Molecular signalsMolecular signalsat the maternal-fetal interfaceat the maternal-fetal interfaceSylvie Hauguel-de Mouzon, ...
F PThe maternal-fetal interfaceadapted from http://jimkean.wordpress.comexposome
Endocrine changesDecreased Insulin sensitivityMaternal concentration of macro-nutrients unchangedIncreased inflammationInc...
Maternal obesity modifies feto-placentalgrowth and body compositionBirth wt (g)01000200030004000 *0Placenta wt (g)20040060...
Consequences of obesity in pregnancyAdiposityInsulinresistancePrenatal programming of obesity-diabetes
Presentation outlineIII – placental signalsII – immune signalsI – metabolic-endocrine signals
Lean OW & Obese pInsulin (µU/ml) 6.3 ± 3.7 14.3 ± 5.6 <0.001Leptin (ng/ml) 13.1 ± 9.1 35.1 ± 20.5 0.001IL-6 (ng/ml) 1.2 ± ...
Leptin in pregnancyLeptin in pregnancyleptinMOTHER95 %95 % 5 %5 %FETUS325 ng/minLepercq , Hauguel-de Mouzon et al., JCEM, ...
Placental Leptinin diabetic and obese womenLepercq et al. Diabetes 1998LeptinmRNA(foldchangevslean)012Lean(14)Obese(17)GDM...
Leptin increases fatty acid uptakein cultured placental cellsPalmiticacid(cpm/106cells)0500100015002000250012 hours*p = 0....
04812CTL 1 4 8 24FoldChangevsbasal0102030***PLA2G604848Time with leptin (hours)PLA2G50102030PLA2G2Leptin stimulatesinflamm...
Activates mitogenesisActivates angiogenesisActivates inflammatory pathways (macrophages)Activates FFA transportExcess lept...
Placenta and adipose tissue havesimilar cytokine repertoireTrayhurn, P. et al. J. Nutr. 2006;136:1935S-1939S
Immunodetection of adpN proteinadipose55no wash wash37kDablankplacentabloodactinAdpNcopy/pgRNA050010001500WAT WBC PLA2000C...
copy/pgRNA050100150200mRNA expression*Foldchangeµg/ml101505protein*0DNA methylation1.01.52.00.5*obeseleanAdiponectin in pr...
Adiponectin receptorsyesplatform+mauthorauthor
System A amino acid transporter isoforms inplacental membranesfrom control and fADN infused mice Rosario F J et al. J Phys...
Review: Adiponectin – Powell et al. Placenta 2013yesplatform+mauthorauthor
Presentation outlineIII – placental signalsII – immune signalsI – metabolic-endocrine signals
CD68+placental macrophages in obesitymaternalBMI 22.5 BMI 30.8 BMI 46.7labeledarea/section(µm2)050001000015000CD68 CD14**O...
P. Cani & N. Delzenne 2009Dietary exposome targets immune pathwaysinflammationinflammationTLR4LPS
TLR42006, Jason K. KimToll-like Receptor 4 inflammatory signalsLPS
plasma(EU/ml)Increased LPS in maternal plasmaBasu, Hauguel-de Mouzon Obesity 2010ObeseLean0.00.501.00.250.75p=0.004
TLR4 expression human term placentaTLR4cytokeratine 7Dapi
Yang, Hauguel-de Mouzon (ongoing studies)*Placenta TLR4 mRNA0246Lean ObeseFoldchangevsbasal
TLR42006, Jason K.KimToll-like Receptor 4 inflammatory signalsLPSFFA
Can maternal lipid diet elicit placental signals ?mono-unsaturated FAoleate C18:1saturated FA palmitate C16:0
FoldIncreasevscontrolFatty acids stimulate TLR4 expressionin human trophoblastsYang, Hauguel-de Mouzon (ongoing studies)01...
Fatty acids stimulatecytokine expression in human trophoblastsFoldIncreasevsctl01020304050Yang, Hauguel-de Mouzon unpublis...
Presentation outlineIII – placental signalsII – immune signalsI – metabolic-endocrine signals
Two sources of circulating cfDNA in Pregnancy1222 + 1
Release of cf DNA by Placental sheddingcell-free DNAcfDNA in maternal blood is 95 % placental (5% fetal)
The placenta of obese women is larger,Inflammed and more apoptotic>>>higher release of cf DNAHypothesis:
pre-gravid BMIBMIdeliveryMaternalweightdelivery (kg)Adipocytediameterdelivery (um)Plasmaleptin(ng/ml)Lean (14) 21.8+2.8 27...
cf DNA in systemic circulationof obese vs lean womenPlasmacfDNA(pg/ml)0100200300400500lean obeseGAPDHDYS14∗maternal origin
cfDNA(pg/ml)pre-gravid BMI (kg/m2) pregnancy BMI (kg/m2) gestational wt gain (kg)0200400600800 r= 0.57, p=0.002 r= 0.41, p...
