Acute effects of pharmacological modifications of fatty acid metabolism on human satiety

The role of NEFA in eating behaviour is still poorly known. Our objective was to examine whether etomoxir (ETO), an inhibitor of NEFA oxidation, or (−)-hydroxycitrate (HCA), an inhibitor of lipogenesis which may indirectly stimulate NEFA oxidation, alters satiety. Post-lunch satiety was measured in eight normal-weight male subjects who were deprived of time cues and received on three occasions either ETO (320mg), HCA (2g) or placebo (PLA) in random order. Between lunch and dinner, blood was withdrawn continuously and collected every 10min for measures of plasma concentrations of glucose, insulin, lactate, TAG, NEFA, β-hydroxybutyrate (BHB), leptin and ghrelin. Results showed that HCA began to decrease hunger and desire to eat compared to PLA and ETO 210min after lunch and increased satiety duration compared to PLA by 70 (se 23) min (P<0·05), but did not modify energy intake at dinner. ETO did not affect any variable of satiety. HCA increased NEFA concentrations during the pre-dinner period, whereas ETO increased and decreased plasma concentrations of NEFA and BHB, respectively. Mean differences in plasma NEFA concentrations between HCA and PLA were predictive of the differences in satiety duration between treatments (r2 0·71, P<0·01). Among treatments, plasma leptin concentration at dinner onset was the only blood variable correlated with energy intake at this meal (r −0·75, P<0·0005). In healthy, normal-weight men, acute HCA increased the intensity and duration of satiety possibly via increased NEFA disposal for oxidatio

High Compared with Moderate Protein Intake Reduces Adaptive Thermogenesis and Induces a Negative Energy Balance during Long-term Weight-Loss Maintenance in Participants with Prediabetes in the Postobese State : A PREVIEW Study

Background: Weight loss has been associated with adaptations in energy expenditure. Identifying factors that counteract these adaptations are important for long-term weight loss and weight maintenance. Objective: The aim of this study was to investigate whether increased protein/carbohydrate ratio would reduce adaptive thermogenesis (AT) and the expected positive energy balance (EB) during weight maintenance after weight loss in participants with prediabetes in the postobese state. Methods: In 38 participants, the effects of 2 diets differing in protein/carbohydrate ratio on energy expenditure and respiratory quotient (RQ) were assessed during 48-h respiration chamber measurements similar to 34 mo after weight loss. Participants consumed a high-protein (HP) diet In = 20; 13 women/7 men; age: 64.0 +/- 6.2 y; BMI: 28.9 +/- 4.0 kg/m(2)) with 25:45:30% or a moderate-protein (MP) diet (n = 18; 9 women/9 men; age: 65.1 +/- 5.8 y; BMI: 29.0 +/- 3.8 kg/m(2)) with 15:55:30% of energy from protein:carbohydrate:fat. Predicted resting energy expenditure (REEp) was calculated based on fat-free mass and fat mass. AT was assessed by subtracting measured resting energy expenditure (REE) from REEp. The main outcomes included differences in components of energy expenditure, substrate oxidation, and AT between groups. Results: EB (MP = 0.2 +/- 0.9 MJ/d; HP = -0.5 +/- 0.9 MJ/d) and RO (MP = 0.84 +/- 0.02; HP = 0.82 +/- 0.02) were reduced and REE (MP: 73 +/- 0.2 MJ/d compared with HP: 78 +/- 0.2 MJ/d) was increased in the HP group compared with the MP group (P <0.05). REE was not different from REEp in the HP group, whereas REE was lower than REEp in the MP group (P <0.05). Furthermore, EB was positively related to AT (r(s) = 0.74; P <0.001) and RQ (r(s) = 0.47; P <0.01) in the whole group of participants. Conclusions: In conclusion, an HP diet compared with an MP diet led to a negative EB and counteracted AT similar to 34 mo after weight loss, in participants with prediabetes in the postobese state. These results indicate the relevance of compliance to an increased protein/carbohydrate ratio for long-term weight maintenance after weight loss.Peer reviewe

Effects of a High-Protein Diet on Cardiometabolic Health, Vascular Function, and Endocannabinoids—A PREVIEW Study

