the epigenetics of obesity: individual, social, and ... •epigenetics is an ... faseb journal,...

The Epigenetics of Obesity: Individual, Social, and

Environmental Influences

K. J. Claycombe, Ph.D.

What can happen to our gene(s)

that would cause obesity?

Modification

via

Epigeneticalterations

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



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

Cover, Science, August 15th, 2014, Vol. 345

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)

FASEB Journal, 25(7): 2167-2179, 2011

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

Example of Basic Science Studies of

Epigenetics

Obesity and Epigenetics of Adipose tissue

(USDA ARS Research Program)

Large for Gest. Age Normal IUGR

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?

Animal model of

obesity and epigenetics

Experimental Design

20%

protein

Normal Energy2 wk Gestation Lactation

20%

protein

20%

proteinHigh Energy

Experimental Diet (12 wks)

FO F1

8 %

protein


8 %

protein

8 %

proteinHigh Energy


20%

protein

Normal Energy

2 wk Gestation Lactation

20%

protein

20%

proteinHigh Energy


8 %

protein

Normal Energy


8 %

protein

8 %

proteinHigh Energy

Experimental Diet (12 wks)Adaptive and

compensatory

programming

20%

protein

Normal Energy


20%

protein

20%

proteinHigh Energy


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

)

How to measure fat tissue

changes over time

in live animals?

Magnetic Resonance Imaging (EchoMRI)

Quantitate

fat mass

measurement by

Echo MRI

20%

protein


20%

protein

20%

proteinHigh Energy


FO F1

8 %

protein


8 %

protein

8 %

proteinHigh Energy


10 fold

increase

2.5 fold

increase

Low Adipose Tissue Weight and Catch-up Growth

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

Effects of prenatal and

postnatal diet on

imprinted

gene expression?

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

E

promter

H19

Igf2 DMR2

CH3 CH3 CH3

ICR

CH3 CH3 CH3

IGF2 transcription activation

IGF2 transcription repression

E

promter

H19

Igf2 DMR2

ICR

CTCF

ICR/ H19 DMR Methylation in Adipose Tissue

0

1

2

3

4

5


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

Is there metabolic

phenotype associated

with catch-up growth?

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


0

1

2

3

4

5

6LP-NF NP-NFLP-HF NP-HF

Fold

Incr

ease

a,b

a,b

a

b

Effects of LP prenatal and HF postnatal diet on Adipose Tissue IGF2 mRNA Expression

Adipose Tissue Growth and Regulators

Normal Obesity


Normal Obesity

IGF2 IGF2


High Fat Diet

Normal Obesity

+

IGF2 IGF2


High Fat Diet

Normal Obesity

+Exercise

IGF2 IGF2

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

Other

metabolic tissues?

Effects of LP prenatal diet on Muscle Metabolism and mt Function

Claycombe et al.,

Journal of nutritional biochemistry

26(2):184-189, 2015

Effects of LP prenatal diet on Brown adipose tissue function

Claycombe et al., Journal of Nutritional Biochemistry 26(7):729-735, 2015

Acknowledgment

Thank you

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