GPR55: a New Promising Target for Metabolism?

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e tudurí and others GPR55 and metabolism 58: 3 R191–R202 Review

GPR55: a new promising target for metabolism?

Eva Tudurí1,2, Monica Imbernon1,2,3, Rene Javier Hernández-Bautista1,2,3, Marta Tojo1,2,3, Johan Fernø4, Carlos Diéguez1,2,3 and Rubén Nogueiras1,2,3

1Instituto de Investigaciones Sanitarias (IDIS), CIMUS, University of Santiago de Compostela, Santiago de Correspondence Compostela, Spain should be addressed 2CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain to E Tudurí or R Nogueiras 3Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain Email 4Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway [email protected] or [email protected]

Abstract

GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new Key Words cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral ff GPR55 tissues, this receptor has emerged as a regulator of multiple biological actions. ff adipose tissue Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of ff diabetes II GPR55. In this review, we will focus on the role of GPR55 in energy balance and ff cannabinoids glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to

treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed. Journal of Molecular Endocrinology (2017) 58, R191–R202 Journal of Molecular Endocrinology

The endocannabinoid system in energy balance

The endocannabinoid system (ECS) is involved in a wide such as the gastrointestinal (GI) tract, adipose tissue, liver range of biological processes that include psychological, and muscle (Ligresti et al. 2016). cardiovascular or respiratory functions. However, one of A significant amount of research has demonstrated the aspects that have attracted more attention over the that activation of the CB1 receptor by cannabinoid last years is undoubtedly its ability to modulate energy ligands stimulates food intake (Di Marzo & Matias 2005), metabolism. The best-characterized endocannabinoids reduces GI motility (Calignano et al. 1997) and increases are N-arachidonoylethanolamide (anandamide, AEA) and lipogenesis and steatosis in the liver (Osei-Hyiaman et al. 2-arachidonoylglycerol (2-AG), which exert their effects 2008). In addition, activation of CB1 increases lipogenesis by binding to the specific G-protein-coupled receptors and inflammation and reduces lipolysis, in the white CB1 and CB2 (Ligresti et al. 2016). These receptors are adipose tissue (WAT) (Silvestri & Di Marzo 2013). abundantly expressed throughout the central nervous Furthermore, CB1 activation impairs insulin sensitivity, system (CNS), including areas that control food intake as evidenced by reduced glucose uptake in the skeletal and energy expenditure (hypothalamus and brainstem) muscle (Esposito et al. 2008). CB1 is the main receptor of and reward-related responses (nucleus accumbens), as well the ECS involved in metabolic functions. Hence, selective as in peripheral tissues affecting metabolic homeostasis, inhibitors for this receptor have been developed, with the

10.1530/JME-16-0253 Journal of Molecular Endocrinology GPR55 distributionandfunctioninmain humanandrodentmetabolictissues. Figure 1 to interactwithandbemodulatedbyendogenous ( and 14%homologywithCB1CB2,respectively actions. ThesequenceofGPR55onlyexhibits13% suggesting itsinvolvementinmultiplebiological ‘Distribution ofGPR55inhumansandrodents’section), brain andperipheraltissues( G and antagonists( it interactswithsomecannabinoidreceptoragonists by GlaxoSmithKlineandAstraZenecarevealedthat cannabinoid receptorwhen receptor 55(GPR55)wasinitiallyidentifiedasanovel 2007 stimulus ( cannabinoid receptorthatrespondstothe CB1 and/or CB2 have shown that there is an additional either CB1andCB2agonistsknock-outmicefor consequences ofCB1andCB2activation,studiesusing Although thereisagoodunderstandingofthe GPR55: aputative cannabinoid receptor discontinued becauseofitspsychiatricsideeffects. approved asanti-obesitytherapy, althoughitwaslater CB1 inverseagonistSR141716Apyrazole(Rimonabant) Elbegdorj DOI: 10.1530/JME-16-0253 http://jme.endocrinology-journals.org α Review 12/13 ). Theseven-transmembraneG-protein-coupled andG Begg t al. et q proteinsandiswidelyexpressedinboth et al. 2013 Baker 2005 ). However, ithastheability t al et , Baker in silico . 2006 Ross 2009 et al. e

