ross 5-7-15

Perinatal Origins of

Childhood and Adult Obesity

Michael G. Ross, M.D., M.P.H.

Mina Desai, Ph.D.

Department of Obstetrics & Gynecology

Harbor-UCLA Medical Center

Metabolic Syndrome

• Traits:

• Obesity

• Hypertension

• Type 2 diabetes mellitus

• Dyslipidemia

• Mortality: Leading cause of death in the United States

• Obesity: U.S. adults 65% overweight, 31% obese,

Childhood obesity 20%

• Hypertension: 29% of U.S. population

• Diabetes: 27% of U.S. population

Obesity Trends* Among U.S. Adults

CDC, 1985(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults

CDC, 1995(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

<10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults

CDC, 2005(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)

<10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. Adults

CDC, 2009

15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. Adults

CDC, 2013

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% 30%-34% ≥35%

Prevalence of Obesity* Among U.S.

Children and Adolescents (2 –19 Years)0

5

1

0 1

5 2

0

Perc

en

t

1971-1974 1976-1980 1988-1994 2003-2006

National Health and Nutrition Examination Surveys

*Sex-and age-specific BMI > 95th percentile based on the CDC growth charts

■ 2-5 years ■ 6-11 years ■ 12-19 years

3 fold

Etiology of Obesity

Food Availability

High Fat Diets

Reduced Energy

Expenditure

Propensity for

Obesity

Developmental

Programming

Developmental Programming

Altered cell number

and differentiation

Modified gene expression

altered function

Fetal Nutrition, Stress

? Environmental Toxins

Programming vs. Mutations

Genetic mutations: Long epochs,

irreversible

Programmed phenotypes: Respond to

acute environmental stresses

Environmental Stresses on Survival

Drought and Famine •Famine: nutrient reduction

Famine/drought during pregnancy

results in low birth weight infants

“Thrifty Phenotype”

Increased food intake, gorging

Efficient metabolism

Reduced energy expenditure

Survival Advantage in an

environment of reduced nutrient

availability

“Thrifty” vs. “Inadvertent Thrifty”

Phenotype• Intrauterine Growth Restricted Newborns

– Improved Fecundity:

• Maternal medical illness

– Etiologies:

• Substance abuse, cigarette smoking

– Twins and higher order:

• Natural and In Vitro Fertilization

• Enhanced Neonatal Survival: viability 400 g

High fat, high calorie diet

Thrifty Phenotype Obesity

Barker Hypothesis

Developmental Programming

Small for Gestational Age (SGA) and/or

Low Birth Weight (LBW) human newborns

• Paradoxical increased risk of

hypertension, obesity, and diabetes as

adult

Hertfordshire Birth Records

1911-1949

Electronic Medical Record

Birth Weight and Metabolic Syndrome

Prevalence of Metabolic Syndrome according to birth weight in

407 men, aged 65 years, born in Hertfordshire

Birth Weight and Adult DiseasesEpidemiological Studies

Obesity

Diabetes

Cardiovascular Disease

Hypertension

Lipids

Fatty Liver

Immuno-compromise, Allergies

Addiction, Substance abuse

The relationship between deciles of birth weight and systolic blood

pressure (SBP) among Swedish males at 18 years old

Nilsson: J Hypertens, Volume 15(12).December 1997.1627–1631

Fig. 1

Birth Weight and Blood Pressure

Ponderal Index and Coronary Heart Disease395 deaths in 6856 men in Helsinki

Ponderal

index at birth

(kg/m3)

Body mass index at 12 years (kg/m2)

Hazard

ratio

>18 -18 -17 -16

-29

>29

-27

-25

4

3

2

1

0

5

Eriksson JG et al BMJ 2001

Birth Weight and Type 2 Diabetes1179 Pima Indians aged 201179 Pima Indians aged 20--39 years39 years

McCance DR et al BMJ 1994;308:942-5

0

10

20

30

<2.5 -3.0 -3.5 -4.0 4.0

Birthweight (kg)

Ag

e a

dju

sted

pre

va

len

ce (

68%

CI)

