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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
F P
The maternal-fetal interface
adapted from http://jimkean.wordpress.com
exposome
Endocrine changes
Decreased Insulin sensitivity
Maternal concentration of macro-nutrients unchanged
Increased inflammation
Increased Endotoxemia
Gestational exposome of obese women
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)
Consequences of obesity in pregnancy
AdiposityInsulin resistance
Prenatal programming of obesity-diabetes
Presentation outline
III – placental signals
II – immune signals
I – metabolic-endocrine signals
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
Leptin in pregnancyLeptin in pregnancy
leptinMOTHER95 %95 % 5 %5 %
FETUS
325 ng/min
Lepercq , Hauguel-de Mouzon et al., JCEM, 2001
leptin
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
*
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
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)
Activates mitogenesis
Activates angiogenesis
Activates inflammatory pathways (macrophages)
Activates FFA transport
Excess leptin modifies placental function
???? facilitates fat accretion in the fetus
Placenta and adipose tissue have similar cytokine repertoire
Trayhurn, P. et al. J. Nutr. 2006;136:1935S-1939S
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
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
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
Review: Adiponectin – Powell et al. Placenta 2013
yesplatform+mauthorauthor
Presentation outline
III – placental signals
II – immune signals
I – metabolic-endocrine signals
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
P. Cani & N. Delzenne 2009
Dietary exposome targets immune pathways
inflammation
inflammationT
LR
4
LPS
TL
R4
2006, Jason K. Kim
Toll-like Receptor 4 inflammatory signals
LPS
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
TLR4 expression human term placenta
TLR4cytokeratine 7Dapi
Yang, Hauguel-de Mouzon (ongoing studies)
*
Placenta TLR4 mRNA
0
2
4
6
Lean Obese
Fo
ld c
han
ge
vs b
asal
TL
R4
2006, Jason K. Kim
Toll-like Receptor 4 inflammatory signals
LPS
FFA
Can maternal lipid diet elicit placental signals ?
mono-unsaturated FAoleate C18:1
saturated FA palmitate C16:0
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
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
Presentation outline
III – placental signals
II – immune signals
I – metabolic-endocrine signals
Two sources of circulating cfDNA in Pregnancy
1
2
2
2 + 1
Release of cf DNA by Placental shedding
cell-free DNA
cfDNA in maternal blood is 95 % placental (5% fetal)
The placenta of obese women is larger, Inflammed and more apoptotic
>>> higher release of cf DNA
Hypothesis:
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
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
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
A: lean B: obese
lean obese0
20
40
arb
itra
ry u
nit
s
C
Increased apoptosis in adipose tissue of obese women
cfDNA Increased fat mass in obese womenis an impetus for propagating inflammatory signals to the FP unit
Endocrine changes
Insulin sensitivity decreased
Metabolic inflammation
Molecular signals from obese women
Endotoxemia
Gut microbiota modified
Placental signalsInflammation
Crosstalks lipid- immune pathways
Placental signals
Excess fetal adiposity
TThhaannk Yk Yoou u !!
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.
Circulating cell-free (naked) DNA
Placental DNA
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
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)
Gut microbiome in obese and lean twins
Nature 2009 Gordon Knight Turnbaugh
lean
obese
10736
Transfer function
Endocrine functionsteroids
HCG/HPLleptin
cytokines
Utilization of placental energy substrates
ATP
Oxidation
Storage
LipidsPhospholipids
Glycogen
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