Early‐life determinants of overweight and obesity
Obesity Reviews, Monasta et al., 11 (10): 695-708, 2010
Early‐life determinants of overweight and obesity
Obesity Reviews, Monasta et al., 11 (10): 695-708, 2010
Environmental
Social
Environmental
Environmental
EnvironmentalEnvironmental
Social
Environmental
Individual
Early‐life determinants of overweight and obesity
Obesity Reviews, Monasta et al., 11 (10): 695-708, 2010
Environmental
Epigenetics
• Epigenetics is an inheritable changes
that affects gene expression without
DNA base pair sequence changes
• Examples of epigenetic phenomena
- DNA methylation
- histone modifications
- chromatin remodeling
“What your grandparents ate could affect your health”
For example, when a paternal grandmother experienced
drastic changes in food availability as a child, then granddaughters had
an increased risk for
cardiovascular mortality as an adult
Do prenatal experiences shape culinary tastes?
consumed
plain flavored or garlic capsules
around 24 weeks of pregnancy
Pregnant volunteers
Volunteers easily sniffed out
which came from the garlic consumer
Sniffed unlabeled bottles of
amniotic fluid and breast milk
Babies born from two groups of volunteers
who consumed plain flavored or garlic capsules
Videotape images were generated
when babies were given garlic milk
Other supporting evidence (animal study)
Pregnant Wistar rats
standard rat chow
Maintained on their respective diets
throughout pregnancy and lactation
After weaning, offspring were fed
either control chow or junk diets for
either 3 weeks and for 3 months
FASEB Journal, 25(7): 2167-2179, 2011
Conclusions:
Mice whose mothers had a junk food diet
developed altered development of the
central reward system, resulting in
increased fat intake and altered response
of the reward system to excessive junk-
food intake in postnatal life
LP fed dams and offspring Phenotyes
hypertension (Langley-Evans et al, Clin Nutr 1994; 13: 319–324)
increased fat deposition and altered feeding behavior(Lucas et al., Br J Nutr 1996; 76: 605–612, Bellinger et al.,
Br J Nutr 2004; 92: 513–520, and
Bellinger et al., Int J Obes (Lond) 2006; 30: 729–738)
impaired glucose homeostasis, dyslipidaemia(Burdge et al., Prostaglandins Leukot Essent Fatty Acids 2008; 78: 73–79)
impaired immunity(Calder and Yaqoob, Nutr Res 2000; 20: 995–1005)
increased susceptibility to oxidative stress(Langley-Evans and Sculley, Mech Ageing Dev 2005; 126: 804–812)
Increased propensity for
catch up growth Normal growth
Sutton et al., Endocrinology 2010;151(4):1570-80
Intrauterine growth restriction and catch-up growth
Maternal under
nutritionNormal diet
Low birth weight Normal weight
Maternal under
nutrition
Low birth weight
Increased propensity for
catch up growth
High Fat
diet
Epigenetic
Programming?
