencedirectly to the liver
    • 13. SAT vs VAT lipolytic and lipogenicfunction020406080100120insulin sensitivitypercentinhibitionofIPAstimulatedlipolysis%USATVATP=0.046*Ex-vivo basal adipocyte lipolysis experimentsHuda et al submittedUSAT and UVAT mRNA expressionInsulin sensitivity assessed as insulin suppression ofisopreterenol-stimulated lipolysisExpressionrelativetoPPIA(%)051015SubcutaneousVisceral*INSRExpressionrelativetoPPIA(%)050100150200***LPLSubcutaneousVisceralLPL is a lipogenic enzymeInsulin receptorLipoprotein lipase
    • 14. Improved vascular function is a keyadaptation to pregnancyEndothelium-dependent microvascular functionStewart et al JCEM 2007P<0.001Required for placentalformation and perfusion
    • 15. Hypertriglyceridaemia:the need for vascular protectionRasmussen et al Scan J Clin Lab Inv 2009Data compiled from different overlappinglongitudinal studies* Significantly different from baseline0.000.501.001.502.002.503.003.500 5 10 15 20 25 30 35 40 45 50 55 60 65weeks (gestation)mmol/LTriglycerideTriglyceride** ***Mackay et al unpublished
    • 16. Late gestational lipid metabolismHuda et al Clinical Lipidology 2009
    • 17. High Density Lipoprotein (HDL)Reverse cholesterol transportDelivery of cholesterol tosteroidogenic tissuesVascular protection:-• Prevents LDL oxidation• Inhibits ROS generation andinflammatory signalling• Inhibits apoptosis & necrosis• Promotes cell survival bycarrying protective agentssuch as S-1-P
    • 18. 5 10 15 20 25 30 35 40 45 50 55 60 65weeks (gestation)mmol/LHDL0.000.501.001.502.002.503.003.50mmol/LtriglycerideHDL TriglycerideHDL increases over gestationDelivery30%increasePlacental circulationestablishedData compiled from different overlapping longitudinal studiesn=225Mackay et al unpublished
    • 19. HDL and endothelium-dependent vascularfunction in pregnancy1.000.750.500.250.00-0.25-0.501000050000-5000-10000-15000-20000Gestational change in HDL (mmol/L)GestationalchangeinEDMVF(PUMOhm.min)r=0.42, p=0.013,r2=18% independent of maternal age, parity and smoking statusGestational change =Post natal HDL - T3 HDLNo significant associationwith endothelium-independentmicrovascular functionn=34 Mackay et al unpublished
    • 20. Concentration vs functionBut.............HDL concentration tells us nothing about HDL function
    • 21. AUC HDL (mmol/L*weeks)incrementalAUCparaoxonase(ug/mL*weeks)r=0.47, p=0.043, r2=17%Paraoxonase – PON-1• Responsible for most of the anti-oxidative effects of HDL• Protects against atherogenesis• Synthesised in the liver, carried byHDL• Hydrolytic activity decreases lipidperoxides• Mixed data on the effect of gestationon PON-1 activityn=19Mackay et al unpublished
    • 22. Maternal Obesity
    • 23. Maternal obesity and hormonesMeyer et al JCEM 2013Huda et al unpublishedP=0.0380246810121416Progesterone Placental lactogenProgesteroneorplacentallactogen(ug/mL)healthy overweight obese
    • 24. Jarvie et al unpublishedFat acquisition during pregnancyin lean and obese women0510152025303540455015 25 35gestation (weeks)fatmass(kg)leanobeseLean 4.3 kgObese 4.0 kgLean and obese women accumulate similar mass of fatSee Ellie’s poster No. 15 for more detailon the contributory elements of energymetabolism to this fat gain in lean andobese women
    • 25. Maternal BMI and triglyceride response topregnancy00.511.522.533.515 20 25 30 35 40 45BMI (kg/m2)Triglyceride(mmol/L)Trimester 1 Trimester 2 Trimester 3 Postnatal154%66%Meyer et al JCEM 2013Actually a larger TG response inhealthy weight than obese womenHealthy weight women are moremetabolically flexible