Hovi P et al. N Engl J Med 2007;356:2053-2063

Glucose, Insulin Concentrations and the Insulin-Resistance Index

Adults with Very Low Birth Weight (VLBW) versus Adults Born at Term

Birth Weight and Insulin Resistance

Models of Fetal Programming

• Maternal Obesity

• Low Birth Weight

• Environmental Toxins: Bisphenol A

• Phenotype

• Mechanisms of Appetite and Adipose

Programming

Prevalence of Maternal Obesity

◌ ≥ 200 lb

● ≥ 250 lb

□ ≥ 300 lb

■ > 29 kg/m3

In USA women at first prenatal visit

2 fold

Model of Maternal Obesity

High Fat Diet

OFFSPRING

• Litter size: Culled to 4 males and 4 females at birth

• Nursing: All pups nursed by same dams until p21

• Weaning: At p21 to ad Libitum food and water

Body Weight of Male Offspring

1 Day 3 Weeks 6 Months

Mean ± SE; * p < 0.01

Control HF

Bo

dy W

eig

ht

(g)

0

2

4

6

8

Control HF

Bo

dy W

eig

ht

(g)

0

20

40

60

80 *

Control HF

Bo

dy W

eig

ht

(g)

0

300

400

500

600 *

Accelerated Growth During Nursing

Control Mat-OB Control Mat-OB Control Mat-OB

Percentage Body Fat: Male Offspring

3 Weeks 6 Months

Mean ± SE; * p < 0.001

Control HF

Bo

dy F

at

(%)

0

2

4

6

8

10

12

14

16

*

Control HF

Bo

dy F

at

(%)

0

5

10

15

20

25

30 *

Early Onset Obesity

Control Mat-OB Control Mat-OB

Plasma Triglycerides: Male Offspring

1 Day 3 Weeks

Mean ± SE; * p < 0.01

Control HF

Tri

gly

ceri

de (

mg

/dl)

0

40

80

120

160

*

Tri

gly

ceri

de (

mg

/dl)

0

40

80

120

160

*

Control HF

Hypertriglyceridemia

Control Mat-OB Control Mat-OB

Systolic Blood Pressure

6 Week Obese Males

Control HF

Blo

od

Pre

ssu

re (

mm

Hg

)

0

120

130

140

150

160

*

* P < 0.05 vs. Control

Early Onset Hypertension

Control Mat-OB

Glucose, Insulin and GTT

3 Month Obese Males

Time (mins)

Blo

od

Glu

co

se (

mg

/dl)

0

80

120

160

200Control

HF

*

*

*

* **

0 15 30 60 120 180

Control HF

Glu

co

se (

mg

/dl)

0

60

80

100

120

140

160

*

Control HF

Insu

lin

(n

g/m

l)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6 *

Insulin Resistance

Control Mat-OB

Control Mat-OB

Mat-OB

Low Birth Weight Trends in USA15

12

9

6

3

1981 1985 1990 1995 2000 2005 2010

+28%

+12%

-1%

All races

WhiteHispanic

Black

Change from

1989

+16%

Model of Intrauterine Growth Restriction (IUGR)

Maternal Food Restriction (FR)

OFFSPRING

• Litter size: Culled to 4 males and 4 females at birth

• Nursing: All pups cross-fostered to ad libitum fed Control dams

until p21

• Weaning: At p21 to ad Libitum food and water

Body Weight of Male Offspring

1 Day 3 Weeks 9 Months

Mean ± SE; * p < 0.01 Desai et al, Am J Physiol, 2005

Control FR

Bo

dy W

eig

ht

(g)

0

2

4

6

8

*

Control FR/AdLib

Bo

dy

We

igh

t (g

)

020

30

40

50

60

*

Control FR/AdLib

Bo

dy W

eig

ht

(g)

0500

600

700

800

*

Rapid Catch-up Growth

Control IUGR Control IUGR Control IUGR

% Body Fat of Male Offspring

3 Weeks 9 Months

Mean ± SE; * p < 0.001 Desai et al, Am J Physiol, 2005

Control FR/AdLib

% B

od

y F

at

0

4

8

12

16

Control FR/AdLib

% B

od

y F

at

0

5

10

15

20

25*

Adult Obesity

Control IUGR Control IUGR

Systolic Blood Pressure

3 Month Obese Adult Males

Control IUGR

Blo

od

Pre

ssu

re

(m

mH

g)

120

130

140

150

160*

* P < 0.05 vs. Control

Hypertension

Lipid Profile

9 Month IUGR Obese Adult Males

Mean ± SE; * p < 0.001 Desai et al, Am J Obstet Gynecol, 2007

Hypertriglyceridemia

Control FR/AdLib

Tri

gly

ce

rid

e (

mg

/dl)

0

40

60

80

100

120

*

Control FR/AdLibC

ho

leste

rol

(mg

/dl)

0

60

80

100

Triglyceride Cholesterol

Control IUGR Control IUGR

Glucose, Insulin and GTT

9 Month IUGR Adult Males

Time (mins)

