Obesity

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Obesity Addiction Neuroimaging Studies
Gene-Jack Wang, M.D. Brookhaven Center for
Translational Neuroimaging
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Obesity
Newsday / Walt Handelsman Oct 10, 2002
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Factors Contributing to Obesity

• Culture,
• Genetics,
• High energy
• intake,
• Lowered energy
• expenditure,
• Abnormal eating
• behavior.

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Signals that Control Food Intake
Hypothalamus
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Eating Habits
Many obesity researchers focus on how the body's
fuel and fat levels control appetite. But as
comfort eaters know, habits and desires often
override metabolic need.
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Body Weight Drug Treatment

• Drugs (stimulants e.g. amphetamine, cocaine,
  methylphenidate) that increase brain dopamine
  concentration are anorexigenic.
• Drugs (antipsychotic e.g. Haloperidol,.. ) that
  block dopamine D2 receptors increase appetite and
  result in significant weight gain.

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Dopamine D2 images of Drug Addiction
Cocaine
11Craclopride
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Low Dopamine (DA) State in Addiction
Dopamine
Non Drug Abuser
Addicted Subject
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Obesity

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

• Do obese subjects have abnormal dopamine
  receptors?

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Dopamine Receptors
11Craclopride
2
0
ml/gm
Control Subjects
Wang et al, Lancet 2001
11
Dopamine Receptor and BMI

• Obese subjects

p lt 0.002

• Control subjects

BMI
p 0.3
Dopamine Receptor Concentration
Wang et al, Lancet 2001
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Implication

• Dopamine modulates motivation and reward circuits
  and hence dopamine deficiency in obese subjects
  may perpetuate pathologic eating as a means to
  compensate for the decreased activation of reward
  circuits.

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Dopamine
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Food

• Eating is highly reinforcing behavior, just like
  taking drugs and as for drugs it can elicit
  powerful conditioned responses.

• Are the conditioned responses associated with DA
  release? That is would DA be released by viewing
  food without eating it?

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Food Stimulation

• 1) Subjects were asked to describe their
  favorite foods and how they like to eat them
  while they were presented with foods that they
  had reported as among their favorite ones.
• Food was warmed to enhance the smell and the
  subjects were presented with it so that they
  could view it and smell it and a cotton swab
  impregnated with the food was placed in their
  tongues so they could taste it.
• A given food item was presented for 4 minutes and
  then it was exchanged for a new one.

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Neutral Stimulation
Subjects viewed neutral images and/or were asked
to describe in as much detail as possible their
family genealogy.
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Methylphenidate ( MP) block the Dopamine
Transporter ( )
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
signal
signal
MP enhances weak signals
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Study Design
Subjects were scanned 4 times with
11Craclopride over a two day period. Six
subjects participated study 1 on the first day
and four subjects participated study 2 on the
first day of the studies
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Brain Dopamine Response to Food Stimulation
Sum images of 10 normal weight subjects
(11Craclopride)
1.5
DA D2 Receptor Availability
0
ml/g
p lt 0.11
p lt 0.02
p lt 0.005
(Bmax/Kd)
Placebo/Neutral
Placebo/Food
MP/Neutral
MP/Food
Volkow, Wang, et al, Synapse 2002
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Extracellular DA vs Self-report of Hunger
Desire for Food Ritalin
r 0.76 p lt 0.01
Desire for Food
Hunger
Change Bmax/kd
Volkow, Wang, et al, Synapse 2002
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Implication

• These results support the role of DA
  neurotransmission in dorsal striatum in mediating
  food motivation in human brain.

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Brain Metabolic Response to Food Stimulation
85
Food Presentation
0
µmol/100g/min
18FDG
Neutral Presentation
Right
Wang et al, Neuroimage 2004
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Statistical Parameter Map of Metabolic Changes
between Food and Neutral stimulation

• Twelve normal weight subjects.
• Insula is a brain region modulating emotional
  responses to appetitive stimuli.
• Orbitofrontal cortex is a brain region involved
  with salience attribution.

