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