An unfavorable lipid profile and being overweight are known mediators in the development of cardiovascular disease (CVD) risk. The effect of diet, particularly high in protein, remains under discussion. Therefore, this study examines the effects of a high-protein (HP) diet on cardiometabolic health and vascular function (i.e., endothelial function, arterial stiffness, and retinal microvascular structure), and the possible association with plasma endocannabinoids and endocannabinoid-related compounds in overweight participants. Thirty-eight participants (64.5 ± 5.9 (mean ± SD) years; body mass index (BMI) 28.9 ± 4.0 kg/m2) were measured for 48 h in a respiration chamber after body-weight maintenance for approximately 34 months following weight reduction. Diets with either a HP (n = 20) or moderate protein (MP; n = 18) content (25%/45%/30% vs. 15%/55%/30% protein/carbohydrate/fat) were provided in energy balance. Validated markers for cardiometabolic health (i.e., office blood pressure (BP) and serum lipoprotein concentrations) and vascular function (i.e., brachial artery flow-mediated vasodilation, pulse wave analysis and velocity, and retinal microvascular calibers) were measured before and after those 48 h. Additionally, 24 h ambulatory BP, plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and pregnenolone (PREG) were analyzed throughout the day. Office and ambulatory BP, serum lipoprotein concentrations, and vascular function markers were not different between the groups. Only heart rate (HR) was higher in the HP group. HR was positively associated with OEA, while OEA and PEA were also positively associated with total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations. Vascular function markers were not associated with endocannabinoids (or endocannabinoid-related substances). In conclusion, the HP diet did not affect cardiometabolic health and vascular function in overweight participants after completing a weight-loss intervention. Furthermore, our data indicate a possible association between OEA and PEA with TC and LDL cholesterol

Effects of a High-Protein Diet on Cardiometabolic Health, Vascular Function, and Endocannabinoids-A PREVIEW Study

An unfavorable lipid profile and being overweight are known mediators in the development of cardiovascular disease (CVD) risk. The effect of diet, particularly high in protein, remains under discussion. Therefore, this study examines the effects of a high-protein (HP) diet on cardiometabolic health and vascular function (i.e., endothelial function, arterial stiffness, and retinal microvascular structure), and the possible association with plasma endocannabinoids and endocannabinoid-related compounds in overweight participants. Thirty-eight participants (64.5 +/- 5.9 (mean +/- SD) years; body mass index (BMI) 28.9 +/- 4.0 kg/m(2)) were measured for 48 h in a respiration chamber after body-weight maintenance for approximately 34 months following weight reduction. Diets with either a HP (n= 20) or moderate protein (MP;n= 18) content (25%/45%/30% vs. 15%/55%/30% protein/carbohydrate/fat) were provided in energy balance. Validated markers for cardiometabolic health (i.e., office blood pressure (BP) and serum lipoprotein concentrations) and vascular function (i.e., brachial artery flow-mediated vasodilation, pulse wave analysis and velocity, and retinal microvascular calibers) were measured before and after those 48 h. Additionally, 24 h ambulatory BP, plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and pregnenolone (PREG) were analyzed throughout the day. Office and ambulatory BP, serum lipoprotein concentrations, and vascular function markers were not different between the groups. Only heart rate (HR) was higher in the HP group. HR was positively associated with OEA, while OEA and PEA were also positively associated with total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations. Vascular function markers were not associated with endocannabinoids (or endocannabinoid-related substances). In conclusion, the HP diet did not affect cardiometabolic health and vascular function in overweight participants after completing a weight-loss intervention. Furthermore, our data indicate a possible association between OEA and PEA with TC and LDL cholesterol.Peer reviewe

Effects of a High-Protein Diet on Cardiometabolic Health, Vascular Function, and Endocannabinoids—A PREVIEW Study