R
Wang et al, Neuroimage 2004
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Metabolism in orbitofrontal cortex during food
stimulation

• Orbitofrontal cortex is a brain region involved
  with salience attribution and drive, may underlie
  the motivation to procure food, which may be
  subjectively experienced as desire for food and
  hunger.

Wang et al, Neuroimage 2004
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Implication

• The enhanced orbitofrontal cortex activation by
  food stimulation may reflect downstream effects
  from dopamine stimulation.
• Dopaminergic involvement in the drive for food
  consumption in humans is in part mediated by its
  effects in orbitofrontal cortex.
• The results could explain the deleterious effects
  of constant exposure to food stimuli (e.g.
  advertisements, candy machines, food channels,
  stores) in overeating.

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Brain Activation during Cocaine Theme Interview
18FDG
Wang et al, Life Science 1999
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Cocaine Craving Insular Metabolism

• - Right Insula, p lt 0.01
• O - Left Insula, p lt 0.008

p lt 0.0002
Wang et al, Life Science 1999
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Prospective
Activation of the temporal insula, a brain region
involved with autonomic control, and of the
orbitofrontal cortex, a brain region involved
with expectancy and salience attribution, during
the cocaine theme support their involvement with
craving in cocaine addicted subjects.
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Obesity
VS
Drug Abuse

• What makes obese subjects different from drug
  abusers?

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Obesity

• Would obese subjects have an enhanced sensitivity
  in the brain regions involved with sensory
  processing of the food?

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Averaged FDG images
Control subjects
Obese subjects
55
0
µmol/100g/min
L
R
What brain regions differ?
Wang et al, NeuroReport 2002
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Enhanced Somatosensory Cortex Metabolism in Obese
Subjects

• Ten obese subjects (n 10, BMI gt 40) and 25 lean
  subjects (BMI lt 25).
• At baseline condition after fasting for 14-16
  hours.
• Obese subjects had higher metabolism than lean
  subjects in the somatosensory areas where the
  mouth, lips and tongue are represented.

FDG
Wang et al, NeuroReport 2002
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Implication

• The enhanced activation in somatic parietal areas
  for mouth, tongue and lips in obese subjects
  suggests that enhanced sensitivity in regions
  involved in the sensory processing of food may
  make food more rewarding and may be one of the
  variables contributing to their excess food
  consumption.

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Addiction
Environment
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Brookhaven PET Group
Scientists Joanna Fowler (organic chemist) David
Alexoff (engineer) Helene Benveniste
(anesthesiologist) Anat Biegon (pharmacologist) St
ephen Dewey (anatomist) Yu-Shin Ding (organic
chemist) Richard Ferrieri (physical chemist) S.
John Gatley (pharmacologist) Rita Goldstein
(psychologist) Kuo-Shan Lin (organic
chemist) Jean Logan (theoretical chemist) Yeming
Ma (physical chemist) David Schlyer (inorganic
chemist) Michael Schueller (biomedical
physicist) Frank Telang (neurologist) Peter
Thanos (neuroscientist) Paul Vaska
(physicist) Nora Volkow (psychiatrist) Gene-Jack
Wang (nuclear med physician)
Support Staff Karen Apelskog (protocol
coordinator) Pauline Carter (nurse) Victor Garza
(chemist) Barbara Hubbard (nurse) Millard Jayne
(nurse) Payton King (Lab Technician) Hai-Dee Lee
(Lab Technician) Noel Netusil (nurse) Colleen
Shea (chemist) Azael Villanueva (biomedical
engineering) Donald Warner (electronics) Youwen
Xu (chemist) Lisa Zimmerman (study
coordinator) Post Doctoral/Fellow Nelly Klein
(psychologist) Kim Lindsey (pharmacologist) Igor
Izrailtyan (anesthesiologist) Daryn Moeller
(anesthesiologist) Alex Morgan (physician) Lisa
Cotton (psychologist)
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Support
Department of Energy (Office of Biology
Environmental Research) National Institute on
Drug Abuse Office of National Drug Control Policy