La Formació d'esters i amides dels àcids grassos naturals com un mecanisme per explicar els seus efectes en la salut humana

Abstract

The effects of cannabinoids on appetite in humans have been known since ancient times. Following cannabis smoking modern users report an intensification of the sensory and hedonic properties of food, which impels the over-consumption of palatable food. These effects are media-ted by activation of brain cannabinoid receptors by delta9-tetrahydrocannabinol (THC), the main psychoactive compound present in the resin of marijuana plant. The endogenous ligands of can-nabinoid receptors are called endocannabinoids (eCBs), the most known are 2-arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine (AEA or anandamide). 2-AG and AEA are ester or amide deriva-tives of arachidonic acid, and they belong respectively, to two families of cannabimimetic lipid compounds, the 2-monoacylglycerols (2-MG) and N-acylethanolamines (NAE). 2-MG and NAE are respectively ester and amide derivatives of all natural long-chain fatty acids. The eCB system is a key regulator of both the homeostatic and hedonic regulation of food intake. The high expression of eCB receptors in brain areas that modulate not only appetite but also pain, emotion, cognition and motor functions highli-ght the role of the eCB in many pathophysiological processes. The eCB system is over-active in obesity. It has been recently demonstrated that the eCB system can promote food intake by increasing odor detection in mice. An increase in the body mass index (BMI) in humans has been associated to defi-cits in olfactory capacity. These findings suggest a possible interaction between the eCB system, olfaction and obesity. ECBs are under evaluation as biomarkers of number physiopathological conditions. The lack of interchangeability of eCB concentrations in biological matrices between laboratories, limit their usefulness in clinics and translational research. To overcome these problems researchers should take into account a number of issues concerning sample procurement, preservation, pro-cessing and analysis. The artefactual 2-MG generation in plasma, the chemical isomerization of 2-MG and the artefactual generation of N-acylethanolamines (NAE) in blood are some of the chal-lenges to be confronted. The main aim of this thesis are i) to develop and validate analytical meth-odology for the quantification of eCBs and cannabimimetic compounds to be used as biomarkers in clinical and translational studies; ii) to evaluate the interaction between the eCB system, olfactory capacity and obesity. In the first part of this thesis we have validated a method for the determina-tion of a range of NAE and 2-MG in human plasma. We have been able to overcome and/or control most factors contributing to eCB quantification variability. The most relevant finding is that the arte-factual generation of 2-MG can be controlled by using the lipase inhibitor Orlistat. In the second part of this thesis we evaluated the olfactory function and we measured the plasma concentrations of eCBs and cannabimimetics in a cross sectional study of 161 females with BMI ranging from un-der-weight to morbidly obese. The main results of this study show that obese subjects have a low-er olfactory capacity than non-obese ones and that elevated circulating 2-AG plasma concentra-tions are linked to a lower olfactory capacity. In agreement with previous studies we show that elevated 2-AG concentrations are linked to high BMI and obesity.