ross 5-7-15
TRANSCRIPT
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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
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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
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Obesity Trends* Among U.S. Adults
CDC, 1985(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
No Data <10% 10%–14%
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Obesity Trends* Among U.S. Adults
CDC, 1995(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)
<10% 10%–14% 15%–19%
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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%
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Obesity Trends* Among U.S. Adults
CDC, 2009
15%–19% 20%–24% 25%–29% ≥30%
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Obesity Trends* Among U.S. Adults
CDC, 2013
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% 30%-34% ≥35%
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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
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Etiology of Obesity
Food Availability
High Fat Diets
Reduced Energy
Expenditure
Propensity for
Obesity
Developmental
Programming
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Developmental Programming
Altered cell number
and differentiation
Modified gene expression
altered function
Fetal Nutrition, Stress
? Environmental Toxins
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Programming vs. Mutations
Genetic mutations: Long epochs,
irreversible
Programmed phenotypes: Respond to
acute environmental stresses
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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
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“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
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High fat, high calorie diet
Thrifty Phenotype Obesity
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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
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Hertfordshire Birth Records
1911-1949
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Electronic Medical Record
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Birth Weight and Metabolic Syndrome
Prevalence of Metabolic Syndrome according to birth weight in
407 men, aged 65 years, born in Hertfordshire
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Birth Weight and Adult DiseasesEpidemiological Studies
Obesity
Diabetes
Cardiovascular Disease
Hypertension
Lipids
Fatty Liver
Immuno-compromise, Allergies
Addiction, Substance abuse
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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
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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
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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)
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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
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Models of Fetal Programming
• Maternal Obesity
• Low Birth Weight
• Environmental Toxins: Bisphenol A
• Phenotype
• Mechanisms of Appetite and Adipose
Programming
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Prevalence of Maternal Obesity
◌ ≥ 200 lb
● ≥ 250 lb
□ ≥ 300 lb
■ > 29 kg/m3
In USA women at first prenatal visit
2 fold
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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
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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
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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
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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
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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
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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
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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%
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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
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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
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% 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
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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
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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
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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
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Maternal Undernutrition and Overnutrition:
Offspring Programming of Metabolic Syndrome
Obesity
Adiposity
Hypertension
Hyperlipidemia
Fatty Liver
Diabetes
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Non-alcoholic
fatty liver
disease
Increased fat
storage
Reduced satiety
FAT
FAT
FAT
FAT
FAT
Double Hit: High Fat Diet
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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
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Bisphenol A (BPA)
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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
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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
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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
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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
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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
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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
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Major Contributors of ObesityFood Intake
Fat
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“Appetite Efficiency”
Time Spent Eating vs. Obesity Rate
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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
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PVN
ARCPOMC
NPY
Appetite Regulation
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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
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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
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Hypothalamic Neurospheres
Undifferentiated
Early Differentiation
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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
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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
![Page 58: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/58.jpg)
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)
![Page 59: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/59.jpg)
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
![Page 60: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/60.jpg)
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
![Page 61: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/61.jpg)
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
![Page 62: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/62.jpg)
Mechanism of Enhanced Appetite
Appetite (NPY) neurons Satiety (POMC) neurons
Increased Food Intake
Altered Nutrition / BPA
![Page 63: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/63.jpg)
What Programs Adiposity ?
• Adipose Proliferation and Differentiation
• Lipogenesis
![Page 64: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/64.jpg)
Adipogenesis
Preadipocyte
Mature
Adipocytes
Differentiation
Increased Number
of PreadipocytesProliferation
Hypertrophy
Lipid filled
Adipocytes
Pref1
PPARg
C/EBPa
SREBP1
![Page 65: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/65.jpg)
Primary Cell Culture
• Adipose tissue from 1 day old offspring
• Preadipocytes
• Adipocyte
Control IUGR
![Page 66: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/66.jpg)
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
![Page 67: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/67.jpg)
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
![Page 68: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/68.jpg)
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
![Page 69: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/69.jpg)
Mechanisms for Developmentally
Programmed Obesity
Appetite
Fetal
Nutrition/
BPA
![Page 70: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/70.jpg)
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
![Page 71: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/71.jpg)
Adipose Stem Cells:
Epigenetic Regulation
![Page 72: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/72.jpg)
![Page 73: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/73.jpg)
![Page 74: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/74.jpg)
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
![Page 75: Ross 5-7-15](https://reader031.vdocuments.us/reader031/viewer/2022032002/55aa10651a28ab74318b458c/html5/thumbnails/75.jpg)
Journals.cambridge.org/DOH
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