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Freeman o&p2013
- 1. The impact ofobesity on the maternal metabolic adaptation to pregnancy Dilys J Freeman Institute for Cardiovascular and Medical Sciences University of Glasgow
- 2. Dilys J Freeman Disclosedno conflict of interest Presenter Disclosure Information
- 3. • Healthy pregnancy •Obese pregancy • Complicated pregnancy (preeclampsia)
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- 5. Gestational hormonal changes Paulevand Zubieta-Calleja, Textbook in Medical Physiology and Pathophysiology, 2nd Ed
- 6. Taggart (1967) BrJ Nutr 21;439 Fat acquisition during pregnancy
- 7. Adipose tissue adaptationto pregnancy First trimester gain in insulin sensitivity Gain in fat Mid-trimester loss of insulin sensitivity Increased adipose turnover Fetal growth Non-pregnant Mid gestation Term Huda et al Clinical Lipidology 2009 NEFA
- 8. Plasma NEFA fluxvs concentration TG NEFA Adipose Tissue Plasma compartment Liver/ Placenta Utilisation TG NEFA Utilisation Non-pregnant Pregnant
- 9. SAT physiological storagedepot in pregnancy ↑ NEFA release pregnancy hormones insulin resistance + VLDL
- 10. Adipose tissue depots– relative contribution Visceral (VAT) Subcutaneous Upper body (USAT) Lower body (LSAT) 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5 total lipolysis net lipolysis mmol/L/ugDNAglycerolorNEFA USAT VAT Huda et al submitted P=0.005 * P=0.026 * USAT is more lipolytic than VAT in the third trimester of pregnancy Ex-vivo basal adipocyte lipolysis experiments
- 11. Effect on lipolysis: ++- + + + -/?-+/? Forrest et al unpublished SAT and VAT lipolysis regulated differently Receptor profile suggests: - in VAT pregnancy hormones reduce lipolysis - in SAT pregnancy hormones promote lipolysis and adrenergic-driven lipolysis is reduced
- 12. SAT as areservoir of fatty acids in health • Based on the functionality and size of the SAT depot, we would suggest that in healthy pregnancy plasma NEFA are derived from this depot • In the non-pregnant (Jensen et al JCEM 2008), USAT is estimated to be the source of 60% of circulating NEFA, LSAT 15-20% and VAT 6-17% • SAT provides a “safer” depot for gestationally-acquired fat as VAT releases NEFA into the portal circulation and hence directly to the liver
- 13. SAT vs VATlipolytic and lipogenic function 0 20 40 60 80 100 120 insulin sensitivity percentinhibitionofIPA stimulatedlipolysis% USAT VAT P=0.046 * Ex-vivo basal adipocyte lipolysis experiments Huda et al submitted USAT and UVAT mRNA expression Insulin sensitivity assessed as insulin suppression of isopreterenol-stimulated lipolysis ExpressionrelativetoPPIA(%) 0 5 10 15 Subcutaneous Visceral * INSR ExpressionrelativetoPPIA(%) 0 50 100 150 200 *** LPL Subcutaneous Visceral LPL is a lipogenic enzyme Insulin receptor Lipoprotein lipase
- 14. Improved vascular functionis a key adaptation to pregnancy Endothelium-dependent microvascular function Stewart et al JCEM 2007 P<0.001 Required for placental formation and perfusion
- 15. Hypertriglyceridaemia: the need forvascular protection Rasmussen et al Scan J Clin Lab Inv 2009 Data compiled from different overlapping longitudinal studies * Significantly different from baseline 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 0 5 10 15 20 25 30 35 40 45 50 55 60 65 weeks (gestation) mmol/LTriglyceride Triglyceride * * * * * Mackay et al unpublished
- 16. Late gestational lipidmetabolism Huda et al Clinical Lipidology 2009
- 17. High Density Lipoprotein(HDL) Reverse cholesterol transport Delivery of cholesterol to steroidogenic tissues Vascular protection:- • Prevents LDL oxidation • Inhibits ROS generation and inflammatory signalling • Inhibits apoptosis & necrosis • Promotes cell survival by carrying protective agents such as S-1-P
- 18. 1.00 1.20 1.40 1.60 1.80 2.00 2.20 0 5 1015 20 25 30 35 40 45 50 55 60 65 weeks (gestation) mmol/LHDL 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 mmol/Ltriglyceride HDL Triglyceride HDL increases over gestation Delivery 30% increase Placental circulation established Data compiled from different overlapping longitudinal studies n=225 Mackay et al unpublished
- 19. HDL and endothelium-dependentvascular function in pregnancy 1.000.750.500.250.00-0.25-0.50 10000 5000 0 -5000 -10000 -15000 -20000 Gestational change in HDL (mmol/L) GestationalchangeinEDMVF(PUMOhm.min) r=0.42, p=0.013, r2=18% independent of maternal age, parity and smoking status Gestational change = Post natal HDL - T3 HDL No significant association with endothelium- independent microvascular function n=34 Mackay et al unpublished