An unfavorable lipid profile and being overweight are known mediators in the development of cardiovascular disease (CVD) risk. The effect of diet, particularly high in protein, remains under discussion. Therefore, this study examines the effects of a high-protein (HP) diet on cardiometabolic health and vascular function (i.e., endothelial function, arterial stiffness, and retinal microvascular structure), and the possible association with plasma endocannabinoids and endocannabinoid-related compounds in overweight participants. Thirty-eight participants (64.5 ± 5.9 (mean ± SD) years; body mass index (BMI) 28.9 ± 4.0 kg/m2) were measured for 48 h in a respiration chamber after body-weight maintenance for approximately 34 months following weight reduction. Diets with either a HP (n = 20) or moderate protein (MP; n = 18) content (25%/45%/30% vs. 15%/55%/30% protein/carbohydrate/fat) were provided in energy balance. Validated markers for cardiometabolic health (i.e., office blood pressure (BP) and serum lipoprotein concentrations) and vascular function (i.e., brachial artery flow-mediated vasodilation, pulse wave analysis and velocity, and retinal microvascular calibers) were measured before and after those 48 h. Additionally, 24 h ambulatory BP, plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and pregnenolone (PREG) were analyzed throughout the day. Office and ambulatory BP, serum lipoprotein concentrations, and vascular function markers were not different between the groups. Only heart rate (HR) was higher in the HP group. HR was positively associated with OEA, while OEA and PEA were also positively associated with total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations. Vascular function markers were not associated with endocannabinoids (or endocannabinoid-related substances). In conclusion, the HP diet did not affect cardiometabolic health and vascular function in overweight participants after completing a weight-loss intervention. Furthermore, our data indicate a possible association between OEA and PEA with TC and LDL cholesterol

High Risk of Acute Kidney Failure in Kidney Transplant Recipients Early after Bariatric Surgery

Bariatric surgery is routinely proposed to patients suffering from obesity including kidney transplant recipients. In this specific population, bariatric surgery has a positive impact in long-term outcomes in terms of patient and graft survival. We report here the cases of 4 patients with five post-kidney transplantation bariatric surgeries who experimented acute renal injury early after surgery. Creatinine rising occurred between day 14 and day 20 after surgery. In all cases, it was due to dehydration leading to a pre-renal acute renal failure. The specific care of kidney transplanted patients is discussed: single kidney associated with pre-existing altered kidney function associated with concomitant use of nephrotoxic drugs. Specific education intervention before surgery associated with careful early management of hydration after surgery is mandatory for these patients

Effects of a High-Protein/Moderate-Carbohydrate Diet on Appetite, Gut Peptides, and Endocannabinoids—A Preview Study

Favorable effects of a high-protein/moderate-carbohydrate (HP/MCHO) diet after weight loss on body weight management have been shown. To extend these findings, associations between perception of hunger and satiety with endocannabinoids, and with glucagon-like peptide-1 (GLP-1) and polypeptide YY (PYY) were assessed. At approximately 34 months after weight loss, 22 female and 16 male participants (mean age 64.5 ± 5.9 years; body mass index (BMI) 28.9 ± 3.9 kg/m2) completed a 48 h respiration chamber study. Participants were fed in energy balance with a HP/MCHO diet with 25%:45%:30% or a moderate-protein/high-carbohydrate (MP/HCHO) diet with 15%:55%:30% of energy from protein:carbohydrate:fat. Endocannabinoids and related compounds, relevant postprandial hormones (GLP-1, PYY), hunger, satiety, and ad libitum food intake were assessed. HP/MCHO versus MP/HCHO reduced hunger perception. The lower decremental area under the curve (dAUC) for hunger in the HP/MCHO diet (−56.6% compared to MP, p < 0.05) was associated with the higher AUC for 2-arachidonoylglycerol (2-AG) concentrations (p < 0.05). Hunger was inversely associated with PYY in the HP/MCHO group (r = −0.7, p < 0.01). Ad libitum food intake, homeostatic model assessment for insulin resistance (HOMA-IR) and incremental AUCs for gut peptides were not different between conditions. HP/MCHO versus MP/HCHO diet-induced reduction in hunger was present after 34 months weight maintenance in the post-obese state. HP/MCHO diet-induced decrease of hunger is suggested to interact with increased 2-AG and PYY concentrations

Effects of a High-Protein/Moderate-Carbohydrate Diet on Appetite, Gut Peptides, and Endocannabinoids—A Preview Study

