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



Foetal hyperinsulinism

compartments


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



Fetal hyperinsulinism leads to multiple changes

compartments


Adipocyte

Glucose uptake

Metabolism

glucose steal

glucose

Foetal Hyperinsulinism – A Vicious Circle

circulating fetal glucose

steeper maternal –fetal glucose gradient

glucose fluxto fetus

Hyperinsulinism


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)

**


LipidDroplets

Free fattyacid

Free fattyacid

Dissociation


~~~~~

~~~~~


~~~~~~~~~~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


LipidDroplets

Free fattyacid

Free fattyacid

Dissociation


~~~~~

~~~~~


~~~~~~~~~~FABP

Oxidation � Mitochondria� Peroxisomes

Biological activity� Signal transduction� Gene regulation� Eicosanoid formation

97-99% FA

Lipoproteins

Free fattyacid

~~~~~

~~~~~

Lipidresynthesis

Storage in Lipid

Droplets


?

~~~~~

~~~~~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


LipidDroplets

Free fattyacid

Free fattyacid

Dissociation


~~~~~

~~~~~


~~~~~~~~~~FABP

Oxidation � Mitochondria� Peroxisomes

Biological activity� Signal transduction� Gene regulation� Eicosanoid formation

Lipidhydrolysis

97-99% FA

Lipoproteins

Free fattyacid

~~~~~

~~~~~

Lipidresynthesis

Storage in Lipid

Droplets


?

~~~~~

~~~~~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



compartments

Adipocyte

Liver

fattyacids

fattyacids

fattyacids

Foetal hyperinsulinism may stimulateextraction of polyunsaturated fatty acids


vein

arteries

PUFA


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


SR-BI

HDL

HDL

CE

A-I

A-I

Selective pathway

PLTG

Storage in Lipid Droplets

v


LDL receptor CEACAT

PLACENTA


Steroidsynthesis

Secretionto fetus


SR-BI

HDL

HDL

CE

A-I

A-I

Selective pathway

PLTG

Storage in Lipid Droplets

v


LDL receptor CEACAT

PLACENTA


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



Foetal glucose & insulin lead to multiple effectson metabolism at feto-placental interface

compartments


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



Foetal glucose & insulin lead to multiple effectson metabolism at feto-placental interface

compartments


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

Regulatory Role of the Placenta in Materno-Fetal Nutrient ... · Foetal age: 6.2 ± 1.3 mo •...

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Transcript of Regulatory Role of the Placenta in Materno-Fetal Nutrient ... · Foetal age: 6.2 ± 1.3 mo •...