Regulatory Role of the Placenta in Materno-Fetal Nutrient ... · Foetal age: 6.2 ± 1.3 mo •...
Transcript of Regulatory Role of the Placenta in Materno-Fetal Nutrient ... · Foetal age: 6.2 ± 1.3 mo •...
Regulatory Role of the Placenta in Materno -Fetal Nutrient Transfer
Kick-off Meeting, March 21-23, 2012Gernot Desoye
For non commercial-purposes only
The Human Placenta
Moe et al, 1995; Rossant & Cross Nature Rev Gen 2001
Hendricks Obstet Gynecol 24:357, 1964
weeks of gestation
% o
f wei
ghta
t 40
wk
Placental growth precedes foetal growth
0
20
40
60
80
100
120
24 26 28 30 32 34 36 38 40 42
placenta
fetus
Foetal and placental weight correlate
Weight/Diameter
Boyd & Hamilton, The Human Placenta 1970; Desoye & Shafrir, Mol Asp Med 1994
1g placenta tissuesustains:
Human 6 g
Rat/Mouse 10 g
Sheep 10 g
Guinea Pig 20 g
Foetal anthropometric parameters* directly associated with:
• Placental volume at week 14 of gestation
• Rate of placental growth between week 14 and 17 of gestation
*abdominal circumference, femoral length, head circumference, biparietal diameter
Thame et al Eur J Clin Nutr 58: 894, 2004
Body Composition at Delivery
• Fat mass: 12 – 15 %
• Fat free mass: 85 – 88 %
LGA AGA SGA
Bod
y F
at (
%)
NGTGDMP=0.002 P=0.002
NGT Col 2 Col 3
LGA AGA
Fat
Fre
e M
ass
(g)
P=0.0009 P=0.0008
Body Fat (%) in Offspring of Womenwith GDM and Obesity
Petersen 1988; Catalano AJOG 2003; Durnwald AJOG 200 4; Sewell AJOG 2006
BMI<25 BMI ≥≥≥≥25
P=0.006
characterised by:
Fat Free Mass : Diabesity ~ control
Fat Mass : Diabesity > control
Kehl et al. 1996; Petersen 1988; Catalano AJOG 2003 ; Durnwald AJOG 2004, Sewell AJOG 2006
Foetus in Diabesity
Padoan et al, AJOG 2004
Foetal Body Fat is Reduced in FGR
FGR: Fetal AC < 2 SD
Abnormal Doppler:
A. umbilicalis
A. uterina
Fat mass
Leanbodymass
AGA
FGR
Foetal Growth
• Fat Free Mass / Lean Body MassGenes
• Fat MassIntrauterine Environment
Moulton; J Biol Chem , 1923Sparks; Sem in Perinat, 1989
MOTHER
PLACENTA
FETUS
+
Glucose Glucose
FFA FFA
Increase in
utilizationsubstrate
Energystorage
Fatdeposition
Aminoacids
Aminoacids
+
THE ‘FUEL-MEDIATED‘TERATOGENESIS CONCEPT
GrowthWhiteadipocytes
syncytiotrophoblast endothelium
fetalmaternal stroma
Foetal hyperinsulinism
compartments
glucose glucose insulin
AF insulin at 14-20 wks gestation(n=247)
Higher AF insulin (by 1 MOM)
associated with
3-fold risk for foetal birth weight > 90th centile:
OR 3.1[95% CI: 1.3-4.9; P=0.048]
Carpenter MW Diabetes Care 24: 1259, 2001
Third trimester amniotic fluid insulin& childhood growth at age 6
50
100
150A
mni
otic
fluid
insu
lin(p
mol
/l)
ns
p<0.05p<0.05
Symmetryindex
<1.0 1.0-1.2 >1.2
13 29 14
Symmetry index = Observed weight/median for age
Observed height/median for age
Metzger et al. Arch Dis Childh 65:1050, 1990
syncytiotrophoblast endothelium
fetalmaternal stroma
Foetal hyperinsulinism
compartments
glucose glucose insulin
Nutrient transfer across theplacenta:
Glucose
The foetus does notproduce glucose
The foetus requires ~ 40 g glucose per day
Pathways of Materno-Foetal Transport
Glucose:
* saturable* stereospecific* Na -indep .* GLUT1* mvm:bm ~ 3:1
* [gluc ] >[gluc ]m ffetalblood
intervillousspace
GLUT 1 in Term Placentas
Hahn et al, Cell Tiss Res 280, 1995
GLUT3
Term Placenta
