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Attenuated Peptide YY Release in Obese Subjects Is Associated with Reduced Satiety

Departments of Metabolic Medicine (C.W.l.R., M.P., C.M.B., K.J.W., A.K., R.P.V., J.G., M.A.G., S.R.B.), Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom; Department of Endocrinology (R.L.B.), University College London, London WC1E 6BT, United Kingdom; and Department of Endocrinology (S.J.B.A.), King’s College Hospital, London SE5 9RS, United Kingdom

Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Department of Metabolic Medicine, 6th Floor Commonwealth Building, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.

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 exogenous administered PYY_3–36 on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY_3–36. Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY_3–36 infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity.

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