Orlistat inhibits gastric, pancreatic, and carboxyl ester lipases, preventing the hydrolysis of triglycerides to free fatty acids and monoglycerides, and as such is widely used to treat obesity.1 With a 120 mg dose before each meal in healthy subjects, orlistat is reported to accelerate gastric emptying and attenuates the secretion of glucose-dependent insulinotropic peptide without affecting plasma responses of cholecystokinin, glucagon-like peptide-1, pancreatic polypeptide, or insulin. 2 It also targets additional serine hydrolases in the nervous system, such as diacylglycerol lipase (DAGL), which is responsible for the conversion of DAG to 2-AG. Orlistat potently inhibits human recombinant DAGLα with an IC50 value of 60 nM and at 1 µM inhibits the formation of 2-AG in intact cells in vitro.3
1
Hadváry, P., Lengsfeld, H., and Wolfer, H. Inhibition of pancreatic lipase in vitro by the covalent inhibitor tetrahydrolipstatin. Biochem J256357-361(1988).
2
Enç, F.Y., Önes, T., Akin, H.L., et al. Orlistat accelerates gastric emptying and attenuates GIP release in healthy subjects. Am J Physiol Gastrointest Liver Physiol296G482-G489(2009).
3
Bisogno, T., Cascio, M.G., Saha, B., et al. Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochem Biophys Acta1761205-212(2006).
Bisogno, T., Cascio, M.G., Saha, B., et al. Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochem Biophys Acta1761205-212(2006).
Enç, F.Y., Önes, T., Akin, H.L., et al. Orlistat accelerates gastric emptying and attenuates GIP release in healthy subjects. Am J Physiol Gastrointest Liver Physiol296G482-G489(2009).
Hadváry, P., Lengsfeld, H., and Wolfer, H. Inhibition of pancreatic lipase in vitro by the covalent inhibitor tetrahydrolipstatin. Biochem J256357-361(1988).
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