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The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R² = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY_1–36 to PYY_3–36 was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY_3–36 was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY_3–36 in humans caused a graded reduction in food intake (R² = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of …