( accumbens, caudatenucleus,striatumandputamen of thehumanbrainincludinghypothalamus,nucleus have beenreported. species needtobecarefullyconsidered as somedifferences ( 78% homologywiththehumansequence,respectively rat andmouse information regardingGPR55proteinlevels.Inaddition, identified indetail( The distributionof Distribution ofGPR55inhumansandrodents of thoseligands( could beresponsibleforthenon-CB1/CB2receptoreffects small syntheticcannabinoidligands;therefore,GPR55 (phytocannabinoids) and (endocannabinoids), plant hypothalamus, cerebellumandstriatum( in hippocampus,thalamus,forebrain,frontalcortex, rodent CNSalsoshowedawideexpression addition, thereisevidencethatGPR55expressedatthe in monkeystriatum( Díaz 2011 GPR55 andmetabolism Sawzdargo Ryberg Published byBioscientifica Ltd. The GPR55receptorispresentinmultipleareas , et al. Sylantyev et al 2016 et al. . 2007 ), andGPR55mRNAhasalsobeenfound t al. et 1999 Gpr55 Baker ), sotheresultsderivedfromdifferent Gpr55 , 2013 genesequenceshare75%and i. 1 Fig. et al Martinez-Pinilla Henstridge Downloaded fromBioscientifica.com at09/27/202106:40:29PM mRNAexpressionhasbeen . 2006 , ); however, thereisless Wu , t al. et et al. Ryberg 58 t al. et 2011 : 2013 3 et al Gpr55 Chiba ). Studiesin 2014 . 2007 , Méndez- mRNA t al. et R192 ). In ). via freeaccess

Review e tudurí and others GPR55 and metabolism 58:3 R193

protein level in the dorsal root ganglia neurons, where was also detected throughout lifespan, as well as in its activation enhances the excitability of sensory neurons ovariectomized rats. In contrast, WAT Gpr55 decreased (Lauckner et al. 2008). during gestation, possibly as a result of enhanced leptin At the peripheral level, Gpr55 is widely distributed. levels, as well as after orchidectomy (Imbernon et al. Several reports detected Gpr55 expression throughout 2014). Thus, rodent WAT Gpr55 expression is modulated the GI in both human (Henstridge et al. 2011) and by nutritional status, gonadal steroids, gestation, rodents (Ryberg et al. 2007, Lin et al. 2011, Schicho et al. postnatal development and pituitary factors. GPR55 is 2011, Schicho & Storr 2012, Li et al. 2013). The gene also expressed in both human and mice oscteoclasts and expression pattern differs between areas, with higher osteoblasts, and GPR55 agonists favor in vitro osteoclasts levels in mouse jejunum and ileum than those in resorption (Whyte et al. 2009). In addition, GPR55 is colon or stomach (Ryberg et al. 2007). Apart from also present in cell lines derived from human bone and being found in the submucosa (Lin et al. 2011), Gpr55 cartilage sample (Henstridge et al. 2011). Human immune is also expressed in neurons from the myenteric plexus cells express GPR55, indicating it could be implicated (Lin et al. 2011, Li et al. 2013) pointing to a possible role in chemotaxis, although this is still under investigation of Gpr55 in GI physiological functions such as motility (Balenga et al. 2011, Henstridge et al. 2011). GPR55 has and secretion. Gpr55 mRNA has also been described in also been detected in other organs and tissues such as the liver of humans (Moreno-Navarrete et al. 2012) and placenta, proximal tubule cells of kidney and mast cells mice (Romero-Zerbo et al. 2011); however, the hepatic (with unknown functions) (Henstridge et al. 2011). function of the LPI/GPR55 system is still unknown. In the pancreas, both human (Song et al. 2012) and The complex pharmacology of GPR55 (ligands and rodent (Romero-Zerbo et al. 2011, McKillop et al. 2013) interactions with CB1/CB2 agonists/antagonists) islets express GPR55 as indicated from gene and protein (special focus on LPI, the endogenous ligand) expression studies. Furthermore, immunohistochemical analysis of rat and mouse pancreas sections showed GPR55 Although we are starting to learn the biological functions expression specifically in insulin-secretingβ -cells, but of GPR55, achieving a good understanding is quite not in glucagon- or somatostatin-releasing α- and δ-cells, difficult due to the lack of functional selectivity within respectively (Romero-Zerbo et al. 2011, McKillop et al. the pharmacology of this receptor (Ross 2009) (Table 1). 2013). Very recently, the presence of GPR55 in few mouse The effects of cannabinoids through GPR55 have been glucagon-secreting cells and in a major portion of human investigated using different pharmacological approaches Journal of Molecular Endocrinology α-cells has been reported (Liu et al. 2016). Regarding the such as the [35S]GTPγS-binding assay (measurement of adipose tissue, both GPR55 protein and mRNA have been GPR55 agonist-induced GDP–GTP exchange as an indicator detected in human and rodents. The expression of GPR55 of receptor activation), intracellular Ca2+ transients, in human WAT was firstly reported by Moreno-Navarrete phosphorylation of ERK or activation of GTPase proteins and coworkers (Moreno-Navarrete et al. 2012). When and β-arrestin recruitment models (Oka et al. 2007, comparing obese and lean subjects, the authors observed 2009, Ryberg et al. 2007, Lauckner et al. 2008, Waldeck- increased GPR55 expression in visceral adipose tissue Weiermair et al. 2008, Henstridge et al. 2009, Kapur et al. (VAT) from obese patients, with the highest level in those 2009, Ross 2009, 2011, Pertwee et al. 2010, Whyte et al. who also had type 2 diabetes (T2D). A similar pattern 2015, Zeng et al. 2015). Moreover, in vivo studies was detected in human subcutaneous adipose tissue have allowed a better knowledge of the physiological (SAT). Accordingly, plasma LPI levels were also higher in relevance of GPR55 signaling in processes such as energy obese patients compared to those in lean subjects and metabolism (Romero-Zerbo et al. 2011, Diaz-Arteaga et al. correlated with fat percentage and BMI in women. A 2012, Moreno-Navarrete et al. 2012, Imbernon et al. 2014), recent study reported that a number of factors regulate inflammation Staton( et al. 2008), vascular function rodent WAT Gpr55 expression. Imbernon and coworkers (Daly et al. 2010), bone physiology (Whyte et al. 2009), showed increased WAT Gpr55 after fasting, which was cancer (Perez-Gomez et al. 2012, Andradas et al. 2016) and reversed after refeeding and also after leptin treatment GI disorders (Hasenoehrl et al. 2016). Taking into account (Imbernon et al. 2014). The measurements of circulating the large amount of physiological systems in which GPR55 LPI showed the inverse pattern to that observed for the is involved, the design of potent and tissue-specific GPR55 receptor expression. Augmented WAT Gpr55 expression ligands remains an important field to develop new drugs.

