br Funding This work was partially supported by the National

Funding This work was partially supported by the National Institute on Alcohol Abuse and Alcoholism, award R00AA021264, startup funds from the Department of Immunology, Herbert Wertheim College of Medicine, and the Office of Research and Economic Development at FIU, and pilot funds from Dr. Wertheim and Nicole Family Foundation, award # 9134 800010163.
Conflicts of interest
Acknowledgment
Cannabinoid Therapeutics for Obesity One physiological system that may be therapeutically exploited to control obesity is the endocannabinoid system (ECS). This system classically consists of two cannabinoid receptors (CB1 and CB2), two major endogenous ligands [2-arachidonyl glycerol (2-AG) and anandamide (AEA)], and the enzymes involved in the synthesis and breakdown of these ligands. The ECS plays a crucial role in both the central and peripheral control of body weight and food intake, affecting insulin sensitivity, glucose homeostasis, and fat accumulation [1]. Cannabinoid agonists increase the desire for and consumption of non-nutritious foodstuffs, an observation that led to development of a CB1 antagonist (Rimonabant) for treating obesity. Rimonabant, while clinically efficacious and initially hailed as a potential blockbuster, was removed from clinical use after only 2 years owing to adverse psychological effects, including suicidal ideation.
GPR55: A Cannabinoid- and Lipid-Sensitive Receptor The description of a third cannabinoid-sensitive receptor in 2007, called G protein-coupled receptor 55 (GPR55), brought the ECS again to the forefront with the hope of generating anti-obesity drugs that lacked the adverse effects of Rimonabant. GPR55 is a classical rhodopsin-like seven transmembrane GPCR that, despite showing cannabinoid sensitivity, shares less than 15% sequence identity with the cannabinoid receptors and lacks the classical cannabinoid binding pocket [2]. Human GPR55 shares approximately 80% sequence identity with rat and mouse orthologues and is found at high levels in human spleen, intestines, stomach, and HBC [2]. Research into GPR55 expanded rapidly but erratically, resulting in a rather confusing pharmacological profile. GPR55 certainly displays sensitivity to diverse cannabinoid compounds, including Rimonabant, but the most consistently described ligand is the endogenous lipid, lysophosphatidylinositol (LPI) [2]. Following a recent nomenclature review of lysophospholipid-sensitive receptors, GPR55 has been provisionally named LPI1. It is now understood that several of the previously described physiological effects of LPI are mediated via GPR55 [2]. GPR55 couples to Gα13 G-proteins to activate the small GTPase RhoA, mobilise Ca2+ release from intracellular stores, and activate multiple transcription factors [2].
Species-Specific Effects of GPR55 and LPI on Body Weight Although studies are scarce, recent evidence suggests that GPR55 might play a role in regulating human body weight. In a cohort of Japanese women, a Gly195Val missense polymorphism of GPR55 was associated with increased incidence of anorexia nervosa [3]. The Gly195Val mutation appeared to reduce–but not abolish–GPR55 function, although effects on receptor expression were not investigated [3]. A separate study investigated GPR55 expression and circulating levels of LPI in lean, obese and diabetic individuals. GPR55 in visceral fat correlated with higher body-fat percentage and overall weight, with the highest GPR55 levels being recorded in diabetic patients [4]. Circulating plasma LPI levels also correlated with body fat percentage and overall weight [4]. Interestingly, these associations were strong in female participants but weak or absent in males. There is so far no explanation for the difference, although sexual dimorphism is not uncommon in the regulation of energy homeostasis. Furthermore, LPI induced Ca2+ release in cultured primary adipocytes and increased the expression of genes involved in fat deposition in explants of visceral fat [4]. In summary, clinical and in vitro studies suggest that GPR55 activation by LPI might be linked to increased weight and fat deposition in humans, and pharmacological blockade of GPR55 may be beneficial in controlling excessive weight gain.