    • 26. baselinegestation(weeks)metabolic marker(concentration)Location of fat and adaptation topregnancyMetabolicmarkerFatdepotPearsoncorrelationcoefficientunivariateContributionto variancemultivariateP value Adjusted†contributionto variancemultivariateAdjustedP valueVLDL-1 UVAT -0.23 19.3% 0.005 13.3% 0.026USAT 0.15 14.4% 0.013 12.9% 0.028VLDL-2 UVAT -0.32 13.1% 0.027 5.3% 0.075Incremental area under the curve† adjusted for maternal age, parity, smoking status, deprivation category and gestations at samplingJarvie et al unpublished
    • 27. Metabolic flexibility in pregnancyHigh UVAT/ USATLow UVAT/USATSattar & Freeman Chpt 5; 45-55Maternal Obesity Ed Gillman & Poston
    • 28. Obese pregnancy & microvascularfunctionPredictors of endothelium-dependentmicrovascular function in obesepregnancy:• obesity, 19.3%, p<0.001• gestation, 11.2% p<0.001• IL-6, 4.0%, p=0.002• IL-10, 2.4%. P=0.018Endothelium dependentEndothelium independentStewart et al JCEM 2007P<0.001P=0.021
    • 29. Baseline metabolic markers -independent association with fat depotMetabolicmarkerFatdepotPearsoncorrelationcoefficientunivariateContributionto variancemultivariateP value Adjusted†contributionto variancemultivariateAdjustedP valueLeptin USATUVAT0.680.659.1%6.3%0.0020.0098.9%4.0%0.0070.039Adiponectin UVAT -0.46 8.4% 0.020 9.4% 0.018IL-6 USAT 0.57 8.4% 0.009 8.2% 0.013CRP USAT 0.55 11.2% 0.004 9.7% 0.007End DepMicrovascularFunctionUVAT -0.43 7.7% 0.025 5.7% 0.062† adjusted for maternal age, parity, smoking status, deprivation category and baseline gestationBaselineJarvie et al unpublished
    • 30. Hypertrophy vs hyperplasia of adipocytesIncreased flux of non-esterified fatty acids (NEFA)Central obesityNon-obese or lowerbody obesitymacrophage infiltrationand adipokine secretionlipolysisHypertrophy Hyperplasia
    • 31. Ex-vivo maternal USAT adipocyteCRP secretionUSAT and UVAT adipocyteswere prepared by collagendigestion from fat biopsies at C-section.CRP secretion from theseadipocytes was measured usinga suspension array (Bioplex).USAT, but not UVAT, adipocyteCRP secretion correlated withthird trimester maternal plasmaCRP levels. CRP basal release (SAT)logmaternalCRP(plasma)r=0.66r=0.66, p=0.005Huda et al unpublished
    • 32. Pregnancy exposure to metabolicmarker - independent association withfat depotMetabolicmarkerFatdepotPearsoncorrelationcoefficientunivariateContributionto variancemultivariateP value Adjusted†contributionto variancemultivariateAdjustedP valueCRP USAT 0.47 7.6% 0.047 8.3% 0.037End DepMicrovascularFunctionUSAT -0.59 12.1% 0.007 13.3% 0.009Total area under the curve† adjusted for maternal age, parity, smoking status, deprivation category and gestations at samplingJarvie et al unpublished
    • 33. Maternal BMI and HDL concentration11. 20 25 30 35 40 45BMI (kg/m2)HDLcholesterol(mmol/L)Trimester 1 Trimester 2 Trimester 3 Post natal20%12%n=98Mackay et al unpublished
    • 34. Pregnancy Complications
    • 35. O’Brien et al (2003) Epidemiology1 BMI unit 0.5% PE prevalenceTorloni et al (2009) Obesity Rev1 BMI unit 0.9% GDM prevalenceMaternal BMI and incidence of GDMand PE
    • 36. Obesity and the development of type 2diabetes in the non-pregnantExcess dietary fatNEFA spilloverpancreatic beta cellmuscleliverHypertrophic obesityEctopic lipid accumulation
    • 37. Adipocyte function in PEFCISIcontrol vs. PEFCISI(%)-50050100150Control ControlPE PESATVAT0.04FCISIControl vs. PEFat cell insulin sensitivity index (FCISI) –the ability of insulin to suppress betaadrenergic stimulated lipolysisHuda et al unpublishedIn PE, SAT adipocytes as insulin resistantas VAT
    • 38. Plasma NEFA flux vs concentrationTG NEFAAdiposeTissuePlasmacompartmentLiver/PlacentaUtilisationTG NEFA UtilisationTG NEFA Utilisationlipolysis ↓ utilisationNon-pregnantPregnantPregnant - pathological
    • 39. Ectopic fat is the problem not obesityStefan et al Arch Intern Med 2008
