Upload
the-bixby-center-on-population-and-reproductive-health
View
70
Download
0
Tags:
Embed Size (px)
Citation preview
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