Maternal Obesity and Placental Function

Theresa Powell, PhD

Center for Pregnancy and Newborn Research

Department of Obstetrics and Gynecology

University of Texas Health Science Center

San Antonio, Texas

Copyright © 2012 American Medical Association. All rights reserved.

Prevalence of Obesity and Trends in the Distribution of Body Mass Index Among US Adults, 1999-2010Prevalence of Obesity and Trends in Body Mass Index Among US Children and Adolescents, 1999-2010

Flegal et al JAMA. 2012; 307(5):491-497.Ogden et al JAMA. 2012; 307(5):483-490.

Frequency of overweight and obesity:

All adults 69.2 % overweight and obese 35.9 % obese

Mexican American women 20-39 years of age:

Obesity and Overweight ( BMI >25) 69% Obesity (BMI >30) 38%

Mexican American Children

2-19 years of age: 21% with BMI >95 percentile

Obesity in Pregnancy

Maternal pregnancy risks

miscarriage/stillbirth, gestational hypertension, pre-eclampsia, gestational diabetes

Fetal risks

increased incidence of birth defects (folate insensitive)

fetal overgrowth LGA (large for gestational age)

birth trauma, increased surgical deliveries

Long term (programming) effects for the childobesity

Type 2 diabetesdyslipidemiahypertension

Obesity in Pregnancy:Hispanic Mothers in South Texas

Maternal Metabolism

What is the metabolic phenotype of the obese mother

without gestational diabetes?

Altered Placental Function

How does placental function change in cases of maternal

obesity, what regulates those changes?

Fetal Overgrowth

What is the mechanism underlying fetal overgrowth in

obese mothers?

Maternal Obesity: Metabolism

mat. HOMA-IR0

0.5

1

1.5

2

2.5

3

Insulin0

100

200

300

400

500

600

pg

/ml

24 48

Mat Glu0

10

20

30

40

50

60

70

80 Normal

High BMI

mg

/dl

20 32

*

*Fasting Glucose

Maternal Obesity: Metabolism

Leptin0

5

10

15

20

25

30

35

40

45Normal BMI

High BMI

ng

/ml

*

15 20 25 30 35 40 45 50 55 600

1

2

3

4

5

6

7

R² = 0.176775583410343

High Mol Wt Adiponectin

Maternal BMI

/mgml

25 48

Maternal Obesity: Inflammation

IL-6 IL-8 IL-1b TNF0.0

1.0

2.0

3.0

4.0

5.0

6.0

Normal BMI

High BMI

pg

/ml

*Irving Aye

n=25

n=48

Maternal Obesity: Hyperlipidemia

Maternal BMI (kg/m2)

Mat

ern

al N

EF

As

(M

)

20 30 40 50200

400

600

800

1000

1200

n=54p<0.01

Maternal Metabolism in HighBMI Pregnancy

Normal Glycemia with Insulin Resistance

High fasting Insulin

High Leptin

Low Adiponectin

Hyperlipidemia

Birth weight is correlated with pre-pregnancy BMI

N=49

r=0.42

p<0.01

Jansson, N et al 2008, Am J Clin Nutr 87:1743-1749.

Does the “Pedersen Hypothesis” apply to obese pregnancy?

• 50 years ago Pedersen suggested fetal overgrowth in diabetic pregnancies was related to

increased transplacental transfer of glucose increased release of insulin by the fetal beta cell stimulated growth and subsequently macrosomia.

• True for obesity in pregnancy ?

• Critical role of the placenta in determining fetal growth rates.

Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am J Obstet Gyn, 2011 204:479-487 Catalano and Hauguel-De Mouzon

Placental Function and Fetal Overgrowth

We hypothesized that placental nutrient transport is increased in obese women leading to fetal overgrowth and its associated long term health consequences.

Syncytiotrophoblast

Anneliese Olsson

Placental Anatomy: syncytiotrophoblast

PlasmaMembrane Isolation

Is Placental Nutrient Transport Altered in Obese Mothers?