Mol Hum Reprod 2001 7:1173 JCEM 1998 83:4097
GLUT4
JCEM 1998 83:4097
Hyperglycemia in vitro induces GLUT1 translocation in
term human trophoblastsHahn et al., Diabetologia 43: 173, 2000
Hyperglycemia in vitro downregulates glucose uptake
and GLUT1 in human term trophoblastsHahn et al., FASEB J 12: 1221, 1998
Placental Glucose Transportersin vitro Regulation
D-g
luco
se(m
mol
.min
-1.to
tal p
lace
ntal
wei
ght-1
)
0
50
100
150
200
250
300 Control
Diet Insulin
GDM
Total transplacental nettransfer of glucose
Osmond et al, Diabetologia 2001
Maternal glucose: 8 mM
Glucose uptake and transfer depend on maternal-fetal concentration gradient
uptake
transfer
Maternal - fetal glucose gradient (mM)
Glu
cose
(µ
mol
es/m
in/g
)
Hauguel S et al. Pediatric Res 20: 269, 1986
Transplacental glucose transport dependson maternal and foetal blood flow
Illsley et al. Trophoblast Res. 2, 535, 1987Illsley et al. Trophoblast Res. 2: 535, 1987
Transplacental Glucose Flux
Depends on the MATERNAL-FOETAL concentration gradient
Is flow limited
syncytiotrophoblast endothelium
fetalmaternal stroma
Fetal hyperinsulinism leads to multiple changes
compartments
glucose glucose insulin
Adipocyte
Glucose uptake
Metabolism
glucose steal
glucose
Foetal Hyperinsulinism – A Vicious Circle
circulating fetal glucose
steeper maternal –fetal glucose gradient
glucose fluxto fetus
Hyperinsulinism
Nutrient transfer across theplacenta:
Lipids – Fatty Acids
Maternal and Foetal Fat During Gestation
EM Widdowson, 1968; P Haggarty Ann Rev Nutr 30:237, 2 010
Foetal lipid accretionmaximum at term of gestation:
7 g/day
Desoye G et al. JCEM 1987
Gestational Changes in Maternal and Foetal Lipids
TG - NEFAFC
TG
PL
P. Haggarty Ann Rev Nutr 30:237, 2010
mother foetusplacenta
LipidDroplets
Free fattyacid
Free fattyacid
Dissociation
Hydrolysis by Lipases
Lipoprotein Receptor
~~~~~
~~~~~
1-3% FAAlbuminComplex
97-99% FALipoproteins
EL
Placental EL is downregulated in FGR and upregulated in obese GDM
Gauster et al, modified from JCEM 92: 2256-63, 2007, Diabetes 60: 2457, 2011
0
1
2
3
EL LPL
lipas
e / R
PL3
0 m
RN
A c
opie
s
AGAFGR
*
*
AGA FGR
0
1
2
3
lean obese lean GDM obese GDM
EL
mR
NA
exp
ress
ion *
Inflammatory cytokines upregulate placental EL
Gauster et al. Diabetes 60: 2457, 2011
0
5
10
15
20
25
30
TNF-α Leptin
EL
mR
NA
expr
essi
on(f
old
chan
geco
mpa
red
to c
ontr
ol)
**
mother foetusplacenta
LipidDroplets
Free fattyacid
Free fattyacid
Dissociation
Lipoprotein Receptor
~~~~~
~~~~~
1-3% FAAlbuminComplex
~~~~~~~~~~FABP
97-99% FA
Lipoproteins
Free fattyacid
~~~~~
~~~~~
Incorporation intoLipoproteins
?
~~~~~
~~~~~FATP~~~~~
Free fattyacid
FAT/CD36~~~~~
Diffusion~~~~~~
~~~~~
Diffusion~~~~~~
FATP~~~~~
FAT/CD36~~~~~
FABPpm
EL
Selective FA contribution to foetalNEFA and cholesteryl ester pools
Lewis RM et al. Br J Nutr 106:463, 2011
NEFACholesteryl
Esters
TG PC
arterial
venous
cord blood
mother foetusplacenta
LipidDroplets
Free fattyacid
Free fattyacid
Dissociation
Lipoprotein Receptor
~~~~~
~~~~~
1-3% FAAlbuminComplex
~~~~~~~~~~FABP
Oxidation � Mitochondria� Peroxisomes
Biological activity� Signal transduction� Gene regulation� Eicosanoid formation
97-99% FA
Lipoproteins
Free fattyacid
~~~~~
~~~~~
Lipidresynthesis
Storage in Lipid
Droplets
Incorporation intoLipoproteins
?
