Obesity is a growing epidemic

1
Obesity is a growing epidemic

• A disease of enormous proportions
• gt65 adults are overweight
• gt30 adults are obese in US
• (Ogden et al, 2006)
• Associated with a number of secondary health
  consequences
• Cardiovascular disease, stroke, diabetes
• (Vague et al, 1980 Gasteyger Tremblay, 2002
  Satcher, 2001)

2
Obesity is the result of energy imbalance
Energy Expenditure
Energy Intake
Decreasing energy intake through diet or
increasing energy expenditure through exercise
is not a popular approach and has not eliminated
the problem
3
Obesigenic Environment

• Bombarded with food cues
• High calorie foods are cheap and easily accessible

4
One successful therapy Gastric Bypass

• Roux-en-Y gastric bypass (RYGBP)
• Restriction and malabsorption
• Small stomach pouch near the gastro-esophageal
  junction and bypassing most of the stomach and
  duodenum
• Adjustable gastric band (AGB)
• Restriction
• Small stomach pouch and narrow passage into the
  remaining stomach

5
RYGBP and AGB

• Decrease body weight, BMI and body fat
• Improvement in hyperinsulinemia, hyperleptinemia
  and dyslipidemia
• Improvement in insulin indices (QUICKI and
  HOMA-IR)
• Differences in ghrelin concentrations
• Decrease in RYGBP
• Increase in AGB

6
Ghrelin

• Produced predominantly in the stomach (fundus)
• Central and peripheral ghrelin injections to
  rodents and humans increases appetite and food
  intake
• Plasma ghrelin levels rise before and fall after
  a meal
• Plasma ghrelin levels are higher in lean or
  dieting individuals than obese

7
Why are there differences in ghrelin levels
between the two procedures?

• 24 Male obese patients
• AGB, RYGBP and Conventional weight loss (CONV)
• Matched for postoperative time, BMI, weight loss
  and percent body fat
• 6 months after surgical procedure or CONV program
  blood samples were taken

8
What they found

• Weight loss-induced increases in ghrelin levels
  in the AGB and CONV groups
• Decreases in ghrelin in the RYGBP group
• Decreases do not depend on weight loss,
  nutrient-related factors or insulin
• Total caloric intake, macronutrient composition
  and insulin levels were comparable between groups
• Decrease in ghrelin levels with the RYGBP depends
  on the surgically-induced bypass of the ghrelin
  producing cells of the fundus

9
Why do we care?

• Ghrelin may enhance hedonic and incentive
  responses to food-related cues and thereby
  increase food intake
• This may occur without nutritional or caloric
  deficiency
• Non-homeostatic food intake versus homeostatic
  (hypothalamic) food intake
• Ghrelin may contribute to the increase in obesity

10
Ghrelin increases brain activity in areas
involved in processing food cues (Malik et al.)

• 20 non-obese subjects
• 3hr after ingestion of standardized meal (neither
  full nor hungry)
• Measured cerebral response to food and non-food
  images (fMRI)
• 12 subjects viewed pictures before and after
  ghrelin administration
• 8 subjects viewed pictures before and after
  vehicle administration
• Blood samples were taken before and after scan
• Subjective rating for hunger were taken after
  each block of images

11
Results

• Ghrelin increased activity in the amygdala,
  orbital frontal cortex, insula, visual areas and
  striatum
• Not in hypothalamic areas
• Ghrelin induced-increase in activation was
  correlated with self-reported hunger
• These regions encode the salience, hedonic and
  incentive value of visual cues
• Likely accounts for the ability of ghrelin to
  motivate us to eat even when we are not energy
  deficient

12
Putting these ideas together

• Gastric bypass populations at Hopkins
• RYGBP results in significant decreases in ghrelin
• Imaging is available
• Moran lab is currently doing translational work
  on the ability of gut peptides to alter
  motivation to eat and food intake

13
Questions

• Does ghrelin contribute to the decreases in
  appetite and food intake in RYGBP patients?
• Does exogenous ghrelin in RYGBP activate brain
  regions involved in reward or homeostatic
  (hypothalamic) areas when looking at highly
  palatable/hedonic food cues?
• Is the ghrelin-induced brain activation after
  RYGBP similar to individuals pre-surgery?

14
Design

• RYGBP patients 6 months after surgery
• Is this the best time?
• Blood samples to see ghrelin levels (and other
  factors)
• fMRI imaging session following protocol of Malik
  et al.
• Half patients will receive ghrelin, half vehicle
• Test effect of ghrelin on food intake
• Sucrose solution during scan?
• Or separate experiment with the same patient
  population?