0 30 60 90 120 150 180 210G

luco

se (

mg

/dl)

080

120

160

200

240

*

* *

*

**

ControlFR/AdLib

Desai et al, Am J Obstet Gynecol, 2007

Insulin Resistance

Control FR/AdLib

Glu

co

se

(m

g/d

l)

0

80

90

100

110

120*

Control FR/AdLib

Ins

uli

n (

ng

/ml)

0.0

0.2

0.4

0.6

0.8

1.0*

Control IUGR

Control IUGR

IUGR

Maternal Undernutrition and Overnutrition:

Offspring Programming of Metabolic Syndrome

Obesity

Adiposity

Hypertension

Hyperlipidemia

Fatty Liver

Diabetes

Non-alcoholic

fatty liver

disease

Increased fat

storage

Reduced satiety

FAT

FAT

FAT

FAT

FAT

Double Hit: High Fat Diet

Postnatal High Fat Diet

Body Composition: Controls and IUGR

* vs Control; # vs High Fat Diet

Control FR/AdLib

Bo

dy

We

igh

t (g

)

0500

600

700

800

900

*

*#

Control FR/AdLib

% B

od

y F

at

010

15

20

25

30

35

*

*

#

#

Normal diet High fat diet

Control IUGRControl IUGR

Bisphenol A (BPA)

NHANES: BPA Levels during Pregnancy

Breast Milk

1.1 ng/ml

Maternal Serum

1 - 2 ng/ml

Placenta

1 – 105 ng/ml

Amniotic Fluid

8.3 – 8.7 ng/ml

Fetal Serum

0.2 – 9.2 ng/ml

Model of Maternal Bisphenol A (BPA)

OFFSPRING

• Litter size: Culled to 4 males and 4 females at birth

• Nursing: All pups nursed by same dams until p21

• Weaning: At p21 to ad libitum food and BPA-free water

Maternal BPA: Birth Weight at 1 Day

SYSBP_M SYSBP_M

Control BPA

Bo

dy W

igh

t (g

)

0

2

4

6

8

Control BPA

MALES FEMALES

Normal Birth Weight

Offspring Body Composition at 3 Weeks

0

5

10

15

MALES FEMALES

Fa

t M

as

s (

g)

0

20

40

60

80

100

MALES FEMALES

To

tal M

as

s (

g) * * * *

Control BPA

Offspring Body Composition at 6 months

0

20

40

60

80

100

MALES FEMALES

Fa

t M

as

s (

g)

0

200

400

600

MALES FEMALES

To

tal M

as

s (

g)

0

5

10

15

20

MALES FEMALES

Fa

t (%

)

*

*

Increased Body Fat

in Males

*

Control BPA

Programming Mechanisms Appetite Increased Food Intake

IMPAIRED MATERNAL

NUTRITION

Altered

adipose

Obesity

Defective

β cell

function

Insulin deficiency

Renal

Renal Insufficiency Hypertension

Blood vessels

Lung

Pulmonary

Insufficiency

Placenta

Placental

Dysfunction

Immune

Immune

Deficiency

Brain

Neurogeneration

Major Contributors of ObesityFood Intake

Fat

“Appetite Efficiency”

Time Spent Eating vs. Obesity Rate

Mechanism of Obesity

Weekly food intake; Mean ± SE

Age (weeks)

4 5 6 7 8 9 10 11 12

Fo

od

In

tak

e (

g/d

ay

)10

15

20

25

30

35

40

*

*

*

* ** *

Control

HF

Age (weeks)

4 5 6 7 8 9 10 11 12

Fo

od

In

tak

e (

g)

10

15

20

25

30

35

40

*

*

**

** * *

Control

FR

Under-Nutrition Over-Nutrition

Increased Food Intake

IUGR Mat-Ob

PVN

ARCPOMC

NPY

Appetite Regulation

ARC Nucleus Development

• ARC cells arise from Neural Stem Cells in periventricular region

• Appetite (NPY) and Satiety (POMC) neurons populate the ARC

during fetal life and this continues to develop during postnatal life

Appetite Regions Neural Stem Cells

3V

A

R

C

In Vivo Neural Stem Cell Migration

1 Day Newborn Hypothalamus

3V = Third Ventricle

Control IUGR

Mig

rati

on

Rate

(B

rdU

Cells)

