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688 Gut 2000;46:688–693 The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans Gut: first published as 10.1136/gut.46.5.689 on 1 May 2000. Downloaded from D Matzinger, L Degen, J Drewe, J Meuli, R Duebendorfer, N Ruckstuhl, M D’Amato, L Rovati, C Beglinger Abstract preabsorptive site to decrease food intake and Background and aims—The mechanism that this eVect is indirectly mediated by release of intraduodenal fat induced inhibition of of CCK. food intake is still unclear. Therefore, we In parallel with these results, several animal tested the ability of duodenal fatty acids to experiments have been carried out.6–8 The suppress food intake at a lunchtime meal; eVect of intraduodenal fat on food intake was in addition, we were interested to test if extensively investigated in rats and pigs; more these eVects were mediated by cholecysto- importantly, the eVect was also studied in sham kinin (CCK) A receptors. fed rats with an open gastric fistula. In this last Subjects and methods—Three sequential experiment, the eVect of intraduodenal fat on double blind, three period crossover stud- food intake was investigated independent of its ies were performed in 12 healthy males eVect on gastric emptying. The results of these each: (1) subjects received intraduodenal experiments support the hypothesis of an fat with or without 120 mg of tetrahydrolip- intestinal signal induced by intraduodenal fat statin, an inhibitor of gastrointestinal li- which initiates a reduction in food intake. pases, or saline; (2) volunteers received The major products of luminal lipid diges- intraduodenal long chain fatty acids, me- tion are monoglycerides and fatty acids.910 In dium chain fatty acids, or saline; (3) humans, there is evidence that only fatty acids subjects received long chain fatty acids or with chain lengths greater than C10 are 11–13 saline together with concomitant intra- eVective in releasing CCK. Thus there is a venous infusions of saline or loxiglumide, a link between fat digestion and the ability of fats specific CCK-A receptor antagonist. The to initiate a feedback response on food intake eVect of these treatments on food intake and release of CCK. and feelings of hunger was quantified. Hence the present study was designed to Results—Intraduodenal fat perfusion sig- further understand the role of digestion http://gut.bmj.com/ nificantly (p<0.05) reduced calorie intake. products of intraduodenal fat in regulating Inhibition of fat hydrolysis abolished this food intake in humans. Three consecutive eVect. Only long chain fatty acids signifi- experimental series were performed. In the first cantly (p<0.05) decreased calorie intake, series we tested the hypothesis that fat hydroly- whereas medium chain fatty acids were sis is a crucial step in the ability of lipid to ini- ineVective. Infusion of loxiglumide abol- tiate feedback inhibition of food intake. Tet- rahydrolipstatin (THL) (also named Orlistat), ished the eVect of long chain fatty acids. on September 30, 2021 by guest. Protected copyright. Conclusions—Generation of long chain a potent and irreversible inhibitor of gastro- intestinal lipases, was used as a tool to prevent fatty acids through hydrolysis of fat is a 14–16 critical step for fat induced inhibition of fat hydrolysis. Department of food intake; the signal is mediated via In the second series we determined if the Research and Division CCK-A receptors. chain length of free fatty acids was crucial for of Gastroenterology, (Gut 2000;46:688–693) initiating feedback inhibition of food intake. University Hospital, We used long chain fatty acids in the form of CH-4031 Basel, Keywords: food intake; long chain fatty acids; medium sodium oleate and medium chain fatty acids in Switzerland chain fatty acids; cholecystokinin the form of sodium caprylate to assess the D Matzinger L Degen importance of chain length. J Drewe In the third experimental series we tested the J Meuli The importance of fat storage and metabolism hypothesis that the feedback response on food R Duebendorfer and its influences on long term control of intake induced by long chain fatty acids is N Ruckstuhl energy balance in humans is well recognised. mediated by CCK by using the specific C Beglinger Welch and colleagues,1 in 1985, observed in CCK-A receptor antagonist loxiglumide humans that infusion of a lipid emulsion into (LOX). Rotta Research the ileum reduced food intake. They suggested Laboratorium SpA, I-20052 Monza, Italy that fat in the small intestine acts as a signal for Materials and methods M D’Amato short term control of food intake; an intra- SUBJECTS L Rovati venous infusion of a similar lipid emulsion had Thirty six male subjects, aged 20–40 years no eVect on eating. Further experiments with Correspondence to: (mean 25.2), participated in the study. Body Dr Christoph Beglinger, lipid infusions into the jejunum or ileum weight of all subjects