Background: Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY1-36 and the pharmacologically active PYY3-36 is indicated to determine the potential role in energy balance regulation. Aim: Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY. Design: Total plasma PYY levels (PYY1-36 + PYY3-36) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY3-36 levels were measured in 17 lean and 15 obese individuals. Results: Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P <0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. In obese patients, weight loss of 5.4 was associated with a 30 decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY3-36 levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects. Conclusion: Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.