Drug Discovery Today  Volume 00, Number 00  July 2011 REVIEWS A potential role for GPR55 in the regulation of energy homeostasis Anna C. Simcocks 1 , Lannie O’Keefe 1 , Kayte A. Jenkin 1 , Michael L. Mathai 1,2 , Deanne H. Hryciw 3 and Andrew J. McAinch 1 1 Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, Melbourne 8001, VIC, Australia 2 The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia 3 Department of Physiology, The University of Melbourne, Melbourne 3010, VIC, Australia G protein-coupled receptor 55 (GPR55) is a putative cannabinoid receptor that is expressed in several tissues involved in regulating energy homeostasis, including the hypothalamus, gastrointestinal tract, pancreas, liver, white adipose and skeletal muscle. GPR55 has been shown to have a role in cancer and gastrointestinal inflammation, as well as in obesity and type 2 diabetes mellitus (T2DM). Despite this, the (patho)physiological role of GPR55 in cell dysfunction is still poorly understood, largely because of the limited identification of downstream signalling targets. Nonetheless, research has suggested that GPR55 modulation would be a useful pharmacological target in metabolically active tissues to improve treatment of diseases such as obesity and T2DM. Further research is essential to gain a better understanding of the role that this receptor might have in these and other pathophysiological conditions. Several G protein-coupled receptors (GPCRs) have been identified that might have a role in the pathophysiology associated with obesity [1]. Much research has focussed on the endocannabinoid system, because of its ability to modulate energy balance (reviewed in [2,3]). A putative GPCR associated with the endocannabinoid system is GPR55 [4]. This receptor might have a role in obesity by acting on peripheral metabolically active tissues, although little is known about the cell signalling pathways initiated by this receptor either under normal conditions or in disease. The endocannabinoid system as a pharmacological target for obesity The prevalence of obesity is increasing at epidemic rates worldwide [5]. The endocannabinoid system is a lipid-derived signalling system [2], which is overactive in the obese state [6,7]. The endo- cannabinoid system comprises at least two types of GPCR: canna- binoid receptor 1 (CB 1 ) [8] and cannabinoid receptor 2 (CB 2 ) [9]. CB 1 and CB 2 are expressed in several organs throughout the body, where they have been shown to be involved in regulating energy homeostasis [6]. Modulation of these receptors occurs via ligands known as ‘endocannabinoids’, including anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) [2]. The endocannabinoid system is responsible, in part, for the regulation of energy homeostasis, both centrally and peripherally via activation of cell-specific sig- nalling pathways [6]. Much of the understanding of this system has come from several studies focussed on CB 1 . A significant amount of research has demonstrated that activation of the CB 1 receptor by cannabinoid ligands stimulates food intake [10], reduces gastrointestinal moti- lity [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 CB 1 receptor has been demonstrated to improve these metabolic abnormalities [14]. CB 2 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 cells of the immune system [16]. Although the obese state is associated with chronic low-grade Reviews  POST SCREEN Corresponding author:. McAinch, A.J. (andrew.mcainch@vu.edu.au) 1359-6446/06/$ - see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2013.12.005 www.drugdiscoverytoday.com 1