Much of the understanding of this

Much of the understanding of this system has come from several studies focussed on CB1. A significant amount of research has demonstrated that activation of the CB1 receptor by cannabinoid ligands stimulates food intake [10], reduces gastrointestinal motility [11], and increases lipogenesis [12] and steatosis in the liver [13]. Activation of the receptor has also been demonstrated to increase lipogenesis accompanied by reduced lipolysis, increased inflammation in the white adipose tissue and insulin resistance, as evidenced by reduced glucose uptake in the skeletal muscle [14]. Importantly, blocking the CB1 receptor has been demonstrated to improve these metabolic abnormalities [14]. CB2 is likely to have a different role in obesity, because this receptor is predominantly involved in the immune response [15] and is most abundantly localised to Dimesna of the immune system [16]. Although the obese state is associated with chronic low-grade inflammation, in which there are increased amounts of circulating proinflammatory markers [17], CB2 has also been shown to have a possible role in obesity and glucose metabolism [18]; however, its exact role in all tissues involved in energy intake and expenditure remains unclear. Currently, CB1 and CB2 are the two known endocannabinoid receptors. However, other putative endocannabinoid receptors might exist that have a role in regulating energy homeostasis, and might be potential drug targets for obesity and other metabolic disorders, such as T2DM. Emerging pharmacological data and studies utilising knockout animals have suggested that additional cannabinoid-sensitive targets [19], including GPR55, GPR18 and GPR119, exist in several tissues. Given that recent evidence has suggested that GPR55 has a role in metabolic conditions 20, 21, we focus in this review on GPR55 and its physiological role, as well as discussing the potential of this receptor as a drug target for obesity and related co-morbidities.
GPR55: a putative endocannabinoid receptor? Although GPR55 has recently been reported as a novel member of the cannabinoid family [4] and has been termed the possible ‘third’ cannabinoid receptor, inconsistencies exist in the literature, with some studies showing reduced or no specificity of GPR55 to these ligands 22, 23, 24. These inconsistencies might be linked to the fact that the ligands were not tested for a dose response before the assays [25]. There is also the possibility that there was a toxic effect of these compounds on the cells, owing to the high dose of the compounds as well as the duration of exposure to these ligands [25] or as a result of biased agonism. For a more comprehensive review on the inconsistent findings for the pharmacology of GPR55, see [26]. Despite this debate around the classification of GPR55 as a novel member of the endocannabinoid system, the role of this receptor in human physiology is still of interest.
Tissue distribution GPR55 has been shown to be expressed in several tissues throughout the body, with a similar distribution between mouse and rat and with some limited investigation of GPR55 expression in human tissue 4, 21, 27. GPR55 mRNA is most abundantly expressed in the adrenal tissue, ileum, jejunum, frontal cortex and striatum in mice [4]. In addition, GPR55 is expressed in tissue that is involved in regulating energy intake and expenditure. Localisation studies in different organisms have shown that this receptor has been identified in the hypothalamus in mice [4] and in different regions of the gastrointestinal tract, including the oesophagus, stomach, jejunum and colon in mouse [4], and jejunum, ileum and colon in rat 28, 29. In the rat small intestine, GPR55 was localised mainly in the submucosa and myenteric plexus [29]. GPR55 mRNA and protein expression have also been located in the liver in rats [27], mice [20] and humans [21], in adipose tissue from rats [20], in visceral and subcutaneous white adipose tissue in humans [21] and in pancreas from rat, specifically the islets of Langerhans [20]. GPR55 tissue expression in brown adipose tissue has yet to be determined. Importantly, the localisation of GPR55 in several tissues involved in regulating energy intake and expenditure suggests a role for this GPCR in the maintenance of energy homeostasis. Interestingly, the localisation of GPR55 in metabolically active skeletal muscle is largely overlooked in the current literature. Despite this, unpublished observations from our laboratory have confirmed the protein expression of GPR55 in rat skeletal muscle (A. Simcocks et al., unpublished).