Favorable effects of a high-protein/moderate-carbohydrate (HP/MCHO) diet after weight loss on body weight management have been shown. To extend these findings, associations between perception of hunger and satiety with endocannabinoids, and with glucagon-like peptide-1 (GLP-1) and polypeptide YY (PYY) were assessed. At approximately 34 months after weight loss, 22 female and 16 male participants (mean age 64.5 ± 5.9 years; body mass index (BMI) 28.9 ± 3.9 kg/m2) completed a 48 h respiration chamber study. Participants were fed in energy balance with a HP/MCHO diet with 25%:45%:30% or a moderate-protein/high-carbohydrate (MP/HCHO) diet with 15%:55%:30% of energy from protein:carbohydrate:fat. Endocannabinoids and related compounds, relevant postprandial hormones (GLP-1, PYY), hunger, satiety, and ad libitum food intake were assessed. HP/MCHO versus MP/HCHO reduced hunger perception. The lower decremental area under the curve (dAUC) for hunger in the HP/MCHO diet (−56.6% compared to MP, p < 0.05) was associated with the higher AUC for 2-arachidonoylglycerol (2-AG) concentrations (p < 0.05). Hunger was inversely associated with PYY in the HP/MCHO group (r = −0.7, p < 0.01). Ad libitum food intake, homeostatic model assessment for insulin resistance (HOMA-IR) and incremental AUCs for gut peptides were not different between conditions. HP/MCHO versus MP/HCHO diet-induced reduction in hunger was present after 34 months weight maintenance in the post-obese state. HP/MCHO diet-induced decrease of hunger is suggested to interact with increased 2-AG and PYY concentrations

The endocannabinoid system and metabolic diseases in humans

Le système endocannabinoïde (SEC) est un système clé de la régulation de la balance énergétique. Les rares études réalisées chez l’Homme concluent à une augmentation des concentrations plasmatiques des endocannabinoïdes, anandamide (AEA) et 2-arachidonoylglycerol (2-AG), chez les sujets obèses ou diabétiques de type 2. Cependant plusieurs questions restent posées et cette thèse s’est spécifiquement intéressée : i) à l’existence d’une cinétique prandiale et au rôle des endocannabinoïdes circulants par rapport à la prise alimentaire, ii) aux effets d’une perte de poids obtenue par court-circuit gastrique sur ces concentrations et iii) aux liens physiopathologiques entre insulinorésistance et SEC. Enfin, nous avons tenté de développer un outil non invasif pour faciliter l’étude du SEC chez l’Homme. Dans la 1ère étude, nous avons mis en évidence pour la première fois une augmentation préprandiale de l’AEA indépendante du poids. Ceci suggère que l’AEA plasmatique pourrait jouer un rôle dans l’initiation de la prise alimentaire chez l’Homme. De façon intéressante, la réduction post prandiale de l’AEA est émoussée chez les sujets obèses insulinorésistants, ce qui peut créer un cercle vicieux vis à vis de l’obésité. Dans la 2ème étude, des résultats préliminaires montrent qu’une même perte de poids obtenue par court-circuit gastrique ou par règles hygiéno-diététiques modifie différemment les concentrations plasmatiques d’AEA qui tendent à augmenter après court-circuit gastrique alors qu’elles ne sont pas modifiées après règles hygiéno-diététiques. Ainsi, le court-circuit gastrique pourrait directement affecter le fonctionnement du SEC localisé au niveau du tractus gastro-intestinal. Dans la 3ème étude, 72 heures de régime hypoglucidique permettent de diminuer significativement la glycémie à jeun et la résistance à l’insuline de 8 sujets diabétiques de type 2, mais pas les concentrations plasmatiques d’endocannabinoïdes, qui ne sont par ailleurs pas modifiées chez ces sujets en fonction du statut nutritionnel. Enfin, nous avons pu déterminer les concentrations des endocannabinoïdes dans la salive humaine, qui sont plus élevées chez les sujets obèses par rapport aux normopondéraux, avec une diminution de l’AEA salivaire associée à la perte de poids, mais sans variation en fonction de la