1. Obesity is a growing epidemic A disease of enormous proportions >65% adults are overweight >30% 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 Intake Energy Expenditure 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?