A: lean B: obeselean obese02040arbitraryunitsC∗Increased apoptosis in adipose tissue of obese women
cfDNA Increased fat mass inobese womenis an impetus forpropagatinginflammatory signalsto the FP unit
Endocrine changesInsulin sensitivity decreasedMetabolic inflammationMolecular signals from obese womenEndotoxemiaGut micro...
Placental signalsExcess fetal adiposity
TThhaannk Yk Yoouu !!
1. Interactions adiponectin, leptin and resistin on glucose metabolism and insulin sensitivity. The normal values of every...
Circulating cell-free (naked) DNAPlacental DNA
FoldincreasevscontrolPalmitate C16:0Haghiac, Hauguel-deMouzon et al. 2012MCP1 IL1α TNFα IL8 IL6Fatty–acids stimulatecytoki...
Lean (n=12) Obese (n=22) pEarly pregnancy BMI 21.2 ± 1.9 32.3 ± 7.7 <0.001GA (weeks) 8.5 ± 2.1 8.9 ± 1.9 0.57Glucose (mg/d...
Gut microbiome in obese and lean twinsNature 2009 Gordon Knight Turnbaughleanobese
10736Transfer functionEndocrine functionsteroidsHCG/HPLleptincytokinesUtilization of placental energy substratesATPOxidati...
cfDNA(pg/ml)p=0.99 p=0.6520 25 30 35 40 45 5005010015020025020 25 30 35 40 45 50cfDNA(pg/ml)0100200300pre-gravid BMI (kg/m...
Hauguel-DeMouzon o&p2013
Hauguel-DeMouzon o&p2013
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  • Our unpublished results suggest that more leptin + more Fatty acid = efficient situation to enhance placental lipid uptake and potentially availability
  • Figure 3. Relative protein expression of System A amino acid transporter isoforms in TPM isolated from control and fADN infused mice  A, representative Western blots for SNAT1, SNAT2 and SNAT4 in TPM isolated from mice placenta at E18.5. B, bar graph summarizing the Western blot data from control (C, n = 6) and fADN (A, n = 6) infused groups. After normalization to β-actin, the mean density of control samples was assigned an arbitrary value of 1. Individual C and A density values were expressed relative to this mean. Values are given as means + SEM. *P &lt; 0.05 versus control; Student&apos;s unpaired t test.
  • In our studies we have used The most abundant fatty acid constituents of the adipose tissue lipid stores -the long-chain mono- unsaturated oleic acid (50%) and the saturated palmitic acid (20 %)
  • In our studies we have used The most abundant fatty acid constituents of the adipose tissue lipid stores -the long-chain mono- unsaturated oleic acid (50%) and the saturated palmitic acid (20 %)
  • In our studies we have used The most abundant fatty acid constituents of the adipose tissue lipid stores -the long-chain mono- unsaturated oleic acid (50%) and the saturated palmitic acid (20 %)
  • Diabetes Res Clin Pract. 2008 Apr;80(1):8-15. Epub 2008 Mar 4. Adipokines and insulin resistance during pregnancy. Zavalza-Gómez AB, Anaya-Prado R, Rincón-Sánchez AR, Mora-Martínez JM.
