hauguel-demouzon o&p2013
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Molecular signals Molecular signals at the maternal-fetal interfaceat the maternal-fetal interface
Sylvie Hauguel-de Mouzon, PhDMetrohealth Medical Center
Case Western Reserve University, Cleveland, USA
IASO, Boston May 013
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F P
The maternal-fetal interface
adapted from http://jimkean.wordpress.com
exposome
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Endocrine changes
Decreased Insulin sensitivity
Maternal concentration of macro-nutrients unchanged
Increased inflammation
Increased Endotoxemia
Gestational exposome of obese women
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Maternal obesity modifies feto-placental growth and body composition
Birth wt (g)
0
1000
2000
3000
4000 *
0
Placenta wt (g)
200
400
600
800 *
Fat mass @ birth (g)
0
100
200
300
400
*
lean obese
n = 789 pregnancies at term delivery
Hauguel-de Mouzon , Catalano (MHMC database)
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Consequences of obesity in pregnancy
AdiposityInsulin resistance
Prenatal programming of obesity-diabetes
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Presentation outline
III – placental signals
II – immune signals
I – metabolic-endocrine signals
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Lean OW & Obese p
Insulin (U/ml) 6.3 ± 3.7 14.3 ± 5.6 <0.001
Leptin (ng/ml) 13.1 ± 9.1 35.1 ± 20.5 0.001
IL-6 (ng/ml) 1.2 ± 0.4 3.2 ± 3.7 0.05
CRP(mg/dl) 0.4 ± 0.3 0.7 ± 0.4 0.03
TNF-alpha (pg/ml)
Adiponectin (g/ml)
1.9 ± 1.3
8.4 ± 1.2
1.8 ± 0.8
11.6 ± 1.3
ns
0.001
Endocrine Exposome in pregnancy with obesity
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Leptin in pregnancyLeptin in pregnancy
leptinMOTHER95 %95 % 5 %5 %
FETUS
325 ng/min
Lepercq , Hauguel-de Mouzon et al., JCEM, 2001
leptin
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Placental Leptin in diabetic and obese women
Lepercq et al. Diabetes 1998
Lep
tin
mR
NA
(f
old
ch
ang
e vs
lea
n)
0
1
2
Lean (14)
Obese (17)
GDM (11)
*
3
*
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Leptin increases fatty acid uptake in cultured placental cells
Pa
lmit
ic a
cid
(cp
m/1
06 ce
lls)
0
500
1000
1500
2000
2500
12 hours
*
p = 0.0001
control leptin
3000
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0
4
8
12
CTL 1 4 8 24Fo
ld C
han
ge
vs
bas
al
0
10
20
30*
*
*PLA2G6
0
4
8
4
8
Time with leptin (hours)
PLA2G5
0
10
20
30
PLA2G2
Leptin stimulates inflammatory pathways
in placental cells
sPhospholipases TNF-alpha
CTL 1 4 8 24
Time with leptin (hours)
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Activates mitogenesis
Activates angiogenesis
Activates inflammatory pathways (macrophages)
Activates FFA transport
Excess leptin modifies placental function
???? facilitates fat accretion in the fetus
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Placenta and adipose tissue have similar cytokine repertoire
Trayhurn, P. et al. J. Nutr. 2006;136:1935S-1939S
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Immunodetection of adpN proteina
dip
os
e
55
no wash wash
37
kDa
bla
nk
placentab
loo
d
actin
Ad
pN
co
py
/p
g R
NA
0
500
1000
1500
WAT WBC PLA
2000
C
WAT
MBC
placenta
Source of adiponectin at the maternal-fetal interface
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co
py
/p
g R
NA
0
50
100
150
200
mRNA expression
*
Fo
ld c
ha
ng
e
g/m
l
10
15
0
5
protein
*
0
DNA methylation
1.0
1.5
2.0
0.5
*
obeselean
Adiponectin in pregnnacy
SHM, DS Unpublished
adipose tissue plasma
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System A amino acid transporter isoforms in placental membranes
from control and fADN infused mice
Rosario F J et al. J Physiol 2012
control mice
adpn mice
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Review: Adiponectin – Powell et al. Placenta 2013
yesplatform+mauthorauthor
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Presentation outline
III – placental signals
II – immune signals
I – metabolic-endocrine signals
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CD68+ placental macrophages in obesity
maternal BMI 22.5 BMI 30.8 BMI 46.7
lab
eled
are
a/se
ctio
n (m
2 )
0
5000
10000
15000CD68 CD14
*
*
ObeseLean
Placenta 2007
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P. Cani & N. Delzenne 2009
Dietary exposome targets immune pathways
inflammation
inflammationT
LR
4
LPS
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TL
R4
2006, Jason K. Kim
Toll-like Receptor 4 inflammatory signals
LPS
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pla
sma
(EU
/ml)
Increased LPS in maternal plasma
Basu, Hauguel-de Mouzon Obesity 2010
ObeseLean0.0
0.50
1.0
0.25
0.75p=0.004
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TLR4 expression human term placenta
TLR4cytokeratine 7Dapi
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Yang, Hauguel-de Mouzon (ongoing studies)
*
Placenta TLR4 mRNA
0
2
4
6
Lean Obese
Fo
ld c
han
ge
vs b
asal
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TL
R4
2006, Jason K. Kim
Toll-like Receptor 4 inflammatory signals
LPS
FFA
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Can maternal lipid diet elicit placental signals ?
