Control of canine gastric emptying of fat by lipolytic products.

Meyer JH, Elashoff JD, Domeck M, Levy A, Jehn D, Hlinka M, Lake R, Graham LS, Gu YG.

Department of Medicine, Veterans Affairs Medical Center, Sepulveda 91343.

Dietary fat is ingested in three forms: 1) in solid food, 2) as aqueous emulsions, and 3) as unemulsified, liquid oil. On the basis of a scant previous literature, we postulated that liquid fat (emulsions or oils) would empty from the stomach at speeds that varied with the amounts ingested but that this dynamic would be modulated by feedback inhibition from lipolytic products. To test these ideas, we used a gamma camera to track gastric emptying of 123I-labeled fat in dogs with chronic pancreatic fistulas by which lipase was excluded from or replenished in the duodenum in varied amounts after dogs were fed 15-, 30-, and 60-g loads of liquid fat given with solid foods or as emulsions. We also tracked concurrent gastric emptying of 113mIn, which marked the solid food phase or the water phase of emulsions. In some studies, we used a potent and specific inhibitor (orlistat) of pancreatic and gastric lipases to assess how lipolytic products modulated emptying of liquid fat. In the absence of pancreatic enzymes, both oils and emulsions emptied initially at high speeds that varied with fat loads, but emptying slowed 20 min after ingestion of emulsions and 60 min after ingestion of unemulsified oil. Studies with orlistat indicated that these changes in rates resulted from liberation of gastric lipolytic products. Emptying of oil emulsions was not altered by duodenal replenishment with pancreatic enzymes, but emptying of unemulsified oil was inhibited in a dose-related fashion, such that maximal inhibition was achieved when pancreatic enzymes were replenished at > or = 40% of normal amounts. Studies with orlistat confirmed that this dose-dependent slowing was due specifically to lipase. Emptying of solid food was much more sensitive to replenishment with enzymes, so that a 10% replenishment maximally inhibited solid emptying.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8023935&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


Effects of the lipase inhibitor orlistat on intake and preference for dietary fat in rats.

Ackroff K, Sclafani A.

Department of Psychology, Brooklyn College, City University of New York 11210, USA.

Orlistat (Ols), a potent inhibitor of pancreatic lipase, was added to the fat source (1 or 4 mg Ols/g fat) of a macronutrient self-selection diet fed to adult female rats. The rats responded to the drug-induced reduction in fat absorption by decreasing their dietary fat intake and increasing their protein and carbohydrate intake in a dose-related manner. Total caloric intake also increased, but body weight gain was inhibited compared with the nondrug control group. When Ols was removed from the diet, nutrient selection, caloric intake, and body weight returned to control levels. In additional short-term experiments (30 min/day), rats developed a preference for a plain fat diet over an Ols-fat diet (4 mg/g fat) and also for a cue flavor paired with plain fat over a flavor paired with Ols-fat. Yet, when not given the choice, the rats consumed nearly as much Ols-fat as plain fat diet. These results indicate that, by reducing fat absorption, Ols reduced the attractiveness of dietary fat, although it did not make the fat diet aversive. In clinical use, lipase inhibitors may be effective in reducing dietary fat intake by reducing both the consumption and absorption of fat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8760203&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


Evidence for a multi-domain structure for hormone-sensitive lipase.

Smith GM, Garton AJ, Aitken A, Yeaman SJ.

Department of Biochemistry and Genetics, Medical School, University of Newcastle, Newcastle upon Tyne, UK.

Hormone-sensitive lipase (HSL) is a multi-functional enzyme involved in several aspects of lipid metabolism. Limited tryptic digestion of HSL led to selective loss of activity against lipid substrates but not against the water-soluble substrate, p-nitrophenyl butyrate. Following labelling of the active site of HSL with either [3H]di-isopropylfluorophosphate or [14C]orlistat, tryptic digestion of HSL generated a stable radiolabelled domain of molecular mass approx. 17.6 kDa, consistent with this representing a catalytic domain of HSL capable of hydrolysing water-soluble but not lipid substrates. Following phosphorylation of HSL by cyclic AMP-dependent protein kinase, limited tryptic digestion produced a stable phosphorylated domain of molecular mass 11.5 kDa. Based on these experimental data a model for a domain structure of HSL is proposed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8906873&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


[How safe are the new obesity drugs? Indications and contraindications of orlistat and sibutramine]

[Article in German]

Richter WO.

Institut fur Fettstoffwechsel und Hamorheologie, Windach/Ammersee. ifn-richter t-online.de

Sibutramine and Orlistat are suitable "supporting drugs" for use in patients trying to lose weight. Orlistat reduces the absorption of fat from the intestine by about one-third. Over the long term too, the weight loss achieved under Orlistat (9%) has been greater than that seen under placebo (6.5%). Increased fat losses via the stools are associated with side effects and abandonment of treatment. Sibutramine inhibits the uptake of serotonin and noradrenaline in the synaptic gap, thus enhancing the CNS effects of these two transmitters, and prolonging the sensation of satiety. The most common side effects of sibutramine are dry mouth, headache and fatigue. The effects of sibutramine on weight reduction are similar to those of orlistat. For both drugs, the indications have been defined, and in the case of sibutramine, interactions with other medications have to be taken into account.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10726144&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


New developments in obesity.

Katsilambros N.

First Department of Propaedeutic Medicine, Athens University Medical School, Laiko General Hospital, 17 Agiou Thoma Street, GR 115 27, Athens, Greece

Obesity is an important health problem. Worldwide epidemiological data show that its frequency is rising steeply, probably because of a reduction in physical activity and bad eating habits. Health risks are most prominent in the central type of obesity, due to the relatively increased lipolytic activity, which leads to a series of events. The overall results of treatment are not satisfactory. Drugs, such as orlistat, fluoxetine, and ephedrine/caffeine, may be useful. The first results with leptin treatment are encouraging, but not yet optimal. Research on various neuropeptides and beta3-agonists is promising. Prevention of obesity is extremely important but difficult.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10745148&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)