- 20. Concentration vs function But............. HDLconcentration tells us nothing about HDL function
- 21. 10.07.55.02.50.0-2.5-5.0 2500 2000 1500 1000 500 0 -500 -1000 incremental 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 by HDL • Hydrolytic activity decreases lipid peroxides • Mixed data on the effect of gestation on PON-1 activity n=19 Mackay et al unpublished
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- 23. Maternal obesity andhormones Meyer et al JCEM 2013 Huda et al unpublished P=0.038 0 2 4 6 8 10 12 14 16 Progesterone Placental lactogen Progesteroneorplacental lactogen(ug/mL) healthy overweight obese
- 24. Jarvie et alunpublished Fat acquisition during pregnancy in lean and obese women 0 5 10 15 20 25 30 35 40 45 50 15 25 35 gestation (weeks) fatmass(kg) lean obese Lean 4.3 kg Obese 4.0 kg Lean and obese women accumulate similar mass of fat See Ellie’s poster No. 15 for more detail on the contributory elements of energy metabolism to this fat gain in lean and obese women
- 25. Maternal BMI andtriglyceride response to pregnancy 0 0.5 1 1.5 2 2.5 3 3.5 15 20 25 30 35 40 45 BMI (kg/m2) Triglyceride(mmol/L) Trimester 1 Trimester 2 Trimester 3 Postnatal 154% 66% Meyer et al JCEM 2013 Actually a larger TG response in healthy weight than obese women Healthy weight women are more metabolically flexible
- 26. baseline gestation (weeks) metabolic marker (concentration) Location offat and adaptation to pregnancy Metabolic marker Fat depot Pearson correlation coefficient univariate Contribution to variance multivariate P value Adjusted† contribution to variance multivariate Adjusted P value VLDL-1 UVAT -0.23 19.3% 0.005 13.3% 0.026 USAT 0.15 14.4% 0.013 12.9% 0.028 VLDL-2 UVAT -0.32 13.1% 0.027 5.3% 0.075 Incremental area under the curve † adjusted for maternal age, parity, smoking status, deprivation category and gestations at sampling Jarvie et al unpublished
- 27. Metabolic flexibility inpregnancy High UVAT/ USAT Low UVAT/USAT Sattar & Freeman Chpt 5; 45-55 Maternal Obesity Ed Gillman & Poston
- 28. Obese pregnancy µvascular function Predictors of endothelium-dependent microvascular function in obese pregnancy: • obesity, 19.3%, p<0.001 • gestation, 11.2% p<0.001 • IL-6, 4.0%, p=0.002 • IL-10, 2.4%. P=0.018 Endothelium dependent Endothelium independent Stewart et al JCEM 2007 P<0.001 P=0.021
- 29. Baseline metabolic markers- independent association with fat depot Metabolic marker Fat depot Pearson correlation coefficient univariate Contribution to variance multivariate P value Adjusted† contribution to variance multivariate Adjusted P value Leptin USAT UVAT 0.68 0.65 9.1% 6.3% 0.002 0.009 8.9% 4.0% 0.007 0.039 Adiponectin UVAT -0.46 8.4% 0.020 9.4% 0.018 IL-6 USAT 0.57 8.4% 0.009 8.2% 0.013 CRP USAT 0.55 11.2% 0.004 9.7% 0.007 End Dep Microvascular Function UVAT -0.43 7.7% 0.025 5.7% 0.062 † adjusted for maternal age, parity, smoking status, deprivation category and baseline gestation Baseline Jarvie et al unpublished
- 30. Hypertrophy vs hyperplasiaof adipocytes Increased flux of non-esterified fatty acids (NEFA) Central obesity Non-obese or lower body obesity macrophage infiltration and adipokine secretion lipolysis Hypertrophy Hyperplasia
- 31. Ex-vivo maternal USATadipocyte CRP secretion USAT and UVAT adipocytes were prepared by collagen digestion from fat biopsies at C- section. CRP secretion from these adipocytes was measured using a suspension array (Bioplex). USAT, but not UVAT, adipocyte CRP secretion correlated with third trimester maternal plasma CRP levels. 3.02.52.01.51.0 1.2 1.0 0.8 0.6 0.4 0.2 0.0 log CRP basal release (SAT) logmaternalCRP(plasma) r=0.66 r=0.66, p=0.005 Huda et al unpublished
- 32. Pregnancy exposure tometabolic marker - independent association with fat depot Metabolic marker Fat depot Pearson correlation coefficient univariate Contribution to variance multivariate P value Adjusted† contribution to variance multivariate Adjusted P value CRP USAT 0.47 7.6% 0.047 8.3% 0.037 End Dep Microvascular Function USAT -0.59 12.1% 0.007 13.3% 0.009 Total area under the curve † adjusted for maternal age, parity, smoking status, deprivation category and gestations at sampling Jarvie et al unpublished
- 33. Maternal BMI andHDL concentration 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2 15 20 25 30 35 40 45 BMI (kg/m2) HDLcholesterol(mmol/L) Trimester 1 Trimester 2 Trimester 3 Post natal 20% 12% n=98 Mackay et al unpublished