Glucose • Facilitated diffusion- gradient dependent

• Glucose transporters (GLUT family) • GLUT 1 and 9

GLUT 3- endothelial cells

• NOT insulin dependent

Glucose

Glucose

MVM BM

n=9 n=12n=12

55 KdGLUT 1

n=12 n=12n=9

55 KdGLUT 1

GLUT 1 Expression

MVM BM

BM GLUT 1 expression correlates with birth weight

Ome Acosta

Is Placental Nutrient Transport Altered in Obese Mothers?

Amino Acids• Multiple transport proteins are

• responsible for uptake and transfer

• of AAs

• Non-Essential AA: System A• sodium dependent

• SNAT 1, 2 and 4

• Essential AA: System L • exchanger

• LAT1 and LAT2, CD98

Na+

AA

Leucine

AA

MVM BM

System A Expression: MVM

SNAT2 SNAT4

n=10 n=12 n=10 n=12

System A activity correlates with birth weight

27002900310033003500370039004100430045000

20

40

60

80

100

120

140

Birth weight (g)

MV

M M

eA

IB u

pta

ke

p

mol/

mg

x 3

0s

N=21R=0.60P<0.001

Is Placental Nutrient Transport Altered in Obese Mothers?

Fatty Acids

Multi-step process• Lipase activity to release

fatty acids from TG

Uptake by fatty acids transport proteins

• Bound in the cytoplasm by

• fatty acid binding proteins

• Released to the fetal circulation.

TG

FATP

MVM BM

FABP

LPLFAs

FATP

Fatty Acid Transporter Expression

What regulates increased nutrient transporter expression in obese mothers?

• The placenta, uniquely juxtapositioned between the maternal and fetal blood supplies, must integrate both maternal supply and fetal demand signals.

• Metabolic signals are diverse and include:• macronutrients (glucose, amino acids, fatty acids)

• hyperinsulinemia

• elevated adipokines (leptin, TNF-a, IL1-b)

• low levels of adiponectin

Insulin and Leptin stimulate amino acid uptake in villous explants

Jansson N, et al. 2003J Clin Endocrinol Metab. 88(3):1205-11.

Nina Jansson

Mammalian Target of Rapamycin

A large number of upstream regulators of mTOR Complex 1 

mTORRaptor

S6K1

Thr 389P

RPS6

P

Translation

4E-BP1

PThr 37, 46 & 70

Ser 235 & 236

Insulin/IGF-I receptor

P

AKT IRS-1

PI3K Pp85

hVps34

TSC1/2

Glucose

Amino acids

ATPOxygen

Tyr 612

PThr308

FFA

LRb

CortisolREDD1

mTOR and placental amino acid transport

Rosario FJ et al J Physiol. 2013

Placental mTOR

P-4EBP36/47 P-4EBP70 P-RS60

50

100

150

200

250 Normal

High BMI

Re

lati

ve

De

ns

ito

me

try

*

*

Francesca Gaccioli

Toll like Receptor 4

SFA and MUFA

Pro-Inflammatory Response

LPS

Oleic acid stimulates amino acid uptake through a TLR4 mechanism

Lager S, et al .J Lipid Res. 2013

Susanne Lager

0

1

2

3

4

5

6

0 0.002 0.02 0.2

[TNF-a] ng/ml

MeA

IB u

pta

ke p

mo

l/m

g/m

in

ANOVA p=0.004 n = 6 for each concentration

**

**

Amino acid uptake is stimulated by TNF-a in primary cultured trophoblast cells

TNF-a

Jones et al, 2009 Am J Physiol, Cell Physiol 297:1228-1235.

Helen Jones

Effects of SFA, MUFA and LCPUFA on trophoblast amino acid uptake

Study participants (n=35):• Obese (≥30 kg/m2) pre-pregnancy BMI. • Singleton pregnancies.• Exclusion criteria: concurrent inflammatory, vascular, or metabolic disease (such as

diabetes, pre-eclampsia), tobacco or street drug use, high usual intake of DHA.