  • Hauguel-DeMouzon o&p2013

    1. 1. Molecular signalsMolecular signalsat the maternal-fetal interfaceat the maternal-fetal interfaceSylvie Hauguel-de Mouzon, PhDMetrohealth Medical CenterCase Western Reserve University,Cleveland, USAIASO, Boston May 013
    2. 2. F PThe maternal-fetal interfaceadapted from http://jimkean.wordpress.comexposome
    3. 3. Endocrine changesDecreased Insulin sensitivityMaternal concentration of macro-nutrients unchangedIncreased inflammationIncreased EndotoxemiaGestational exposome of obese women
    4. 4. Maternal obesity modifies feto-placentalgrowth and body compositionBirth wt (g)01000200030004000 *0Placenta wt (g)200400600800 *Fat mass @ birth (g)0100200300400*lean obesen = 789 pregnancies at term deliveryHauguel-de Mouzon , Catalano (MHMC database)
    5. 5. Consequences of obesity in pregnancyAdiposityInsulinresistancePrenatal programming of obesity-diabetes
    6. 6. Presentation outlineIII – placental signalsII – immune signalsI – metabolic-endocrine signals
    7. 7. Lean OW & Obese pInsulin (µU/ml) 6.3 ± 3.7 14.3 ± 5.6 <0.001Leptin (ng/ml) 13.1 ± 9.1 35.1 ± 20.5 0.001IL-6 (ng/ml) 1.2 ± 0.4 3.2 ± 3.7 0.05CRP(mg/dl) 0.4 ± 0.3 0.7 ± 0.4 0.03TNF-alpha (pg/ml)Adiponectin (µg/ml)1.9 ± 1.38.4 ± 1.21.8 ± 0.811.6 ± 1.3ns0.001Endocrine Exposomein pregnancy with obesity
    8. 8. Leptin in pregnancyLeptin in pregnancyleptinMOTHER95 %95 % 5 %5 %FETUS325 ng/minLepercq , Hauguel-de Mouzon et al., JCEM, 2001leptin
    9. 9. Placental Leptinin diabetic and obese womenLepercq et al. Diabetes 1998LeptinmRNA(foldchangevslean)012Lean(14)Obese(17)GDM(11)*3*
    10. 10. Leptin increases fatty acid uptakein cultured placental cellsPalmiticacid(cpm/106cells)0500100015002000250012 hours*p = 0.0001control leptin3000
    11. 11. 04812CTL 1 4 8 24FoldChangevsbasal0102030***PLA2G604848Time with leptin (hours)PLA2G50102030PLA2G2Leptin stimulatesinflammatory pathwaysin placental cellssPhospholipases TNF-alphaCTL 1 4 8 24Time with leptin (hours)
    12. 12. Activates mitogenesisActivates angiogenesisActivates inflammatory pathways (macrophages)Activates FFA transportExcess leptin modifies placental function???? facilitates fat accretion in the fetus
    13. 13. Placenta and adipose tissue havesimilar cytokine repertoireTrayhurn, P. et al. J. Nutr. 2006;136:1935S-1939S
    14. 14. Immunodetection of adpN proteinadipose55no wash wash37kDablankplacentabloodactinAdpNcopy/pgRNA050010001500WAT WBC PLA2000CWATMBCplacentaSource of adiponectin at the maternal-fetal interface
    15. 15. copy/pgRNA050100150200mRNA expression*Foldchangeµg/ml101505protein*0DNA methylation1.01.52.00.5*obeseleanAdiponectin in pregnnacySHM, DS Unpublishedadipose tissue plasma
    16. 16. Adiponectin receptorsyesplatform+mauthorauthor
    17. 17. System A amino acid transporter isoforms inplacental membranesfrom control and fADN infused mice Rosario F J et al. J Physiol 2012control miceadpn mice
    18. 18. Review: Adiponectin – Powell et al. Placenta 2013yesplatform+mauthorauthor
    19. 19. Presentation outlineIII – placental signalsII – immune signalsI – metabolic-endocrine signals
    20. 20. CD68+placental macrophages in obesitymaternalBMI 22.5 BMI 30.8 BMI 46.7labeledarea/section(µm2)050001000015000CD68 CD14**ObeseLeanPlacenta 2007
    21. 21. P. Cani & N. Delzenne 2009Dietary exposome targets immune pathwaysinflammationinflammationTLR4LPS
    22. 22. TLR42006, Jason K. KimToll-like Receptor 4 inflammatory signalsLPS
    23. 23. plasma(EU/ml)Increased LPS in maternal plasmaBasu, Hauguel-de Mouzon Obesity 2010ObeseLean0.00.501.00.250.75p=0.004
    24. 24. TLR4 expression human term placentaTLR4cytokeratine 7Dapi
    25. 25. Yang, Hauguel-de Mouzon (ongoing studies)*Placenta TLR4 mRNA0246Lean ObeseFoldchangevsbasal
