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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.

	Abstract

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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.

	Introduction

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Tetrahydrolipstatin (Orlistat) is a reversible inhibitor of gastrointestinal lipases that is widely used in the pharmacotherapy of morbid obesity (1). Furthermore, Orlistat accelerates gastric emptying, reduces pyloric pressure, and enhances antropyloroduodenal motility (2, 3, 4, 5). However, whereas the effects of the drug on lipase inhibition and gastric motility are undisputed, there has been some controversy regarding its impact on the postprandial secretion of gastrointestinal hormones, namely cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide-1-(7–36)-amide (GLP-1), and ghrelin (2, 3, 4, 6, 7, 8, 9). This question is of high clinical relevance because any interference with the secretion of these satiety hormones may lead to central nervous appetite induction and thus counteract the weight-lowering effects of the drug.

Therefore, in the present studies, we addressed whether the secretion of the GLP-1, CCK, PYY and ghrelin as well as postprandial appetite regulation is affected by Orlistat treatment and, if so, whether there is an interaction between these effects and the changes in gastric and gallbladder emptying induced by the drug.

	Patients and Methods

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Study protocol

The study protocol was approved by the ethics committee of the medical faculty of the Ruhr-University Bochum before the experiments (registration no. 2186). Written informed consent was obtained from all participants.

Study design

A total of 25 healthy volunteers, aged between 20 and 32 yr (mean ± SD: 24.6 ± 3.13 yr), were examined. Their body mass index was within the normal range (19.1–25.0 kg/m²; mean ± SD: 22.0 ± 1.96 kg/m²). None of the participants had a history of gastrointestinal or endocrine disorders or was taking any medication.

All participants were examined in the morning between 0800 and 0900 h after an overnight fast on two separate occasions. At the beginning of the test, subjects ingested a mixed solid-liquid standard test meal. The solid phase of the meal consisted of one egg, two slices of white bread, and 5 g margarine containing 100 mg [¹³C]sodium-octanoic acid (250 kcal; 1047 kJ), whereas the liquid phase consisted of 200 ml dairy cream with two teaspoons of chocolate powder (550 kcal; 2303 kJ). Either 120 mg Orlistat (Xenical; Hoffmann-La Roche, Basel, Switzerland) or matching placebo were ingested together with the test meal. Subsequently measurements of gastric emptying and gallbladder volume were performed, and the feelings of appetite, hunger, fullness, and prospective food consumption were assessed using visual analog scales. The subjects were positioned in the supine position throughout the experiments with the upper body lifted by 30°. An iv cannula was placed into an antecubital vein for blood sampling and kept the patent using a constant saline drip (0.9% NaCl), and venous blood samples were drawn frequently and processed as described (10).

Measurements

Plasma concentrations of ghrelin, GLP-1 (total hormone levels), and PYY were determined using RIAs as described (11). CCK measurements were carried out using isolated rat pancreatic acini as described (12).

Gallbladder size was determined over 120 min after meal ingestion by serial ultrasound imaging as described (12), and gastric emptying was determined over 240 min after meal ingestion using a noninvasive ¹³C sodium-octanoate breath test as described (10). Visual analog scales were used to assess the feelings of hunger, satiety, fullness, and the prospective food consumption at baseline and at 15-min intervals over a period of 2 h after meal ingestion (13).

Statistical analysis

Results are expressed as means ± SEM. Integrated incremental plasma concentrations of GLP-1, CCK, and PYY were calculated according to the trapezoidal rule (baseline subtracted). Concentration time series were analyzed using paired repeated-measures ANOVA using Statistica version 5.0 (Statsoft Europe, Hamburg, Germany). This analysis provides P values for the overall differences between the experiments (A), differences over time (B), and for the interaction of experiment with time (AB). If a significant interaction of treatment and time (AB) was documented (P < 0.05) or for the comparison of time-independent variables, individual values were compared by paired one-way ANOVA. All other continuous variables were compared using Student’s t test. Correlation analyses were carried out using GraphPad Prism (version 4.0; GraphPad Software, La Jolla, CA).

	Results

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In the placebo experiments, approximately 67% of the initial gastric content were still retained in the stomach at the end of the 240-min observation period, whereas the percentage retention was 44% after Orlistat administration (P < 0.0001). The gastric emptying half-lives were 236 ± 20 and 156 ± 10 min, respectively (P < 0.0001).

Orlistat led to a significant inhibition of gallbladder contractility (P < 0.001). The overall percentage reduction of gallbladder volume was 79 ± 2% in the placebo experiments and 49 ± 3% after Orlistat treatment (P < 0.0001).

The rise in postprandial plasma concentrations of GLP-1, PYY, and CCK was significantly lower after Orlistat administration (P < 0.01; Fig. 1). Thus, integrated incremental plasma concentrations of GLP-1 were 829 ± 72 pmol/liter^–1·min with Orlistat and 1233 ± 81 pmol/liter^–1·min with placebo (P = 0.001); the area under the curve of PYY levels were 1750 ± 187 and 3574 ± 547 pmol/liter^–1·min, respectively (P = 0.0049); and integrated CCK concentrations were 131 ± 17 and 452 ± 34 pmol/liter^–1·min, respectively (P < 0.0001). Ghrelin plasma concentrations declined after meal ingestion (by 27%; P < 0.0001) but were completely unaffected by Orlistat administration (P = 0.18).