Recruitment

Study visit 1: Enrollment/baseline

26 weeks 32 weeks

Study visit 2: Compliance

36 weeks

Study visit 3: Compliance

Placenta collection and

analysis

Term

800 mg/day DHA or Placebo

DHA Supplementation in Obese Mothers: Study Design

DHA supplementation in obese pregnant women

SV1 Pla

cebo

SV3 Pla

cebo

SV1 DHA

SV3 DHA

0

2

4

6

8

10

Pe

rce

nt

of

tota

l FA

SV1 SV3 SV1 SV3 Placebo DHA

*

DHA supplementation: effects on placental function

DHA supplementation: effects on placental function

MVM expression

Placental membrane DHA (%)

FA

TP

4 /

tota

l pro

tein

0 5 10 15 200.0

0.2

0.4

0.6

0.8P < 0.01r = 0.49

Q = 0.04

BPM expression

Placental membrane DHA (%)

GL

UT

1 /

tota

l pro

tein

0 5 10 15 200.0

0.5

1.0

1.5

2.0

P < 0.05r = 0.43

Q = 0.09

GLUT1 (BPM) FATP4 (MVM)70 kDa55 kDa

Fatty Acids and Placental Function

• We have demonstrated that saturated and monounsaturated fatty acids stimulate trophoblast System A amino acid uptake in a TLR4 dependent manner.

• Omega3 long chain polyunsaturated fatty acids inhibit amino acid uptake by System A.

• DHA supplementation modulates placental nutrient transport capacity in obese mothers.

Jansson N et al 2008, Am J Clin Nutr 87:1743-1749.

r = -0.592, p<0.001

Maternal adiponectin, placental function and fetal growth

Hypothesis: Maternal adiponectin down-regulates placental nutrient transport and inhibit fetal growth.

Jones HN et al., 2010, Diabetes 59:1161-1170

N=6, ANOVA<0.05

C I IAd Ad0

2

4

6

8

10

12

14

16

Sys

tem

A a

ctiv

ity

pm

mo

;/m

g/m

in *

Chronic maternal infusion adiponectin in pregnant mice

Infusion (mini-osmotic pump) of full length adiponectin Gestational days 14.5-18.5 in mice

Decreased pup weight ( -20%)Decreased placental amino acid transport

System A0

40

80

120

Sy

ste

m A

up

tak

e

pm

ol/m

g p

rote

in/1

5 s

ec

*

System L0

0.1

0.2

0.3

0.4

0.5

0.6C A

Sy

ste

m L

up

tak

e

pm

ol/m

g p

rote

in/1

5 s

ec

*

Rosario et al 2012 J Physiol 590:1495-1509

Adiponectin in Pregnancy

Adiponectin is insulin sensitizing in adult tissues but causes insulin resistance in placenta.

Adiponectin is high in lean women and acts to inhibit placental insulin signaling. This would tend to decrease amino acid uptake in normal healthy pregnancies.

Obese women have low adiponectin which would promote insulin stimulated amino acid transfer across the placenta.

High BMIHigher fasting insulin, leptin, cytokines Low adiponectinHyperlipidemia –SFA and MUFALow omega3 LCPUFA

Maternal metabolic factors stimulate the placenta to transportnutrients

Increased nutrient delivery to the fetus stimulates growth through insulin release

Omega3 LCPUFA

From Lager and PowellJ of Pregnancy 2013

Integration of Signals: Mother Fetus Placenta

The placenta integrates signals from both the mother and fetus.

Extrinsic signals such as hormones, cytokines, maternal nutrient and energy levels

Intrinsic placental signaling pathways for nutrient sensing, inflammation, and growth.

Obesity, Placenta and Developmental Programming

Understanding the complex placental signaling pathways that lead to alterations in fetal growth will allow for the development of strategies to prevent short- and long-term health consequences of

pathological fetal growth.

Thank you! to the mothers and babies University Hospital in San Antonio

Thomas JanssonPost Docs, Fellows and students

Our funding sources:Swedish Research CouncilNOVO Nordiska

NIH NHLBI R21HL093532CTSA UL1RR025767Mike Hogg FundNIH NIDDK RO1 DK89989NIH NICHD R03 HD058030NIH NICHD R01 HD058045