~~~~~
~~~~~FATP~~~~~
Free fattyacid
FAT/CD36~~~~~
Diffusion~~~~~~
~~~~~
Diffusion~~~~~~
FATP~~~~~
FAT/CD36~~~~~
FABPpm
EL
Human placenta contains lipid bodies in the syncytiotrophoblast
Jones & Fox, Electron Microsc Res 4: 129, 1991
lipids
TG (nMole) PL (g) Cholesterol (g)
lipids
*
*
*
*
normal pregnancy GDM Type-1
TG (nMole)
Cholesterol(g)
PL (g)
Shafrir et al, AJOG 144: 5, 1982
mother foetusplacenta
LipidDroplets
Free fattyacid
Free fattyacid
Dissociation
Lipoprotein Receptor
~~~~~
~~~~~
1-3% FAAlbuminComplex
~~~~~~~~~~FABP
Oxidation � Mitochondria� Peroxisomes
Biological activity� Signal transduction� Gene regulation� Eicosanoid formation
Lipidhydrolysis
97-99% FA
Lipoproteins
Free fattyacid
~~~~~
~~~~~
Lipidresynthesis
Storage in Lipid
Droplets
Incorporation intoLipoproteins
?
~~~~~
~~~~~FATP~~~~~
Free fattyacid
FAT/CD36~~~~~
Diffusion~~~~~~
~~~~~
Diffusion~~~~~~
FATP~~~~~
FAT/CD36~~~~~
FABPpm
EL
LCPUFA are enriched in foetal plasma
Innis S, Placenta 26 Suppl A:S70, 2005
Maternal plasma Foetal plasma
18:2 n-6 20:4 n-6 22:6 n-3
g/100 g FA
DHA is enriched in placenta and cord blood12 hr after maternal 13C-FA administration
Gil-Sánchez A et al., Am J Clin Nutr 92:115, 2010
Cord blood/Maternal
Placenta/Maternal
*
*
Fatty acids in umbilical cord plasma
Ortega-Senovilla H et al. Diabetes Care 32: 120, 2009
PO
LYU
NS
AT
UR
AT
ED
(%
)
PUFA
aa
b
a
bb
***
0
10
20
30
40
AGA GDM
***
V VA A SA
TU
RA
TE
D (
%)
a
b b
a
b b
N=24 N=17
0
10
20
30
40
50
60
AGA GDM
V VA A
Saturated Fatty Acids
syncytiotrophoblast endothelium
fetalmaternal stroma
compartments
Adipocyte
Liver
fattyacids
fattyacids
fattyacids
Foetal hyperinsulinism may stimulateextraction of polyunsaturated fatty acids
glucose glucose insulin
vein
arteries
PUFA
Nutrient transfer across theplacenta:
Lipids – Cholesterol
Cholesterol
• Cell membrane constituent
• Stored in lipid droplets/bodies
• Synthesis of steroid and oxysterols
• Regulation of development (shh modification)
Foetal age: 6.2 ± 1.3 mo
• Normocholesterolemia• Transient Hypercholesterolemia• Hypercholesterolemia
Intimal Lipid Accumulationsin Foetal Aortas
Maternal Hypercholesterolemia EnhancesFatty Streak Formation in Foetal Aortas
Napoli et al. JCI 100, 2680, 1997
Cumulative area with lesions
0
100000
200000
300000
400000
500000
600000
700000
800000
900000
Cum
ulat
ive
Lesi
on A
rea
per S
ectio
n (µ
m²)
Arch ThoracicAorta
AbdominalAorta
EntireAorta
Maternal circulation Placenta Fetal circulation
SR-BI
HDL
HDL
CE
A-I
A-I
Selective pathway
LDLEndocytic pathway
LDL receptor CEACAT
PLACENTA
Pathways of PlacentalLipid Metabolism
LDL and HDL receptor are expressedon the syncytiotrophoblast
Malassine et al. Histochem 1987
EC
ST
1µm
Wadsack & Desoye, unpublished
LDL-R HDL-R
SR-B1
Maternal circulation Placenta Fetal circulation
SR-BI
HDL
HDL
CE
A-I
A-I
Selective pathway
PLTG
Storage in Lipid Droplets
v
LDLEndocytic pathway
LDL receptor CEACAT
PLACENTA
Pathways of PlacentalLipid Metabolism
Steroidsynthesis
Secretionto fetus
Maternal circulation Placenta Fetal circulation
SR-BI
HDL
HDL
CE
A-I
A-I
Selective pathway
PLTG
Storage in Lipid Droplets
v
LDLEndocytic pathway
LDL receptor CEACAT
PLACENTA
Pathways of PlacentalLipid Metabolism
Cholesterol efflux from placentalendothelial cells to the foetal circulation
apoA-IapoE
C
mature HDL
C
CCE
apoE
ABCG1
C
ABCA1
C
nascent HDLC
