How Do We Lose Weight? How Does The Body Control Appetite? A New Research Effort Identifies The Interactions

Lipase inhibition found to weaken the effects of small intestine fat on gastronintestinal activity, appetite and hormones

(June 18, 2003) Bethesda, MD – How do we lose weight?  What actions does the body take to digest the food and control appetite?  Heretofore, many studies have studied these issues separately.  Now a new physiological research effort has identified the interactions between these two functions.

Background

When nutrients react with small intestinal receptors a regulation of gastric emptying and appetite occurs, stimulating the release of gastrointestinal hormones, including CCK (cholecystokinin) and glucagon-like peptide-1 (GLP-1). In healthy subjects, infusion of fat within the first division of the small intestine slows gastric emptying and reduces hunger and subsequent food intake; these effects are, at least in part, mediated by CCK. The slowing of gastric emptying by small intestinal nutrients is associated with a reduction in proximal gastric tone, suppression of antral pressure waves (PW), and stimulation of tonic and phasic pyloric pressures, i.e., the muscular tissue surrounding and controlling the aboral outlet of the stomach. The increase in pyloric motility may be the most important of these mechanisms, because the stimulation of phasic and tonic pyloric pressures is associated with cessation of transpyloric flow.

Studies in animals and humans suggest that the slowing of gastric emptying, suppression of appetite, and stimulation of CCK secretion by fat are dependent on the decomposition of triglyceride to fatty acids. In particular, in animals, lipase, or any fat-splitting, inhibition accelerates gastric emptying of fat. In humans, it has also been established that both pharmacological inhibition of lipase and pancreatic exocrine insufficiency are associated with more rapid gastric emptying of fat. Recent studies also suggest that fat digestion is required for the triggering of gastrointestinal sensations, such as fullness and nausea, as induced by concurrent gastric distension and duodenal infusion of a triglyceride emulsion.

Recent studies used the lipase inhibitor tetrahydrolipstatin (THL), a specific and potent inhibitor of gastric and intestinal lipases. When ingested with a meal in the recommended dose of 120 mg, THL inhibits fat digestion by approximately 30 percent. However, the weight loss in obese subjects may be less than would be predicted by the degree of inhibition of fat absorption.

The motor mechanisms associated with the accelerated gastric emptying of fat induced by lipase inhibition have not been evaluated. Furthermore, no studies have assessed the impact of lipase inhibition on antropyloroduodenal (APD) motility and appetite concurrently. The potential impact of accelerated gastric emptying on appetite is uncertain, but it has been suggested that a slowing of gastric emptying may decrease food intake by enhancing gastric distension.

A New Study

A new study evaluated healthy subjects testing the broad hypothesis that the stimulation of tonic and phasic pyloric pressure activity, inhibition of propulsive APD motor patterns, suppression of appetite, and secretion of gastrointestinal hormones (CCK, GLP-1) by intraduodenal fat are weakened by inhibition of lipase. The research used an intraduodenal infusion to bypass gastric mechanisms (and potential effects of lipase inhibition on gastric emptying) involved in the regulation of food intake.

The authors of “Effects of Fat Digestion on Appetite, APD Motility, and Gut Hormones in Response to Duodenal Fat Infusion in Humans,” are Christine Feinle, Deirdre O'Donovan, Selena Doran, Jane M. Andrews, Judith Wishart, Ian Chapman, and Michael Horowitz, all from the University of Adelaide Department of Medicine, Royal Adelaide Hospital, Adelaide, Australia.  Their findings appear in the May 2003 edition of the American Journal of Physiology – Gastrointestinal and Liver Physiology.

Methodology

Sixteen healthy male subjects, aged 21-39 years, took part in the study. Male subjects were studied because they are most sensitive to dietary manipulation. The subjects were of normal body weight for height [with a body mass index of 19.5-27.6 kg/m² (mean: 24.1 kg/m²)], unrestrained eaters [score of <12 on the restraint section of the 3-factor eating questionnaire], were not taking medication that could affect appetite, body weight, or gastrointestinal function, and had no history of gastrointestinal disease. Subjects with a consumption of alcohol >20 g/day or who smoked were also excluded. Before entry into the study, each subject underwent a prestudy "screening," which included a medical history, a physical examination, clinical laboratory tests, 12-lead ECG, and measurement of vital signs.

The 16 healthy, young, lean men were studied twice in double-blind, randomized, crossover fashion. Ratings for appetite-related sensations, antropyloroduodenal motility, and plasma CCK and glucagon-like peptide-1 concentrations were measured during a 120-min duodenal infusion of a triglyceride emulsion (2.8 kcal/min) on one day with, on the other day without, 120 mg tetrahydrolipstatin, (THL), a potent lipase inhibitor. Immediately after the duodenal fat infusion, food intake at a buffet lunch was quantified (t = 135-165 min).

Results 

All subjects tolerated the study procedures, including nasoduodenal intubation and fat infusion, well. Nine of the 16 subjects did not experience any side effects. The other seven subjects reported transient side effects including loose, oily stools and abdominal bloating. 

Lipase inhibition with tetrahydrolipstatin was associated with reductions in tonic and phasic pyloric pressures, increased numbers of isolated antral and duodenal pressure waves, and stimulation of antropyloroduodenal pressure-wave sequences . Scores for prospective consumption and food intake at lunch were greater, and nausea scores were slightly less, and the rises in plasma CCK and glucagon-like peptide-1 were abolished .

Conclusions

This research demonstrates that lipase inhibition diminishes the the effects of duodenal fat on antropyloroduodenal motility, appetite, and CCK and glucagon-like peptide-1 secretion. The findings also reveal that temporal and spatial organization of APD pressure patterns is a major determinant of gastric emptying and small intestinal transit; changes in gastrointestinal motility in response to food ingestion serve to optimize the interaction of nutrients with small intestinal receptors by slowing gastric emptying and transport of chyme along the gut.

This study illustrates that lipase inhibition completely abolishes the stimulation of both CCK and GLP-1 by small intestinal fat, and this may potentially account for the increase in food intake observed with lipase inhibition. It is expected that these findings will contribute to ongoing efforts to provide new therapies for the control of obesity, now reaching epidemic proportions.

Source: May 2003 edition of American Journal of Physiology – Gastrointestinal and Liver Physiology

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: A copy of the research article is available in pdf format to the press.

Members of the press are invited to obtain a pdf copy of the study and to interview members of the research team. To do so, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.