br Acknowledgments br Introduction Obesity and

Acknowledgments
Introduction Obesity and type 2 diabetes (T2D) are two major chronic non-communicable diseases that are increasing worldwide at an alarming rate; the majority of people with T2D are overweight or obese, and T2D associated with obesity is expected to have doubled by 2030 (Chen et al., 2011). Obesity is characterized by an excess of body weight in the form of fat, whereas the main feature of T2D is hyperglycemia, caused by defects in insulin secretion from pancreatic β-cells and/or resistance to this hormone. Both obesity and alterations in insulin release are closely related to high blood glucose and free fatty isoprenaline levels, and are major risks for cardiovascular disease and other health complications. Growing evidence points to the endocannabinoid system (ECS) as an important regulator of glucose metabolism. The ECS comprises endogenous cannabinoids, metabolizing enzymes that regulate their production and degradation, and two classical cannabinoid receptors: CB1 and CB2. The ECS components can be found in many tissues and cells at the central and peripheral level, and over-activity of the ECS has been observed in humans and animal models with obesity or T2D (Matias et al., 2006). It was therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity. For instance, Rimonabant, a CB1 blocker, was approved for obese and overweight patients with BMI >27kg/m2 and associated risk factors such as dyslipidemia or T2D. However, the presence of undesirable side effects, such as a higher tendency to commit suicide, forced its withdrawal from the human use (European Medicines Agency E, 2009, Bermudez-Silva et al., 2010). One of the more recently identified constituents of the ECS is the GPR55 receptor. GPR55 belongs to the G protein-coupled receptor (GPCR) family, and was firstly cloned by Sawzdargo et al. in 1999 (Sawzdargo et al., 1999). Although several agonists and antagonists of the classical receptors CB1 and CB2 exert actions through GPR55, L-α-lysophosphatidylinositol (LPI) is considered its putative endogenous ligand, and binding of LPI to GPR55 induces rapid phosphorylation of ERK and increases intracellular Ca2+ (Oka et al., 2007). During the last years, numerous publications have described the participation of GPR55 signaling in several physiological and pathophysiological processes including cancer, nociception or inflammation. The present review focuses primarily on the role of the GPR55 receptor in the metabolism of glucose, and synthesizes the evidence found from in vitro and in vivo studies.
GPR55 structure The human GPR55 gene resides on chromosome 2q37 and encodes for the GPR55 receptor, a 319 amino acid protein (Sawzdargo et al., 1999). This receptor shows higher homology with human chemokine receptors (CCR4, 23%), purinoceptors (P2Y5, 29%) and purinoceptor-like orphan receptors (GPR23, 30%; GPR35, 27%) (Sawzdargo et al., 1999) than with the classical cannabinoid CB1 and CB2 receptors (13% and 14%, respectively) (Elbegdorj et al., 2013). When comparing between species, it was revealed that human GPR55 gene sequence shares 75% and 78% homology with rat and mouse, respectively (Ryberg et al., 2007). An important difference respect to CB1 and CB2 is that GPR55 lacks the classical cannabinoid binding pocket. Instead, a GPR55 model in its active conformation showed a binding pocket with many hydrophilic residues (contrary to CB1 and CB2 binding pockets, which are highly hydrophobic), and that accommodates ligands that have inverted-L or T shapes and display long and thin profiles (Kotsikorou et al., 2011).
GPR55 expression, activation and turnover
Biological function
Possible medical applications In addition to the relevance of tissue-specificity, another importat aspect to be considered is the difference between species regarding GPR55 expression and signaling, making very difficult the translation of animal data to human research. And finally, the expanding literature on the expression of GPR55 in several types of human tumors as well as its role in metastasis (Andradas et al., 2016, Kargl et al., 2016, Falasca and Ferro, 2016) is also indeed a challenging handicap, even though the precise role of GPR55 in cancer is not clear yet. Nevertheless, despite presenting some obstacles to be overcome, these possible new strategies deserve further exploration as they might have a significant clinical impact in preventing and managing T2D.