Circ Res. 104: 600, 2009
Phospholipid transfer protein (PLTP)
• Mediates PL transfer between lipoproteins(Huuskonen et al. Biochemistry 2000)
• Involved in vitamin E delivery to endothelial cells(Desrumaux et al. FASEB J 1999)
• Enhances cholesterol efflux to HDL (Wolfbauer et al. Biochim Biophys Act 1999, Oram et al. J Biol Chem 2003)
• Contributes to the remodeling of HDL3 → generationof large HDL2 and nascent HDL particles(Jauhiainen et al. J Biol Chem 1993)
CE
C
HDL2
ApoA-I
PLACENTAENDOTHELIUM
LIVER
Lipid efflux
PLC
ABCA1
ABCG1
CEACAT
NCEH
PLTP modifies HDL
HDL3
CEPLTP
FETUS
Placental PLTP is expressed foeto-placentalendothelium and up-regulated in GDM
Scholler et al. J Clin Endo Metab, 2011
0
50
100
150
200
250liverplacenta
control GDM fetal adultBMI<30 BMI ≥≥≥≥30
****
*****P
LTP
mR
NA
leve
ls[%
]
Insulin increases endothelial PLTP
0
80
100
120
140
160
180
control glucose insulin glucose +insulin
*****
PL
tran
sfer
act
ivity
[%
]
0
50
100
150
200
control glucose insulin glucose +insulin
*** **
inte
nsity
[%
]
Activity Protein
Scholler et al. J Clin Endo Metab, 2011
CE
C
HDL2
ApoA-I
PLACENTAENDOTHELIUM
LIVER
Lipid efflux
PLC
ABCA1
ABCG1
CEACAT
NCEH
PLTP modifies HDL to reduceatherogenic risk
HDL3
CEPLTP
FETUS
syncytiotrophoblast endothelium
fetalmaternal stroma
Foetal glucose & insulin lead to multiple effectson metabolism at feto-placental interface
compartments
glucose glucose insulin
PLTP
Adipocyte
PUFA
Glucose uptake
Metabolism
Liver
preßHDL + HDL2
HDL3
OxysterolsROS
Insulin Upregulates Glycogen only in theEndothelium of Term Human Placenta
5
10
15
20
25
Trophoblast Endothelium
glyc
ogen
(µg/
mg
prot
ein)
control
1 nM insulin
10 nM insulin
after 24 h treatment
* *
n.s.
IRS
?
Insulin receptor
PM
PI3K
PkB
PDK 1/2
PIP3
GSK-3
glycogensynthase
glycogen
Result of fetal insulin
syncytiotrophoblast endothelium
fetalmaternal stroma
Foetal glucose & insulin lead to multiple effectson metabolism at feto-placental interface
compartments
glucose glucose insulin
Oxysterols
PLTP
Adipocyte
PUFA
Glucose uptake
Metabolism
Liver
preßHDL + HDL2
HDL3
glycogen
OxysterolsROS
Take home messages
The human placenta does not appear to limit maternal-to-foetal flux of glucose (and fatty acids)
The rate limiting step for maternal-to-foetal fatty acidtransport is unknown
LCPUFAs are selectively transferred across placentaand extracted in foetus
Take home messages (cont‘d)
The foetal glucose insulin axis is an important driver formaternal-foetal transport as well as for regulatingfoetal fat deposition
The intrauterine environment of the first trimester of gestation may already play a key role in determiningfoetal growth
Note of caution
• A-V difference
• Effect of foetal sex
• Third trimester/term of gestation vs earlierstages
Manchester:
Carolyn Jones
Jerusalem:
Eleazar Shafrir
Melbourne:
Martha Lappas
Padma Murthi
Richard Saffery
Madrid:
Emilio Herrera
Iliana Lopez-Soldado
Henar Ortega
Aachen:
Peter Kaufmann
Gabi Kohnen
Buenos Aires:
Alicia Jawerbaum
Veronica White
Brisbane:
David McIntyre
Cleveland, OH/Paris:
Sylvie Hauguel-de Mouzon
Zagreb:
Josip Djelmis
Marina Ivanisevic
Milano:
Gioia Alvino
Irene Cetin
Silvia Tabano
Munich:
Hans Demmelmair
Mario Klingler
Bert Koletzko
Nottingham:
Lopa Leach
Rome:
Giorgio Sesti
Amsterdam:
Mireille van Poppel
Thank you for your attention!
UrsulaHiden
Christian Wadsack