was within the normal Division of Gastroenterology, caused a decrease in food consumption, early University Hospital, satiation,23 and a delay in gastric emptying45; CH-4031 Basel, Switzerland Abbreviations used in this paper:ID, the eVects were accompanied by an increase in intraduodenal; LCF, long chain fatty acids; LOX, 3 Accepted for publication plasma cholecystokinin (CCK) levels. These loxiglumide; MCF, medium chain fatty acids; THL, 25 November 1999 findings led to the hypothesis that fat acts at a tetrahydrolipstatin; CCK, cholecystokinin. Cholecystokinin and fat products 689 range for age, sex, and height. Each subject Subjects scored their subjective feelings of gave written informed consent for the study. hunger and fullness at 15 minute intervals for The protocol was approved by the human eth- the duration of each experiment using a visual ics committee of the University Hospital, analogue scale from 1 to 10 and indicated their Gut: first published as 10.1136/gut.46.5.689 on 1 May 2000. Downloaded from Basel. Before acceptance, each participant was scores on a questionnaire. The scale and scores required to complete a medical interview, have previously been designed and described in received a full physical examination, and detail.13 participated in an initial laboratory screening. No subject was receiving any medications or Part II: eVect of free fatty acids on food intake had a history of food allergies or dietary The design of the second series was similar to restrictions. part I. The experiment was a randomised, dou- ble blind, three period crossover study in 12 healthy male subjects. One treatment consisted EXPERIMENTAL PROCEDURE of intraduodenal perfusion of free medium Part I: eVect of THL dissolved in olive oil on food chain fatty acids (MCF). MCF in the form of intake sodium caprylate, a fatty acid with eight Three treatments, separated by at least seven carbons, was perfused at a concentration of days, were performed in each subject in a ran- 0.049 g/ml at a rate of 0.5 ml/min, resulting in domised order. On the evening preceding each a load of 8 mmol/h sodium caprylate; this load experiment, subjects swallowed a radio-opaque is equivalent to 26 kcal/h. In the second experi- polyvinyl feeding tube (external diameter 8 ment, intraduodenal perfusion of free long French gauge) which had an opening at the tip chain fatty acids (LCF) was used. LCF in the of the tube. The tube was inserted through the form of sodium oleate, a long chain fatty acid nose because this procedure allowed the tube with 18 carbons, was perfused at a concentra- to be retained overnight and for the duration of tion of 0.086 g/ml at a rate of 0.5 ml/min, the experiment, but also allowed subjects to eat resulting in a load of 8 mmol/h; this load is and drink with minimum discomfort. The tube equivalent to 46 kcal/h. On the third experi- was transported to the duodenum overnight. In mental day, volunteers received intraduodenal the morning, the position of the tube was saline (control) instead of free fatty acids. Sixty located fluoroscopically and the tip of the tube minutes after starting the respective perfusions, was positioned 100 cm distal to the teeth. It subjects were invited to eat and drink as much was firmly attached to the skin behind the ear as they wished. The MCF and LCF loads were to prevent further progression of the tube dur- chosen from previous experiments.17 These ing the experiment. On the day of the data have shown that an intraduodenal rate of experiment, each subject ate breakfast if this 8 mmol/h sodium oleate induces maximal gall was his normal custom but no snacks were bladder contraction in healthy human subjects. http://gut.bmj.com/ allowed after 8 am. At noon, the experiment During the experiments, 7.5 ml of blood were started with continuous perfusion to the drawn into ethylendiaminetetra-acetic acid duodenum. The treatments were identical in (EDTA) coated tubes containing aprotinin design except for the intraduodenal perfusions. (1000 KIU/ml blood) for pre-meal plasma One treatment consisted of intraduodenal CCK and leptin determinations (fasting blood saline perfusion for the duration of the experi- sample and 25, 15, and 5 minutes before the ment. Sixty minutes after starting the per- start of the meal). fusion, subjects were invited to eat and drink as on September 30, 2021 by guest. Protected copyright. much as they wished. In the second and third Part III: eVect of LCF with and without experiments, intraduodenal fat (olive oil) with intravenous LOX on food intake or without 120 mg THL was used instead of The procedures in this series were similar to saline throughout the experiments. A perfusion part II except for the intravenous infusions and rate of 0.5 ml/min (load 41 g) was chosen for a intraduodenal perfusions (MCF were not per- total of 90 minutes; this rate was taken from fused in this part).

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