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- 35. O’Brien et al(2003) Epidemiology 1 BMI unit 0.5% PE prevalence Torloni et al (2009) Obesity Rev 1 BMI unit 0.9% GDM prevalence Maternal BMI and incidence of GDM and PE
- 36. Obesity and thedevelopment of type 2 diabetes in the non-pregnant Excess dietary fat NEFA spillover pancreatic beta cell muscle liver Hypertrophic obesity Ectopic lipid accumulation
- 37. Adipocyte function inPE FCISI control vs. PE FCISI(%) -50 0 50 100 150 Control ControlPE PE SAT VAT 0.04 FCISI Control vs. PE Fat cell insulin sensitivity index (FCISI) – the ability of insulin to suppress beta adrenergic stimulated lipolysis Huda et al unpublished In PE, SAT adipocytes as insulin resistant as VAT
- 38. Plasma NEFA fluxvs concentration TG NEFA Adipose Tissue Plasma compartment Liver/ Placenta Utilisation TG NEFA Utilisation TG NEFA Utilisation lipolysis ↓ utilisation Non-pregnant Pregnant Pregnant - pathological
- 39. Ectopic fat isthe problem not obesity Stefan et al Arch Intern Med 2008
- 40. Plasma markers ofliver fat in the non-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 small dense LDL (Toledo et al Diabetes Care 2006;29:1845-50) • In NAFLD there is depletion of LC PUFA possibly via reduced 5- and 6-desaturase activities (Videla et al, Free Radic Biol Med 2004)
- 41. Increased small denseLDL in obese pregnancy In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal weight women and 35% of obese, 14% of overweight, and none of the normal weight women displayed an atherogenic LDL subfraction phenotype. Trimester 3 0% 20% 40% 60% 80% 100% Healthy Obese % LDL-III % LDL-II % LDL-I P=0.004 P=0.005 Meyer et al JCEM 2013
- 42. Evidence for ectopicfat in PE - decreased LC PUFA synthesis Maternal Cord Maternal and cord blood LC PUFA concentrations Subcutaneous adipose tissue enzyme mRNA expression FADS1 - 5 desaturase FADS2 - 5 desaturase SCD - stearoyl coA desaturase ELOVL2- very long chain FA elongase ELOVL6 – long chain FA elongase MacKay et al Hypertension 2012 Subcutaneous adipose tissue 0 2 4 6 8 10 12 14 FADS1 FADS2 SCD ELOVL2 ELOVL6 mRNAexpression(sqrttarget/PPIA) Control PE IUGR P=0.020 * P=0.001 * P=0.043 #
- 43. Excess dietary fat pancreasplacenta?liver Hypertrophic obesity Ectopic lipid accumulation Ectopic sites of fat storage in pregnancy NEFA spillover visceral adipose tissue blood vessel
- 44. Placental lipidomic analysis Figure1. 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 unpublished University of Wollongong Placental lipids were extracted and analysed on a hybrid triple quadrupole, linear ion trap mass spectrometer (AB Sciex QTRAP 5500) equipped with an automated, chip-based nanospray source (Advion Triersa Nanomate). PE placenta has higher total lipid content and arachidonic acid content than controls
- 45. Implications for placentalfunction – inflammation? Figure 1: Placental samples showing CD68 positive macrophages (brown) under magnification x 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 to the BMI≥35kg/m2 group. Represented as median, inter-quartile range, maximum and minimum of log transformed data. A B >or=35<35 3.5 3.0 2.5 2.0 1.5 1.0 0.5 BMI (kg/m2 )Logmacrophagedensity(countsperfield) p=0.004 Huda et al unpublished
- 46. Pavan et alEndocrin 2004 ……probably via LXR activation OxLDL inhibits trophoblast invasion….. Implications for placental function – trophoblast function?
- 47. Decreased antioxidant defencesin preeclampsia 0 50 100 150 200 250 300 Control PE IUGR Paraoxonaseactivity(ug/mL) P=0.012 n=125 n=57 n=16 Lower paraoxonase activity in preeclampsia Dysfunctional HDL? Mackay et al unpublished
- 48. Maternal obesity -a perfect storm? Maternal obesity lipolysis ’safe’ storage of TG insulin resistance oxidative stress oxidised lipids ectopic fat accumulation lipotoxicity placenta NEFA maternal endothelial /vascular stress trophoblast invasion ? uteroplacental insufficiency altered development, fat metabolism & transport & inflammation offspring obesity adverse maternal outcomeJarvie et al Clin Sci 2010
- 49. Acknowledgements ICAMS Ellie Jarvie Rachel Forrest AnnBrown Fiona Jordan Vanessa Mackay (née Rodie) Frances Stewart Christopher Onyiaodike Naveed Sattar Muriel Caslake Glasgow Collaborators Bill Ferrell Shahzya Huda Scott Nelson University of Manchester Mike Mackness Project students Jack Bray Sam Eather Louise McKenna Iain Martin Nicole Patterson University of Wollongong Barbara Meyer Todd Mitchell Simon Brown University of Surrey Bruce Griffin University of Umea Gunilla Olivecrona
Editor's Notes
- #11 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