View larger version (27K): [in this window] [in a new window]   FIG. 1. Plasma concentrations of GLP-1 (A), PYY (B), CCK (C), and ghrelin (D) after the ingestion of a solid-liquid test meal after the oral administration of 120 mg Orlistat or placebo in 25 healthy male subjects. Data are presented as means ± SEM. P values were calculated using paired repeated-measures ANOVA and denote differences between the experiments (A), differences over time (B), and differences due to the interaction of experiment and time (AB) Asterisks indicate significant differences (P < 0.05) vs. placebo at individual time points (one way ANOVA).

There was a significant linear relationship between gallbladder emptying and the integrated plasma levels of CCK, PYY, and GLP-1 (Fig. 2). In contrast, gastric emptying was unrelated to the secretion of any of the gastrointestinal hormones. The mean ratings for satiety and fullness were positively correlated with gallbladder emptying, whereas hunger and the prospective food consumption were inversely related (details not shown). Of note, 43% of the variation in the reported prospective food consumption could be explained by changes in gallbladder emptying. The associations between gastric emptying and appetite ratings were much weaker than for gallbladder emptying, and significant relationships were found with only hunger (P = 0.025) and prospective food consumption (P = 0.013). Furthermore, there was a significant relationship between satiety and the incremental concentrations of CCK (r² = 0.41, P < 0.0001) and GLP-1 (r² = 0.14, P = 0.0064), whereas no association was found with PYY and ghrelin levels.

View larger version (31K): [in this window] [in a new window]   FIG. 2. A–C, Linear regression analysis between the percentage gallbladder emptying and the integrated incremental plasma concentrations of PYY (A), GLP-1 (B), and CCK (C) after the ingestion of a solid-liquid test meal after the oral administration of 120 mg Orlistat or placebo in 25 healthy male subjects. D–F, Linear regression analysis between the gastric half-emptying times and the respective peak plasma concentrations of PYY (D), GLP-1 (E), and CCK (F). Dashed lines indicate the respective upper and lower 95% confidence intervals. r2 = correlation coefficient squared.

	Discussion

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A number of previous studies have examined the effects of Orlistat on appetite sensations and the secretion of gastrointestinal hormones, but conflicting results have been reported. Thus, Goedecke et al. (7) found no effect of Orlistat treatment on CCK levels and appetite ratings in healthy male subjects, Sahin et al. (8) found no changes in postprandial GLP-1 levels after Orlistat treatment in nondiabetic obese patients, and Damci et al. (9) reported even exaggerated postprandial levels of GLP-1 after Orlistat administration in obese patients with type 2 diabetes. These studies are contrasted by other reports showing impaired postprandial concentrations of GLP-1, PYY, and CCK as well as increased hunger ratings after intestinal lipase inhibition (2, 3, 5, 6, 14). The present results lend support to the latter reports. The discrepancies between these studies are difficult to explain, but certainly methodological issues, such as different meal compositions and the respective routes of nutrient administration (direct intraduodenal infusion vs. oral meal ingestion), need to be considered. Furthermore, in the present study, healthy lean individuals were examined, whereas some of the prior studies have been carried out in obese individuals (8, 9). Nevertheless, the majority of studies seems to support the notion that appetite is acutely increased by Orlistat treatment, most likely as a consequence of an impaired secretion of anorexigenic gastrointestinal hormones.

The significant increase in appetite and prospective food consumption observed in this as well as previous studies (14) may directly counteract the primary therapeutic indication of Orlistat, i.e. the treatment of morbid obesity. Thus, based on these short-term experiments, the reduction of intestinal lipid absorption would be expected to be at least partly outweighed by an increased caloric intake. Against this, intestinal lipase inhibition has proven to efficiently lower body weight in obese patients over chronic treatment durations (15, 16). Furthermore, in a recent prospective trial over 3 yr, eating behavior was not affected by Orlistat treatment, although hunger ratings were still significantly increased at the end of the study period (17). It is therefore possible that, whereas intestinal lipase inhibition acutely lowers the secretion of anorexigenic gastrointestinal hormones and raises appetite sensations, these orexigenic effects play a less important role after longer treatment periods.

Another interesting finding from this study is the inhibition of gallbladder contraction by Orlistat administration and the significant relationship between gallbladder emptying and the postprandial increments in CCK, PYY, and GLP-1 levels. Whereas the most obvious explanation for this relationship seems to be a retardation of gallbladder emptying secondary to the impairment in CCK secretion, a diminished postprandial secretion of bile acid may also in turn reduce the release of gut hormones. It is, however, important to note that these associations were purely correlative in nature, thereby not allowing for direct conclusions regarding the causal relationships between these effects.

Although gastric emptying was significantly accelerated by Orlistat, satiety and fullness as well as the secretion of CCK, PYY, and GLP-1 were still lower than in the placebo experiments. This is rather surprising because retardation of gastric emptying is typically associated with increased fullness and a reduction of gastrointestinal hormone release, thereby leading to a reduction of appetite and food intake (18, 19). The present data suggest that the direct central nervous effects of the gastrointestinal hormones GLP-1, PYY, and CCK are likely more potent in controlling energy homoeostasis than changes in gastric emptying. This finding underlines the importance of gut hormones in the central nervous regulation of appetite and food intake.

In conclusion, the present studies have demonstrated that Orlistat accelerates gastric emptying and markedly reduces the postprandial secretion of the anorexigenic hormones GLP-1, PYY, and CCK. These alterations 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.

	Acknowledgments

 
The excellent technical assistance of Lone Bagger is greatly acknowledged.

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online July 22, 2008

Abbreviations: CCK, Cholecystokinin; GLP-1, glucagon-like peptide-1-(7–36)-amide; PYY, peptide YY.

Received April 29, 2008.

Accepted July 14, 2008.

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