Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion.

Mulder H, Yang S, Winzell MS, Holm C, Ahren B.

Department of Cell and Molecular Biology, Lund University, Lund, Sweden. hindrik.muldur medkem.lu.se

Lipids may serve as coupling factors in K(ATP)-independent glucose sensing in beta-cells. We have previously demonstrated that beta-cells harbor lipase activities, one of which is the hormone-sensitive lipase. Whether beta-cell lipases are critical for glucose-stimulated insulin secretion (GSIS) by providing lipid-derived signals from endogenous lipids is unknown. Therefore, using a lipase inhibitor (orlistat), we examined whether lipase inhibition reduces insulin secretion. Islet lipolysis stimulated by glucose and diglyceride lipase activity was abolished by orlistat. Incubation of rat islets with orlistat dose dependently inhibited GSIS; this inhibition was reversed by 1 mmol/l palmitate, suggesting that orlistat acts via impaired formation of an acylglyceride-derived coupling signal. Orlistat inhibited the potentiating effect of forskolin on GSIS, an effect proposed to be due to activation of a lipase. In perifused islets, orlistat attenuated mainly the second phase of insulin secretion. Because the rise in islet ATP/ADP levels in response to glucose and oxidation of the sugar were unaffected by orlistat whereas the second phase of insulin secretion was reduced, it seems likely that a lipid coupling factor involved in K(ATP)-independent glucose sensing has been perturbed. Thus, beta-cell lipase activity is involved in GSIS, emphasizing the important role of beta-cell lipid metabolism for insulin secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14693706&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


[Study of the month. Long-term (1-2 years) clinical trials with orlistat, a new drug for the treatment of obesity]

[Article in French]

Scheen AJ.

Departement de Medecine, Universite de Liege.

Orlistat (Xenical), whose original mechanism of action consists of the selective inhibition of gastrointestinal lipases, has been recently commercialized for the treatment of obesity. Despite its recent launch and when compared to common anorectic agents, it has been much better evaluated in long-term trials carried out according to the rules of Good Clinical Practice. We will summarize the four recently published randomized, placebo-controlled, double-blind clinical trials lasting up to 1 to 2 years and evaluating the effects of orlistat 3 x 120 mg/day in obese patients (BMI > or = 28 kg/m2).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10548902&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


Case report of abuse of Orlistat.

Cochrane C, Malcolm R.

Department of Psychiatry, Medical University of South Carolina, Charleston 29425, USA. cochranc musc.edu

A case report of abuse of the anti-obesity drug, Orlistat, is reported in a normal-weight woman with an eating disorder and stimulant dependence. The case is discussed with reference to the availability of prescription drugs on the Internet, abuse of nonamphetamines and the side effect profile of Orlistat versus laxatives.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15001013&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity.

Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW.

Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

One of the fundamental principles of pharmacology is that most drugs have side effects. Although considerable attention is paid to detrimental side effects, drugs can also have beneficial side effects. Given the time and expense of drug development, it would be particularly exciting if a systematic method could be applied to reveal all of the activities, including the unappreciated actions, of a potential drug. The present study takes the first step along this path. An activity-based proteomics strategy was used to simultaneously identify targets and screen for their inhibitors in prostate cancer. Orlistat, a Food and Drug Administration-approved drug used for treating obesity, was included in this screen. Surprisingly, we find a new molecular target and a potential new application for Orlistat. Orlistat is a novel inhibitor of the thioesterase domain of fatty acid synthase, an enzyme strongly linked to tumor progression. By virtue of its ability to inhibit fatty acid synthase, Orlistat halts tumor cell proliferation, induces tumor cell apoptosis, and inhibits the growth of PC-3 tumors in nude mice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15026345&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)


Visceral obesity without insulin resistance in late-onset obesity rats.

Bains RK, Wells SE, Flavell DM, Fairhall KM, Strom M, Le Tissier P, Robinson IC.

Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.

We describe a line of transgenic rats in which the males develop a unique autosomal dominant, late-onset obesity (LOB) phenotype. LOB males gradually accumulate fat specifically in visceral, but not peripheral, fat depots despite a normal intake of a low fat diet. LOB females normally develop only mild obesity with advanced age. However, the phenotype can be induced rapidly in young females by ovariectomy and prevented by estrogen replacement. LOB males are highly sensitive to dietary fat. Young, nonobese LOB males gain more weight on a 30% fat diet and lose more weight when treated with the lipase inhibitor, Orlistat, than their nontransgenic littermates. Remarkably, despite severe visceral obesity, LOB rats have normal fasting blood glucose, insulin, and corticosterone; show normal or increased insulin sensitivity in glucose and insulin tolerance tests; have increased plasma adiponectin levels; and display a heightened response to treatment with rosiglitazone. Their visceral adiposity reflects a specific increase in visceral adipocyte number, not size. Analysis of the transgene in LOB rats revealed a deletion in the gene encoding the S26 subunit of the mitochondrial ribosome that results in the production of a truncated protein, which we show to be imported into mitochondria. However, the transgene integrant is complex, so whether this is the sole molecular disruption underlying this phenotype remains to be established. Nevertheless, LOB rats provide a valuable new model of late-onset, male-preponderant, visceral-specific obesity, clearly dissociated from insulin resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15033913&dopt=Abstract orlistat Xenical online refs
xenical (orlistat)