Functional fine-tuning of metabolic pathways by the endocannabinoid system implications for health and disease

Abstract

Although the biological components of the endocannabinoid system (ECS) are well known and have been explored in detail over many decades, its significance seems to enlarge with every new experimental study. The ECS employs a huge network of molecules (receptors, ligands, and enzymatic machinery molecules) whose interactions with other cellular networks have still not been fully elucidated. It has become evident that its historical role in pain alleviation is just the tip of an enormous iceberg of translationally significant information that can be derived from the so-called endocannabinoidome. The ECS is involved in the modulation of a large amount of cognitive and physiological processes involved in the homeostatic regulation of the body. The role and mechanism by which the ECS is involved in the regulation of metabolism is not fully known, but its action is in large part through cyclic AMP/receptor activation-related pathways activated by cannabinoid ligands [1,2]. Endogenous cannabinoids are molecules with the primary function of control of multiple metabolic pathways. They are pre-synthesized and stored in cellular vesicles and released upon endogenous and exogenous stimuli to regulate internal homeostasis. Their targets include classical cannabinoid receptors that belong to the G-protein coupled receptor (GPCR) family as well as their various heteromers (see below), contributing to the complexity of the ECS [3]. Cannabinoid ligands also act through various non-canonical pathways [4], employing secondary messenger systems (changes in intracellular Ca2+ levels, activation of protein kinases) thus preferentially triggering alternative outcomes depending on the initial stimuli. This work aims to contribute to the growing burden of evidence that the ECS might be significantly more used as a pharmacological target for various metabolic disorders, despite carrying a historical label of being legally and ethically compromised.