Title: Regulation of gastrointestinal lipolysis by selective inhibitors of digestive lipases: an indirect approach to treat obesity
Author: jfcavalier
Last saved by: Saritas, Sevim
Company: CNRS

Regulation of Gastrointestinal Lipolysis by Selective Inhibitors of Digestive Lipases: An Indirect Approach to Treat Obesity?
B. Raux,^1 V. Point,^1 C. Vaysse,^2 L. Couëdelo,^2 F. Carrière,^1 J.-F.Cavalier^1 
^1 EIPL CNRS UMR 7282 Marseille, France; ^2 ITERG Bordeaux, France

The number of obese people has significantly increased to reach around 25% of the worldwide population. Obesity is indeed the fifth leading cause of deaths and this pathology is a risk factor for a variety of diseases, such as type II diabetes, high blood pressure, cardiovascular disorders, some cancers... The digestion of dietary lipids mainly results from the hydrolytic activities of gastric (HGL) and pancreatic (HPL) lipases acting in the stomach and the small intestine. During the last decade, inhibiting these digestive lipases to reduce fat absorption has become the main pharmacological approach to the treatment of obesity, with the withdrawal of the appetite-suppressing drugs that act on the central nervous system. The only anti-obesity drug remaining on the market is thus the lipase inhibitor Orlistat (Xenical® by Roche and Alli® by GSK) [1]. This drug however blocks all known lipases and its apparent selectivity for gastrointestinal lipases is only due to the fact it is not absorbed when taken orally and thus only inhibits the enzymes found in the GI tract lumen. Designing more selective inhibitors of digestive lipases remains a challenge of fundamental value for a better understanding of individual lipase function, but can also provide potential drug candidates aiming at the “fight against obesity”. 
In this competitive context, we recently reported that Oxadiazolone derivatives selectively and efficiently inhibit HGL, with no significant effects on HPL activity [2]. Based on these first set of data, a new series of Oxadiazolone core compounds have been synthesized and tested on pure enzymes. Best inhibitors were selected and further used during in vitro simulation of gastrointestinal lipolysis, as well as in vivo, in animal models (rats [3]). All the collected data allow us to investigate the respective direct effects of each lipase during the digestion of dietary lipids, and provide new insight for the regulation of the whole gastrointestinal lipolysis process. 

[1]	F. Carrière et al., Am J Physiol Gastrointest Liver Physiol 2001, 281, G16-28.
[2]	V. Point et al., Eur J Med Chem. 2012, 58, 452-463.
[3]	L. Couedelo et al., J Nutr. 2012, 142, 70-75.