0

20

40

60

80

100

120

*

3V

Nestin = marker of NSC

BrdU = proliferation

* P < 0.01

Control

IUGR

Hypothalamic Neurospheres

Undifferentiated

Early Differentiation

Hypothalamic NSC ProliferationControl IUGR

Control IUGR

Fo

ld c

han

ge

0.0

0.2

0.4

0.6

0.8

1.0

1.2

*

Nestin

Decreased Proliferation

Control IUGR

Fo

ld c

han

ge

0.0

0.2

0.4

0.6

0.8

1.0

1.2

*

Proliferation Index

Hypothalamic NSC Differentiation

Neuron Astrocyte

Decreased Differentiation

Control IUGR

Fo

ld C

han

ge

0.0

0.2

0.4

0.6

0.8

1.0

1.2

*

Tuj1

Control IUGRF

old

Ch

an

ge

0.0

0.2

0.4

0.6

0.8

1.0

1.2

*

GFAP

Differentiated Neural Stem Cell

NPY Neurons

NP

Y C

ells (

% p

er

tota

l c

ells

)

0

2

4

6

8*

Control IUGR

Control IUGR

* P < 0.05 vs. Control

Increased NPY(appetite neurons)

Hypothalamic Tissue Protein: 1 Day FR

Appetite Satiety

Control SGAP

OM

C0.0

0.5

1.0

1.5

2.0

*

Increased Appetite to Satiety Ratio

DNMT1

Control SGA

Ag

RP

0.0

0.5

1.0

1.5

2.0

*

Control IUGR Control IUGR

BPA: Neural Stem Cell Proliferation

BPA (M)

0 1 10 20

Pro

life

rati

on

In

dex

0.0

0.1

0.2

0.3

**

BPA 0M

BPA 10M

Increased Proliferation

MT

T

BPA Neural Stem Cell Differentiation

Control BPA

Fo

ld C

han

ge

0.0

0.5

1.0

1.5

2.0 *AgRP

Control BPA

Fold

Change

0.0

0.5

1.0

1.5

2.0*

NPY

Control BPA

Fold

Change

0.0

0.5

1.0

1.5

2.0

*

POMC

BPA Increases Appetite/Satiety Ratio

Appetite Satiety

Mechanism of Enhanced Appetite

Appetite (NPY) neurons Satiety (POMC) neurons

Increased Food Intake

Altered Nutrition / BPA

What Programs Adiposity ?

• Adipose Proliferation and Differentiation

• Lipogenesis

Adipogenesis

Preadipocyte

Mature

Adipocytes

Differentiation

Increased Number

of PreadipocytesProliferation

Hypertrophy

Lipid filled

Adipocytes

Pref1

PPARg

C/EBPa

SREBP1

Primary Cell Culture

• Adipose tissue from 1 day old offspring

• Preadipocytes

• Adipocyte

Control IUGR

Preadipocytes from 1 Day Newborn

Proliferation

CONTROL

IUGR Pro

life

rati

on

In

dex

0.0

0.2

0.4

0.6

0.8

1.0

*

*

**

**

c

cc

c

Insulin (g/ml)0 5 20 40

Control IUGR

Adipocytes from 1 Day Newborn

Lipid Storage

CONTROL

IUGR

Oil Red Stain; x10

O-R

-O A

bs

orb

an

ce

0.0

0.1

0.2

0.3

*

*

*

* *

*

c

c

cc

Insulin (g/ml)0 5 20 40

Control IUGR

BPA: Preadipocytes

Control BPA (10g)

BPA (M)

Pro

life

rati

ve

In

de

x

0.0

0.2

0.4

0.6

0.8

0 1 10 20

*

**

Adipogenesis Lipogenesis

Increased Proliferation and Lipid Storage

Mechanisms for Developmentally

Programmed Obesity

Appetite

Fetal

Nutrition/

BPA

IUGR NSC

HES1

SIRT1 Mash1

-

HES1Ngn3

Low

Energy

Hes1 gene

Ac

Mash1/Ngn3 genes

POMC

NPY

--

+

NSC

Proliferation

renewal

Neural Stem Cell Programming:

Epigenetic Regulation

Adipose Stem Cells:

Epigenetic Regulation

MOTHER INFANT ADULT OFFSPRING

NormalNormal Normal

Medical Illness

Placental Insufficiency

Twins, Triplets, etc.

IUGR Improved Survival

- Food availability

- High fat diet

Obese/Diabetic

Obese/ BPA

Macrosomic

- Food availability

- High fat diet

Obesity/

Hypertension/

Diabetes

Epidemic of Metabolic Syndrome

Journals.cambridge.org/DOH