Potential metabolic and behavioural roles of the putative endocannabinoid receptors GPR18, GPR55 and GPR119 in feeding

Abstract

Endocannabinoids are ancient biomolecules involved in several cellular (e.g., metabolism) and physiological (e.g., eating behaviour) functions. Indeed, eating behaviour alterations in marijuana users have led to investigate the orexigenic/anorexigenic effects of cannabinoids in animal/ human models. This increasing body of research suggests that the endocannabinoid system plays an important role in feeding control. Accordingly, within the endocannabinoid system, cannabinoid receptors, enzymes and genes represent potential therapeutic targets for dealing with multiple metabolic and behavioural dysfunctions (e.g., obesity, anorexia, etc.). Paradoxically, our understanding on the endocannabinoid system as a cellular mediator is yet limited. For example: (i) only two cannabinoid receptors have been classified, but they are not enough to explain the pharmacological profile of several experimental effects induced by cannabinoids; and (ii) several orphan G protein-coupled receptors (GPCRs) interact with cannabinoids and we do not know how to classify them (e.g., GPR18, GPR55 and GPR119; amongst others). On this basis, the present review attempts to summarize the lines of evidence supporting the potential role of GPR18, GPR55 and GPR119 in metabolism and feeding control that may explain some of the divergent effects and puzzling data related to cannabinoid research. Moreover, their therapeutic potential in feeding behaviour alterations will be considered.

Keywords: Feeding control; GPR119; GPR18; GPR55; endocannabinoid system..

Fig. (1)

Structure of endocannabinoids: AEA, 2-AG, 2-AGE, virodhamine, NADA, PEA and OEA; phytocannabinoids THC and CBD; and synthetic cannabinoids Abn-CBD and rimonabant.

Fig. (2)

Anti-inflammatory actions of GPR18 bafter stimulation by NaGly. NaGly may be produced by macrophages and C6 glyoma cells and/or from dietary fatty acids Bradshaw et al. [162]. NaGly activates MAP/ERK/JNK and mitochondrial signaling pathways via GPR18 for inducing apoptosis of proinflammatory macrophages Takenouchi et al. [140]. In beta cells, NaGly increases intracelullar calcium and induce insulin release through an unknown receptor Ikeda et al. and Takenouchi et al. [163, 164]. NaGly synthesized by two independent ways Bradshaw et al. [162].

Fig. (3)

Metabolic effects of gastrointestinal and pancreatic GPR55 and GPR119. Both receptors seem to produce beneficial effects on glucose metabolism and tolerance by controlling positively insulin release McKillop et al. and Soga et al. [149, 153]. On the other hand, GPR119 is also expressed in the gastrointestinal tract (enteroendocrine system) and it plays an important function as a “fat sensor” regulating the expression and secretion of hormones such as GLP-1, GLP-2 and PYY leading to hypophagia Meadows et al. [85].