brookhaven science associates u.s. department of energy gene-jack wang, m.d. the addiction-obesity...

Brookhaven Science AssociatesU.S. Department of Energy

Gene-Jack Wang, M.D.

The Addiction-Obesity Connection



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United States of Obesity

Time.com June 7, 2004



Cocaine Alcohol Heroin

AbuserControl

[11C]raclopride

Abuser AbuserControl Control

Dopamine D2 images of Drug Addiction

Cocaine Alcohol Heroin


Compulsive overeating shares many of the same characteristics as drug addiction.

Obesity

Do obese subjects have abnormal levels of D2-receptor?

10 severely obese subjects (BMI: 51±5 kg/m2)10 age-matched controls (BMI: 25±3 kg/m2)


Lower dopamine receptors in obese than in control subjects

2

0ml/gm

Control Subjects

Obese Subjects

[11C]raclopride

Wang et al, Lancet 2001

Bmax/Kd

BMIControl subjects

20

25

30

35

40

45

50

55

60

65

1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 3.6 3.8

Obese subjects (n = 10)Control subjects (n = 10)

BMI

Dopamine Receptor Concentration

P < 0.002

P < 0.3


Food Stimulation


Brain Dopamine Response to Food Stimulation(B

max

/Kd)

(Bm

ax/K

d)

2.52.5

33

3.53.5

44

Placebo/NeutralPlacebo/Neutral MP/FoodMP/Food

p < 0.005p < 0.005

1.51.5

00

ml/gml/g

Volkow, et al, Synapse 2002

-2-2

00

22

44

66

88

1010

00 55 1010 1515 2020 2525 3030D

esire

for F

ood

Des

ire fo

r Foo

d

% Change Bmax/kd% Change Bmax/kd

p < 0.01p < 0.01

NeutralNeutral FoodFood



Cue-induced increases in DA were associated with craving

P < 0.002

% Change Bmax/Kd% Change Bmax/Kd

-0.50-0.50

0.00.0

0.500.50

1.01.0

1.51.5

2.02.0

2.52.5

-40-40-30-30-20-20-10-1000101020203030

Putamen

Cha

nge

in C

ravi

ngC

hang

e in

Cra

ving

(Pre

- Po

st)

(Pre

- Po

st)

Relationship between Cue-Induced Decreases in [C-11]raclopride Binding and Cocaine Craving

Cau

date

Cau

date

Puta

men

Puta

men

2.002.00

2.502.50

3.003.00

3.503.50

NeutralNeutralCocaine-CuesCocaine-Cues

Bm

ax/K

dB

max

/Kd

P < 0.05P < 0.05

P < 0.01P < 0.01

Volkow et al, 2006


MP

85

0

µmole/100g/min

Brain Activation with Methylphenidate Induced Cocaine Craving

Placebo

Orbitofrontal Activation

Volkow et al Am J Psychiatry 1999

-30

-20

-10

0.0

10

20

30

0.0 2.0 4.0 6.0 8.0 10m

icrom

ol/1

00g/

min

(MP

- Pla

cebo

)Self Report Craving

r = 0.79, p < 0.0002



% Metabolic Changes

-10

-5

0

5

10

15

20

25

-10 0 10 20 30 40 50 60 70 80

% Changes of feeling of hunger

r = 0.84, p = 0.001

85

0

µmole/100g/min

Neutral Stimuli

Food Stimuli

Wang et al, Neuroimage 2004

Orbitofrontal Activation

Brain Activation with Food Stimuli



Why do some people continue to eat when the stomach is full?18FDG-PET (IGS “on” vs IGS “off” in obese subjects)

Orbitofrontal Cortex(Self-Control)

Hippocampus(Memory)

Striatum(Motivation)

IGS: Implantable gastric stimulator

Emotional eating

3

4

5

6

7

8

9

10

11

12

13

.6 .8 1 1.2 1.4 1.6 1.8 2 2.2 2.4

(n=2)

2

3

ON OFF

p < 0.04

Wang et al, PNAS USA 2006


Decreased brain activation during cognitive inhibition of hunger

hunger

Absolute metabolic changes

-25

-20

-15

-10

-5

0

5

-8 -7 -6 -5 -4 -3 -2 -1 0

r = 0.73, p = 0.02

Orb

itofr

onta

l cor

tex

AmygdalaHippocampus

Cerebellum

CingulateStriatum

-1

0

1

2

3

4

5

0 10 20 30 40 50

Time (min)

Hunger

Food stimulation

Cognitive Inhibition


New intriguing questions

• Do obese subjects have the same ability to suppress craving?

• How about drug addicts?

• Are there differences between men and women in ability to inhibit hunger?

• Are the same brain regions involved in cognitive inhibition as involved in gastric stimulation?


Thank You!

Supported by DOE/OBER


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obese subjects n

onoff p

change bmaxkd p

control subjects n

food stimulation bmaxkd

neutral cocainecues