Experimental Design
20%
protein
Normal Energy2 wk Gestation Lactation
20%
protein
20%
proteinHigh Energy
Experimental Diet (12 wks)
FO F1
8 %
protein
Normal Energy2 wk Gestation Lactation
8 %
protein
8 %
proteinHigh Energy
Experimental Diet (12 wks)
20%
protein
Normal Energy
2 wk Gestation Lactation
20%
protein
20%
proteinHigh Energy
Experimental Diet (12 wks)
8 %
protein
Normal Energy
2 wk Gestation Lactation
8 %
protein
8 %
proteinHigh Energy
Experimental Diet (12 wks)Adaptive and
compensatory
programming
20%
protein
Normal Energy
2 wk Gestation Lactation
20%
protein
20%
proteinHigh Energy
Experimental Diet (12 wks)
8 %
protein
Normal Energy8 %
protein
8 %
proteinHigh Energy
At Birth
at weaning
0
20
40
60
80
100
adipose lean BW
LP NE NP NELP HE NP HE
We
igh
t (
g)
4
4
5
5
6
68% 20%
Bo
dy
we
igh
t (g
)
Quantitate
fat mass
measurement by
Echo MRI
20%
protein
Normal Energy2 wk Gestation Lactation
20%
protein
20%
proteinHigh Energy
Experimental Diet (12 wks)
FO F1
8 %
protein
Normal Energy2 wk Gestation Lactation
8 %
protein
8 %
proteinHigh Energy
Experimental Diet (12 wks)
1.00
3.34
6.25
10.19
13.47
16.27
19.68
1.001.98
3.395.12
6.838.43
10.00
1.00
3.05
6.99
11.69
16.70
21.98
27.13
1.002.25
4.65
7.76
10.93
13.8215.23
0
5
10
15
20
25
30
week 0 week 2 week 4 week 6 week 8 week 10 week 12
LP NE
NP NE
LP HE
NP HE
Ad
ipo
se t
issu
e m
ass
fold
incr
eas
e 19.7
10.0
27.13
15.23
Adipose tissue mass fold increase
Claycombe et al., accepted, J Nutr. 2013
Igf2/H19 Locus
• Insulin-like growth factor 2 (IGF2) was the first imprinted gene identified (Cell, 64:849-859, 1991)
• IGF2 is a major fetal growth factor (Nature 417:945-948, 2002)
• Epigenetics is an inheritable changes that affects gene expression without DNA base pair sequence changes (e.g. DNA methylation, histone modifications)
Effects of LP prenatal and HF postnatal diet on Adipose Tissue IGF2 mRNA Expression
0123456789
101112
Visceral Subcutaneous
LPNF NPNF LPHF NPHF
IGF
-2 m
RN
A
Fo
ld in
cre
ase
Claycombe et al., J Nutr. 2013
0
1
2
3
4
5
Visceral Subcutaneous
LPNF NPNF
LPHF NPHF
Dn
mt3
a m
RN
A
Fo
ld in
cre
ase
Effects of LP prenatal and HF postnatal diet on Adipose Tissue Dnmt3a mRNA Expression
Effects of LP prenatal and HF postnatal diet on GT
50
70
90
110
130
150
0 min 15 min 30 min 60 min 120 min
LPNF NPNF
LPHF NPHFB
loo
d(m
g/d
L)
a
b
a
ba.b
a
a
a
b
a,b
a,b
a
b
a
10000
11000
12000
13000
14000
15000
16000
LPNF NPNF LPHF NPHF
AU
C aa
ab
b
Claycombe et al., J Nutr. 143(10):1533-1539, 2013
Effects of LP prenatal and HF postnatal diet on Plasma Insulin Concentrations
0
100
200
300
400
500
600
LPNF NPNF LPHF NPHF
Insu
lin(p
g/m
l)
Prenatal P=0.28
Postnatal P=0.005
Pre x Post P=0.45
Claycombe et al., J Nutr. 143(10):1533-1539, 2013
Adipose Tissue
Mitochondrial Copy Number
0
1
2
LP-NF
NP-NF
LP-HF
NP-HF
Fold
Incr
ea
se
ANOVAPre NSPost p=0.06Pre x Post NS
Visceral Subcutaneous
0
1
2
3
4
5
6LP-NF NP-NFLP-HF NP-HF
Fold
Incr
ease
a,b
a,b
a
b
Maternal Conditions
Developmental Influences of
Maternal Diet and Exercise F1 Response
Promote Obesity and
Insulin Resistance
Epigenetic Changes
Decreased Numbers of
Beige Adipocytesand
Decreased Energy Utilization
Test of Maternal exercise
(Human study)
High Fat Diet and
Obesity
Modulators?
Skeletal muscle Adipose tissue
Brain and BAT
Endocrine
cross talk
Insulin Resistance
SDH, SIRT3,
mt respirationIGF2
Maternal LP
Diet
UCP-1, PPAR-a