Exercise, the endocannabinoid system and metabolic health

Abstract

As obesity and associated metabolic disorders, such as type 2 diabetes and dyslipidemia, are becoming one of the most serious health problems worldwide, development of effective therapies is a high priority. In the search for treatments, the recently discovered endocannabinoid system (ECS) has begun to garner attention, and a wealth of research is now focusing on this unique neuromodulatory system named after the plant that led to its discovery. The ECS consists of G protein-coupled cannabinoid receptors (CB1 and CB2), their endogenous lipid-derived ligands (endocannabinoids, N-arachidonoylethanolamine, named anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and the enzymes for ligand synthesis and degradation. Endocannabinoids, the organic derivative of cannabis, produced naturally in the body, are well known to modulate many cognitive and emotional processes, through which they influence multiple behavioral responses. However, a number of studies published in recent years indicate that endocannabinoids are also key modulators of energy balance through central and peripheral mechanisms. In the central nervous system, the activation of CB1 receptors by endocannabinoids increases food intake, whereas in the peripheral organs, such as gastrointestinal tract, liver, adipose tissue, and skeletal muscle, endocannabinoids are involved in the regulation of nutrient absorption and glucose and lipid metabolism. Considering the important regulatory role of the ECS in energy metabolism, it is not surprising to observe its dysregulation in obesity. Recent data suggest that ECS overactivity is associated with increased lipogenesis, insulin resistance, and dyslipidemia. Hence, the ECS has become a promising pharmacological target in combating obesity and the associated metabolic disorders. Although some clinical trials with specific CB1 receptor antagonists/inverse agonists have been successful in terms of reduction of body weight and amelioration of obesity-related metabolic abnormalities, the adverse central and peripheral side effects of these compounds have seriously limited their therapeutic potential. However, recent findings show that combined calorie restriction and aerobic exercise can modulate endocannabinoid-related gene expression in adipose tissue of obese women during weight loss, suggesting that ECS may link exercise with metabolic adaptations and energy regulation.