mono-unsaturated FAoleate C18:1
saturated FA palmitate C16:0
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Fo
ld I
nc
reas
e v
s c
on
tro
l
Fatty acids stimulate TLR4 expression in human trophoblasts
Yang, Hauguel-de Mouzon (ongoing studies)
0
10
20
30
40
50
CTL BSA LPS OleatePAlmitate
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Fatty acids stimulate cytokine expression in human trophoblasts
Fo
ld
Incr
ease
vs
ctl
0
10
20
30
40
50
Yang, Hauguel-de Mouzon unpublished
CTL BSA LPS OA PA
IL-6 TNF-alpha
0
2
4
6
8
10
CTL BSA LPS OA PA
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Presentation outline
III – placental signals
II – immune signals
I – metabolic-endocrine signals
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Two sources of circulating cfDNA in Pregnancy
1
2
2
2 + 1
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Release of cf DNA by Placental shedding
cell-free DNA
cfDNA in maternal blood is 95 % placental (5% fetal)
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The placenta of obese women is larger, Inflammed and more apoptotic
>>> higher release of cf DNA
Hypothesis:
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pre-gravid BMIBMI
delivery
Maternal weight
delivery (kg)
Adipocyte diameter
delivery (um)
Plasma leptin
(ng/ml)
Lean (14) 21.8+2.8 27.5+3.0 72+7.5 340+ 52 30+16
Obese (16) 39.2+6.7 45.7+7.3 121+23 501+ 89 67+23
p-value 0.0001 0.0001 0.0001 0.001 0.0001
Study cohort for cf DNA measures
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cf DNA in systemic circulation of obese vs lean women
Pla
sma
cfD
NA
(p
g/m
l)
0
100
200
300
400
500
lean obeseGAPDH
DYS14
maternal origin
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cf D
NA
(p
g/m
l)
pre-gravid BMI (kg/m2) pregnancy BMI (kg/m2) gestational wt gain (kg)
0
200
400
600
800 r= 0.57, p=0.002 r= 0.41, p=0.03
0 10 20 30 40
r= 0.49, p=0.006
0 10 20 30 40 50 0 10 20 30 40 50
Circulating cfDNA and maternal adiposity
GAPDH GAPDH GAPDH
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A: lean B: obese
lean obese0
20
40
arb
itra
ry u
nit
s
C
Increased apoptosis in adipose tissue of obese women
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cfDNA Increased fat mass in obese womenis an impetus for propagating inflammatory signals to the FP unit
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Endocrine changes
Insulin sensitivity decreased
Metabolic inflammation
Molecular signals from obese women
Endotoxemia
Gut microbiota modified
Placental signalsInflammation
Crosstalks lipid- immune pathways
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Placental signals
Excess fetal adiposity
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TThhaannk Yk Yoou u !!
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1. Interactions adiponectin, leptin and resistin on glucose metabolism and insulin sensitivity. The normal values of every hormone are included in the arrows. Negative sign refers that the substance inhibits (−) or increases (+) the effect.
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Circulating cell-free (naked) DNA
Placental DNA
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Fo
ld in
crea
se v
s co
ntr
ol
Palmitate C16:0
Haghiac, Hauguel-deMouzon et al. 2012
MCP1 IL1 TNF IL8 IL6
Fatty–acids stimulatecytokine release in human adipose cells
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Lean (n=12) Obese (n=22) p
Early pregnancy BMI 21.2 ± 1.9 32.3 ± 7.7 <0.001
GA (weeks) 8.5 ± 2.1 8.9 ± 1.9 0.57
Glucose (mg/dl) 72.8 ± 8.5 74.4 ± 11.2 0.66
Total cholesterol (mg/dl) 139. ± 37. 151. ± 36. 0.37
HDL-cholesterol (mg/dl) 43. ± 11. 43 ± 8. 0.96
LDL-cholesterol (mg/dl) 86. ± 31.4 97.6 ± 30.3 0.32
VLDL-cholesterol (mg/dl) 12. ± 3.4 13.4 ± 6.1 0.53
Triglyceride (mg/dl) 75 ± 21.3 83. ± 37. 0.53
FFA (meq/L) 0.6 ± 0.3 0.7 ± 0.3 0.44
Maternal exposome in pregnancy with obesity (1)
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Gut microbiome in obese and lean twins
Nature 2009 Gordon Knight Turnbaugh
lean
obese
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10736
Transfer function
Endocrine functionsteroids
HCG/HPLleptin
cytokines
Utilization of placental energy substrates
ATP
Oxidation
Storage
LipidsPhospholipids
Glycogen
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cfD
NA
(p
g/m
l) p=0.99 p=0.65
20 25 30 35 40 45 50
0
50
100
150
200
250
20 25 30 35 40 45 50
cfD
NA
(pg
/ml)
0
100
200
300
pre-gravid BMI (kg/m2) pre-gravid BMI (kg/m2)
DYS14 SRY
Circulating fetal cfDNA and maternal adiposity