    • 40. Plasma markers of liver fat in thenon-pregnant• Fatty liver is a powerful determinant of plasma small dense LDL(Sugino et al J Atheroscler Thromb 2011;18:1-7)• Fatty liver in type 2 diabetes is associated with increased smalldense LDL (Toledo et al Diabetes Care 2006;29:1845-50)• In NAFLD there is depletion of LC PUFA possibly via reduced5- and 6-desaturase activities (Videla et al, Free Radic Biol Med 2004)
    • 41. Increased small dense LDL in obesepregnancyIn the third trimester, the proportion of small, dense LDL was2-fold higher in obese women than normal weight womenand 35% of obese, 14% of overweight, and none of thenormal weight women displayed an atherogenic LDLsubfraction phenotype.Trimester 30%20%40%60%80%100%Healthy Obese% LDL-III% LDL-II% LDL-IP=0.004P=0.005Meyer et al JCEM 2013
    • 42. Evidence for ectopic fat in PE -decreased LC PUFA synthesisMaternal CordMaternal and cord blood LC PUFAconcentrationsSubcutaneous adipose tissueenzyme mRNA expressionFADS1 - 5 desaturaseFADS2 - 5 desaturaseSCD - stearoyl coA desaturaseELOVL2- very long chain FA elongaseELOVL6 – long chain FA elongaseMacKay et al Hypertension 2012Subcutaneous adipose tissue02468101214FADS1 FADS2 SCD ELOVL2 ELOVL6mRNAexpression(sqrttarget/PPIA)ControlPEIUGRP=0.020*P=0.001*P=0.043#
    • 43. Excess dietary fatpancreas placenta?liverHypertrophic obesityEctopic lipid accumulationEctopic sites of fat storage inpregnancyNEFAspillovervisceraladipose tissuebloodvessel
    • 44. Placental lipidomic analysisFigure 1. A. Total placental lipid, ** P<0.05 vs control and IUGR and B. Placental phosphatidyl choline (PC) arachidonic acid(AA) content * P<0.05 vs control, mean (SEM), in healthy (n=70), preeclampsia (n=19) and IUGR (n=12) pregnancy.Eather, Freeman, Brown, Mitchell, Meyer unpublishedUniversity of WollongongPlacental lipids were extracted and analysed on a hybrid triple quadrupole, linear ion trap massspectrometer (AB Sciex QTRAP 5500) equipped with an automated, chip-based nanospraysource (Advion Triersa Nanomate).PE placenta has highertotal lipid content andarachidonic acidcontent than controls
    • 45. Implications for placental function –inflammation?Figure 1: Placental samples showing CD68 positive macrophages (brown) under magnificationx 40. (A) BMI ≥35 kg/m2, (B) BMI <35 kg/m2. Scale bar (bottom right) represents 50 m.Figure 1C: Boxplot comparing log macrophage counts in the BMI<35kg/m2 group compared tothe BMI≥35kg/m2 group. Represented as median, inter-quartile range, maximum and minimumof log transformed data.AB>or=35<353. (kg/m2 )Logmacrophagedensity(countsperfield)p=0.004Huda et al unpublished
    • 46. Pavan et al Endocrin 2004……probably via LXR activationOxLDL inhibits trophoblast invasion…..Implications for placental function –trophoblast function?
    • 47. Decreased antioxidant defences inpreeclampsia050100150200250300Control PE IUGRParaoxonaseactivity(ug/mL)P=0.012n=125 n=57 n=16Lower paraoxonase activity inpreeclampsiaDysfunctional HDL?Mackay et al unpublished
    • 48. Maternal obesity - a perfect storm?Maternal obesitylipolysis’safe’ storage of TGinsulin resistanceoxidative stressoxidised lipidsectopic fat accumulationlipotoxicityplacentaNEFAmaternalendothelial /vascularstresstrophoblast invasion? uteroplacentalinsufficiencyaltered development, fatmetabolism & transport& inflammationoffspring obesityadverse maternaloutcomeJarvie et al Clin Sci 2010
    • 49. AcknowledgementsICAMSEllie JarvieRachel ForrestAnn BrownFiona JordanVanessa Mackay (néeRodie)Frances StewartChristopher OnyiaodikeNaveed SattarMuriel CaslakeGlasgow CollaboratorsBill FerrellShahzya HudaScott NelsonUniversity of ManchesterMike MacknessProject studentsJack BraySam EatherLouise McKennaIain MartinNicole PattersonUniversity of WollongongBarbara MeyerTodd MitchellSimon BrownUniversity of SurreyBruce GriffinUniversity of UmeaGunilla Olivecrona