n engl j med 349;10 www.nejm.org september 4, 2003 The new england journal of medicine 941 original article Inhibition of Food Intake in Obese Subjectsby Peptide YY 3–36 Rachel L. Batterham, M.B., B.S., Mark A. Cohen, M.B., Ch.B., Sandra M. Ellis, B.Sc., Carel W. Le Roux, M.B., Ch.B., Dominic J. Withers, M.B., B.S., Ph.D., Gary S. Frost, Ph.D., Mohammad A. Ghatei, Ph.D., and Stephen R. Bloom, M.D., D.Sc. From the Department of Metabolic Medi-cine, Imperial College Faculty of Medicineat Hammersmith Campus, Du Cane Rd.,London W12 0NN, United Kingdom.N Engl J Med 2003;349:941-8. Copyright © 2003 Massachusetts Medical Society. background The gut hormone fragment peptide YY 3–36 (PYY) reduces appetite and food intake wheninfused into subjects of normal weight. In common with the adipocyte hormone leptin,PYY reduces food intake by modulating appetite circuits in the hypothalamus. However,in obesity there is a marked resistance to the action of leptin, which greatly limits its ther-apeutic effectiveness. We investigated whether obese subjects were also resistant to theanorectic effects of PYY. methods We compared the effects of PYY infusion on appetite and food intake in 12 obese and 12lean subjects in a double-blind, placebo-controlled, crossover study. The plasma levelsof PYY, ghrelin, leptin, and insulin were also determined. results Caloric intake during a buffet lunch offered two hours after the infusion of PYY was de-creased by 30 percent in the obese subjects (P<0.001) and 31 percent in the lean subjects(P<0.001). PYY infusion also caused a significant decrease in the cumulative 24-hourcaloric intake in both obese and lean subjects. PYY infusion reduced plasma levels ofthe appetite-stimulatory hormone ghrelin. Endogenous fasting and postprandial levelsof PYY were significantly lower in obese subjects (the mean [ ± SE] fasting PYY levelswere 10.2 ± 0.7 pmol per liter in the obese group and 16.9 ± 0.8 pmol per liter in the leangroup, P<0.001). Furthermore, the fasting PYY levels correlated negatively with thebody-mass index (r=¡0.84, P<0.001). conclusions We found that obese subjects were not resistant to the anorectic effects of PYY. Endog-enous PYY levels were low in the obese subjects, suggesting that PYY deficiency maycontribute to the pathogenesis of obesity.abstractCopyright © 2003 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at Stanford University on November 19, 2004 .n engl j med 349;10 www.nejm.org september 4 , 2003 The new england journal of medicine 942besity and its associated patho- logic features are major causes of illnessand death worldwide. In the United States,obesity accounts for 280,000 deaths annually, andat current rates of increase it will supplant smokingas the primary cause of preventable death. 1 How-ever, despite the recognition that even moderateweight loss confers significant health benefits, 2 todate there have been few effective treatments forobesity, although surgery has been shown to be ofuse in selected patients. 3 We recently showed that infusions of the gut hor-mone fragment peptide YY 3–36 (PYY) that producedtypical naturally occurring postprandial levels re-duced 24-hour food intake in human subjects ofnormal weight. 4 Furthermore, long-term adminis-tration of PYY to rodents decreased weight gain.These observations suggest that PYY may be a treat-ment for obesity. Given, however, that the majorityof obese subjects are resistant to the effects of theadipocyte hormone leptin, limiting its effective-ness as an antiobesity treatment, 5,6 we undertook tocompare the effects of PYY infusion on appetite andfood intake in obese and lean subjects. study subjects Healthy obese and lean subjects were recruited byadvertising in local newspapers and on the Ham-mersmith Hospital campus in London. The mean( ± SE) body-mass index (the weight in kilograms di-vided by the square of the height in meters) was33.0 ± 0.9 in the obese group and 20.5 ± 0.1 in thelean group. The inclusion criteria were a body-massindex of 27 to 40 for the obese group and 17 to 23 forthe lean group. All subjects were between the agesof 18 and 50 years (mean, 29.0 ± 2.4 for the obesegroup and 27.3 ± 0.4 for the lean group) and hadhad a stable body weight for at least three months.The criteria for exclusion were smoking, substanceabuse, pregnancy, use of medications (except fororal contraceptives), medical or psychiatric illness,and any abnormalities detected on physical exam-ination, electrocardiography, or screening bloodtests (measurement of complete blood count, elec-trolytes, fasting glucose, and liver function).Twelve subjects (six men and six women) wererecruited for each group. The subjects gave writteninformed consent for the study, and approval wasobtained from the Hammersmith Hospital researchethics committee. The study was carried out in ac-cordance with the principles of the Declaration ofHelsinki. The subjects were screened by a dietitianwho assessed their eating behavior with the DutchEating Behavior Questionnaire 7 and the Eating At-titudes Test questionnaire. 8 They also completed athree-day diet diary to permit us to assess their usu-al eating habits before acceptance into the study.Food preferences were assessed at screening with anine-point hedonic scale to ensure that the food of-fered at the buffet lunch was acceptable. study protocol The study was performed in a randomized, double-blind, placebo-controlled, crossover manner, witheach subject studied on two occasions one weekapart. The subjects’ food intake for the 48 hours be-fore each study day was standardized, and duringthis period they completed food diaries to confirmcompliance. In addition, they consumed an identi-cal meal between 7 p.m. and 8 p.m. on the night be-fore each study. The subjects refrained from alcoholand strenuous exercise for the 24 hours before andafter each study day. They fasted and drank onlywater from 8 p.m. the night before the study. Theyarrived at 8:30 a.m. on each study day. Cannulaswere inserted into veins in both forearms, one forthe collection of blood and the other for the infusionof PYY or saline. After venous cannulation, the sub-jects relaxed for 30 minutes before the start of thestudy protocol. All time cues were removed from thestudy room, so that the subjects were unaware ofthe time. Throughout the study, the subjects wereencouraged to relax by reading or watching videos.Blood was collected every