prise alimentaire. La salive pourrait donc constituer un outil non invasif pour l’étude du SEC chez l’Homme.Ainsi, notre travail confirme les liens entre SEC et pathologies métaboliques chez l’Homme. Nos résultats suggèrent en particulier un rôle physiologique de l’AEA dans la prise alimentaire ainsi que l’importance potentielle du SEC du tractus gastro-intestinal. Nous confirmons la dérégulation statique et dynamique du SEC dans la situation de diabète de type 2. Enfin nous développons un nouvel outil pour l’exploration du SEC chez l’Homme. Nos résultats sont importants car la meilleure connaissance des systèmes impliqués dans la régulation de la balance énergétique est nécessaire pour le développement de nouvelles stratégies thérapeutiques efficaces contre l’obésité et ses pathologies associées.The endocannabinoid system (ECS) is a key system for the regulation of energy balance. Only few studies have been so far carried out in humans but they all lead to conclude that obese subjects have higher plasma fasting levels of the 2 major endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). However, many questions concerning the role of the ECS in the physiopathology of obesity in humans remain still unanswered. This thesis has therefore attempted to address some of these questions by investigating i) the changes of plasma endocannabinoids in response to food intake, ii) the effect of weight loss induced by gastric bypass or lifestyle intervention on these plasma levels and iii) the potential link between insulin resistance and circulating endocannabinoids. Lastly, we have also tested the possibility to develop a non-invasive tool to ease the investigation of the ECS in humans. In the 1st study, we have described for the first time the existence of a pre-prandial peak in plasma AEA, which is independent of body weight. This evidence suggests that circulating AEA levels might work as a meal initiator factor in humans. Importantly, the AEA postprandial decrease is blunted in obese insulin resistant subjects and might therefore favor the persistence of the obese phenotype. In our 2nd study, preliminary results suggest that the same body weight loss obtained through gastric-bypass or lifestyle intervention differently affects plasma AEA levels. In particular, while AEA tend to increase in subjects who have undergone gastric bypass, no changes are observed after a comparable weight loss induced by lifestyle intervention. Thus, a possibility is that the bypass might directly affect the function of the ECS localized within the gastrointestinal tract. In our 3rd study, which was carried out on 8 type 2 diabetic patients, we have shown that 72 hours of a low carbohydrate diet significantly decreases glycaemia and insulin resistance, without affecting the levels and the kinetic of circulating endocannabinoids. Lastly, we demonstrated that endocannabinoids are reliably measured in saliva. Salivary endocannabinoids are higher in obese as compared to normal weight subjects. Body weight loss significantly decreases salivary AEA, while the consumption of a meal does not influence salivary endocannabinoids levels. Altogether our studies confirm the association between ECS deregulation and metabolic disease in humans. In particular, we have demonstrated that plasma AEA might have a physiological role in the regulation of human feeding behavior, and have hinted the potential relevance of the gastro-intestinal ECS in our studies on gastric-bypass patients. We have also shown that in type 2 diabetes, there is a flattening of the kinetics of circulating endocannabinoids. Finally, we have shown that measurement of salivary endocannabinoids is reliable and might be of clinical value. These findings extend our knowledge on one of the systems majorly implicated in energy balance regulation. Such knowledge is a necessary step towards the development of novel therapeutic strategies needed to halt obesity and metabolic disease

