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Orlistat Inhibition of Intestinal Lipase Acutely Increases Appetite and Attenuates Postprandial Glucagon-Like Peptide-1-(7–36)-Amide-1, Cholecystokinin, and Peptide YY Concentrations

Department of Medicine I (M.E., M.K., P.R.R., W.E.S., J.J.M.), St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; Department of Biomedical Sciences (J.J.H.), The Panum-Institute, University of Copenhagen, DK-2400 Copenhagen, Denmark; Department of Internal Medicine (K.-H.H.), Kuopio University Hospital, FI-70211 Kuopio, Finland; Division of Physiology (K.-H.H.), Institute of Biomedicine, and Biocenter of Oulu, University of Oulu, 90220 Oulu, Finland; and Department of Medicine II (F.S.), Clinic Hildesheim, 31134 Hildesheim, Germany

Address all correspondence and requests for reprints to: Dr. Mark Ellrichmann, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany. E-mail: mark.ellrichmann{at}rub.de.

Introduction: Intestinal lipase inhibition using tetrahydrolipstatin (Orlistat) has been widely used in the pharmacotherapy of morbid obesity. However, the effects of Orlistat on the secretion of appetite regulating gastrointestinal hormones and appetite sensations are still debated. We addressed whether Orlistat alters the secretion of glucagon-like peptide-1-(7–36)-amide (GLP-1), cholecystokinin (CCK), peptide YY (PYY), and ghrelin as well as postprandial appetite sensations.

Methods: Twenty-five healthy human volunteers were examined with a solid-liquid test meal after the oral administration of Orlistat or placebo. Gastric emptying, gallbladder volume and the plasma levels of CCK, PYY, GLP-1, and ghrelin were determined and appetite sensations were measured using visual analogue scales.

Results: Gastric emptying was accelerated by Orlistat administration (P < 0.0001), whereas gallbladder emptying was inhibited (P < 0.0001). Plasma levels of CCK (by 53%), PYY (by 40%), and GLP-1 (by 20%) were significantly lowered by Orlistat (P < 0.001), whereas ghrelin levels were unaffected by Orlistat treatment (P = 0.18). Satiety and fullness were lowered by Orlistat (P < 0.0001), whereas appetite and prospective food consumption increased (P < 0.0001). The changes in CCK and PYY levels and the mean hunger ratings after Orlistat treatment were closely related to the inhibition of gallbladder motility.

Conclusions: Orlistat alters gastric and gallbladder emptying and reduces the postprandial secretion of GLP-1, PYY and CCK. These changes in gastrointestinal hormone concentrations may raise appetite sensations and increase food consumption and should therefore be considered as potential side effects when applying lipase inhibitors for the treatment of morbid obesity.