    26. 26. TLR42006, Jason K.KimToll-like Receptor 4 inflammatory signalsLPSFFA
    27. 27. Can maternal lipid diet elicit placental signals ?mono-unsaturated FAoleate C18:1saturated FA palmitate C16:0
    28. 28. FoldIncreasevscontrolFatty acids stimulate TLR4 expressionin human trophoblastsYang, Hauguel-de Mouzon (ongoing studies)01020304050CTL BSA LPS OleatePAlmitate
    29. 29. Fatty acids stimulatecytokine expression in human trophoblastsFoldIncreasevsctl01020304050Yang, Hauguel-de Mouzon unpublishedCTL BSA LPS OA PAIL-6 TNF-alpha0246810CTL BSA LPS OA PA
    30. 30. Presentation outlineIII – placental signalsII – immune signalsI – metabolic-endocrine signals
    31. 31. Two sources of circulating cfDNA in Pregnancy1222 + 1
    32. 32. Release of cf DNA by Placental sheddingcell-free DNAcfDNA in maternal blood is 95 % placental (5% fetal)
    33. 33. The placenta of obese women is larger,Inflammed and more apoptotic>>>higher release of cf DNAHypothesis:
    34. 34. pre-gravid BMIBMIdeliveryMaternalweightdelivery (kg)Adipocytediameterdelivery (um)Plasmaleptin(ng/ml)Lean (14) 21.8+2.8 27.5+3.0 72+7.5 340+ 52 30+16Obese (16) 39.2+6.7 45.7+7.3 121+23 501+ 89 67+23p-value 0.0001 0.0001 0.0001 0.0010.0001Study cohort for cf DNA measures
    35. 35. cf DNA in systemic circulationof obese vs lean womenPlasmacfDNA(pg/ml)0100200300400500lean obeseGAPDHDYS14∗maternal origin
    36. 36. cfDNA(pg/ml)pre-gravid BMI (kg/m2) pregnancy BMI (kg/m2) gestational wt gain (kg)0200400600800 r= 0.57, p=0.002 r= 0.41, p=0.030 10 20 30 40r= 0.49, p=0.0060 10 20 30 40 50 0 10 20 30 40 50Circulating cfDNA and maternal adiposityGAPDH GAPDH GAPDH
    37. 37. A: lean B: obeselean obese02040arbitraryunitsC∗Increased apoptosis in adipose tissue of obese women
    38. 38. cfDNA Increased fat mass inobese womenis an impetus forpropagatinginflammatory signalsto the FP unit
    39. 39. Endocrine changesInsulin sensitivity decreasedMetabolic inflammationMolecular signals from obese womenEndotoxemiaGut microbiota modifiedPlacental signalsInflammationCrosstalks lipid- immune pathways
    40. 40. Placental signalsExcess fetal adiposity
    41. 41. TThhaannk Yk Yoouu !!
    42. 42. 1. Interactions adiponectin, leptin and resistin on glucose metabolism and insulin sensitivity. The normal values of everyhormone are included in the arrows. Negative sign refers that the substance inhibits (−) or increases (+) the effect.
    43. 43. Circulating cell-free (naked) DNAPlacental DNA
    44. 44. FoldincreasevscontrolPalmitate C16:0Haghiac, Hauguel-deMouzon et al. 2012MCP1 IL1α TNFα IL8 IL6Fatty–acids stimulatecytokine release in human adipose cells
    45. 45. Lean (n=12) Obese (n=22) pEarly pregnancy BMI 21.2 ± 1.9 32.3 ± 7.7 <0.001GA (weeks) 8.5 ± 2.1 8.9 ± 1.9 0.57Glucose (mg/dl) 72.8 ± 8.5 74.4 ± 11.2 0.66Total cholesterol (mg/dl) 139. ± 37. 151. ± 36. 0.37HDL-cholesterol (mg/dl) 43. ± 11. 43 ± 8. 0.96LDL-cholesterol (mg/dl) 86. ± 31.4 97.6 ± 30.3 0.32VLDL-cholesterol (mg/dl) 12. ± 3.4 13.4 ± 6.1 0.53Triglyceride (mg/dl) 75 ± 21.3 83. ± 37. 0.53FFA (meq/L) 0.6 ± 0.3 0.7 ± 0.3 0.44Maternal exposome in pregnancy with obesity
    46. 46. Gut microbiome in obese and lean twinsNature 2009 Gordon Knight Turnbaughleanobese
    47. 47. 10736Transfer functionEndocrine functionsteroidsHCG/HPLleptincytokinesUtilization of placental energy substratesATPOxidationStorageLipidsPhospholipidsGlycogen
    48. 48. cfDNA(pg/ml)p=0.99 p=0.6520 25 30 35 40 45 5005010015020025020 25 30 35 40 45 50cfDNA(pg/ml)0100200300pre-gravid BMI (kg/m2) pre-gravid BMI (kg/m2)DYS14 SRYCirculating fetal cfDNA and maternal adiposity
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