The endocannabinoid system and metabolic diseases in humans

Le système endocannabinoïde (SEC) est un système clé de la régulation de la balance énergétique. Les rares études réalisées chez l’Homme concluent à une augmentation des concentrations plasmatiques des endocannabinoïdes, anandamide (AEA) et 2-arachidonoylglycerol (2-AG), chez les sujets obèses ou diabétiques de type 2. Cependant plusieurs questions restent posées et cette thèse s’est spécifiquement intéressée : i) à l’existence d’une cinétique prandiale et au rôle des endocannabinoïdes circulants par rapport à la prise alimentaire, ii) aux effets d’une perte de poids obtenue par court-circuit gastrique sur ces concentrations et iii) aux liens physiopathologiques entre insulinorésistance et SEC. Enfin, nous avons tenté de développer un outil non invasif pour faciliter l’étude du SEC chez l’Homme. Dans la 1ère étude, nous avons mis en évidence pour la première fois une augmentation préprandiale de l’AEA indépendante du poids. Ceci suggère que l’AEA plasmatique pourrait jouer un rôle dans l’initiation de la prise alimentaire chez l’Homme. De façon intéressante, la réduction post prandiale de l’AEA est émoussée chez les sujets obèses insulinorésistants, ce qui peut créer un cercle vicieux vis à vis de l’obésité. Dans la 2ème étude, des résultats préliminaires montrent qu’une même perte de poids obtenue par court-circuit gastrique ou par règles hygiéno-diététiques modifie différemment les concentrations plasmatiques d’AEA qui tendent à augmenter après court-circuit gastrique alors qu’elles ne sont pas modifiées après règles hygiéno-diététiques. Ainsi, le court-circuit gastrique pourrait directement affecter le fonctionnement du SEC localisé au niveau du tractus gastro-intestinal. Dans la 3ème étude, 72 heures de régime hypoglucidique permettent de diminuer significativement la glycémie à jeun et la résistance à l’insuline de 8 sujets diabétiques de type 2, mais pas les concentrations plasmatiques d’endocannabinoïdes, qui ne sont par ailleurs pas modifiées chez ces sujets en fonction du statut nutritionnel. Enfin, nous avons pu déterminer les concentrations des endocannabinoïdes dans la salive humaine, qui sont plus élevées chez les sujets obèses par rapport aux normopondéraux, avec une diminution de l’AEA salivaire associée à la perte de poids, mais sans variation en fonction de la prise alimentaire. La salive pourrait donc constituer un outil non invasif pour l’étude du SEC chez l’Homme.Ainsi, notre travail confirme les liens entre SEC et pathologies métaboliques chez l’Homme. Nos résultats suggèrent en particulier un rôle physiologique de l’AEA dans la prise alimentaire ainsi que l’importance potentielle du SEC du tractus gastro-intestinal. Nous confirmons la dérégulation statique et dynamique du SEC dans la situation de diabète de type 2. Enfin nous développons un nouvel outil pour l’exploration du SEC chez l’Homme. Nos résultats sont importants car la meilleure connaissance des systèmes impliqués dans la régulation de la balance énergétique est nécessaire pour le développement de nouvelles stratégies thérapeutiques efficaces contre l’obésité et ses pathologies associées.The endocannabinoid system (ECS) is a key system for the regulation of energy balance. Only few studies have been so far carried out in humans but they all lead to conclude that obese subjects have higher plasma fasting levels of the 2 major endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). However, many questions concerning the role of the ECS in the physiopathology of obesity in humans remain still unanswered. This thesis has therefore attempted to address some of these questions by investigating i) the changes of plasma endocannabinoids in response to food intake, ii) the effect of weight loss induced by gastric bypass or lifestyle intervention on these plasma levels and iii) the potential link between insulin resistance and circulating endocannabinoids. Lastly, we have also tested the possibility to develop a non-invasive tool to ease the investigation of the ECS in humans. In the 1st study, we have described for the first time the existence of a pre-prandial peak in plasma AEA, which is independent of body weight. This evidence suggests that circulating AEA levels might work as a meal initiator factor in humans. Importantly, the AEA postprandial decrease is blunted in obese insulin resistant subjects and might therefore favor the persistence of the obese phenotype. In our 2nd study, preliminary results suggest that the same body weight loss obtained through gastric-bypass or lifestyle intervention differently affects plasma AEA levels. In particular, while AEA tend to increase in subjects who have undergone gastric bypass, no changes are observed after a comparable weight loss induced by lifestyle intervention. Thus, a possibility is that the bypass might directly affect the function of the ECS localized within the gastrointestinal tract. In our 3rd study, which was carried out on 8 type 2 diabetic patients, we have shown that 72 hours of a low carbohydrate diet significantly decreases glycaemia and insulin resistance, without affecting the levels and the kinetic of circulating endocannabinoids. Lastly, we demonstrated that endocannabinoids are reliably measured in saliva. Salivary endocannabinoids are higher in obese as compared to normal weight subjects. Body weight loss significantly decreases salivary AEA, while the consumption of a meal does not influence salivary endocannabinoids levels. Altogether our studies confirm the association between ECS deregulation and metabolic disease in humans. In particular, we have demonstrated that plasma AEA might have a physiological role in the regulation of human feeding behavior, and have hinted the potential relevance of the gastro-intestinal ECS in our studies on gastric-bypass patients. We have also shown that in type 2 diabetes, there is a flattening of the kinetics of circulating endocannabinoids. Finally, we have shown that measurement of salivary endocannabinoids is reliable and might be of clinical value. These findings extend our knowledge on one of the systems majorly implicated in energy balance regulation. Such knowledge is a necessary step towards the development of novel therapeutic strategies needed to halt obesity and metabolic disease