The circulating and central endocannabinoid system in obesity and weight loss.

Major advances have been made in obesity treatment, focusing on restoring disturbances along the gut-brain axis. The endocannabinoid system (ECS) is a neuromodulatory signaling system, present along the entire gut-brain axis, that plays a critical role in central and peripheral regulation of food intake and body weight. Evidence on the impact of weight loss on the ECS is, however, more limited. Therefore, we set out to review the existing literature for changes in central and circulating endocannabinoid levels after bariatric surgery and other weight loss strategies in humans. The PubMed, Embase and Web of Science databases were searched for relevant articles. Fifty-six human studies were identified. Most studies measuring circulating 2-arachidonoylglycerol (2-AG) found no difference between normal weight and obesity, or no correlation with BMI. In contrast, studies measuring circulating arachidonoylethanolamine (AEA) found an increase or positive correlation with BMI. Two studies found a negative correlation between BMI and cannabinoid receptor type 1 (CB1) receptor availability in the brain. Only one study investigated the effect of pharmacological weight management on circulating endocannabinoid concentrations and found no effect on AEA concentrations. So far, six studies investigated potential changes in circulating endocannabinoids after bariatric surgery and reported conflicting results. Available evidence does not univocally support that circulating endocannabinoids are upregulated in individuals with obesity, which may be explained by variability across studies in several potential confounding factors (e.g. age and sex) as well as heterogeneity within the obesity population (e.g. BMI only vs. intra-abdominal adiposity). While several studies investigated the effect of lifestyle interventions on the circulating ECS, more studies are warranted that focus on pharmacologically and surgically induced weight loss. In addition, we identified several research needs which should be fulfilled to better understand the role of the ECS in obesity and its treatments.