DOI: 10.1530/JME-16-0253 http://jme.endocrinology-journals.org Review −/− mice −/− +/+ −/− −/− −/− −/− −/− −/−

mice mice mice mice mice mice mice mice Effects ofGPR55agonists/antagonistsondifferent metabolicparametersfrom

Drug O-1602 CBD AM-251 O-1602 AM-251 Abn-CBD CID16020046 O-1602 O-1602 O-1602 Abn-CBD Abn-CBD O-1602

GPR55 Action on Action on Agonist Agonist Agonist Antagonist Agonist Agonist Agonist Agonist Agonist Agonist Agonist Antagonist Agonist

andothers and CB2 for GPR55,CB1 EC 13, 39 nM 2.5, 0.21 µM,−,− 13, 13, 13, 2.5, 2.5, 13, 13, 0.445, 3.35, 39 nM,−,− > > > > > > 27.5 µM Printed inGreatBritain 50 30,000 nM 30,000 nM 30,000 nM 30,000 nM 30,000 nM 30,000 nM > > > > > > /IC > > > 30,000, 30,000, 30,000, 30,000, 30,000, 30,000, 30, 30, 30, 50 values > > > 30 30 30

μ μ μ M M M administ. Dose/route i.p. 0.1 µmol/kg, i.p. 0.1 µmol/kg, 10 i.p. 10 mg/kg, i.p. 0.5 mg/kg, i.p. 0.1 mg/kg, mlk, i.p. 0.1 µmol/kg, i.p. 0.1 µmol/kg, i.p. 0.1 µmol/kg, i.p. 20 mg/kg, 0.1–30 i.p. 10 mg/kg, i.p. 200 µg/kg, g i.c.v. 10 µg

mg/kg, i.p.or GPR55 andmetabolism μ Published byBioscientifica Ltd. mol/L

Main outcomes Unchanged energy No effects onGSISor Increased GSISand No effects onlocomotor Slowed wholegut No effects onwholegut No effects onwholegut Increased GSISad Increased GSISad Increased GSISad Improved intestinal Reduced inhibitionof No changesingut Increased foodintake Less severe Small impairmentof intake andfeeding glucose tolerance tolerance improved glucose activity emptying effect ongastric bead expulsion,no transit andcolonic propulsion transit orcolonic propulsion transit orcolonic tolerance improved glucose tolerance improved glucose tolerance improved glucose activity unchanged locomotor leukocyte recruitment, cytokines and proinflammatory decreased inflammation, contractions neurogenic bead expulsion transit andcolonic (DSS) colitis dextran sulfatesodium inflammation during glucose tolerance tolerance andGSIS normal glucose physical activity, and resistance, decreased mass andinsulin pattern, increasedfat in vivo Downloaded fromBioscientifica.com at09/27/202106:40:29PM studies. Ref. Meadows McKillop McKillop Li Li Li Li McKillop McKillop McKillop Stan Ross Li Diaz-Arteaga Stan Song 58 (2012) et al et al et al et al et al : 3 č č et al i i et al ć ć . (2013) . (2013) . (2013) . (2013) . (2013)

et al et al . (2012) et al et al et al et al et al . (2012) (Continued) et al . (2015) . (2015) . (2013) . (2013) . (2013) et al . (2016) . (2016) R194 . (2016) . via freeaccess

Review e tudurí and others GPR55 and metabolism 58:3 R195

Table 1 Continued.

Action on EC50/IC50 values Action on for GPR55, CB1 Dose/route Animal model Drug GPR55 and CB2 administ. Main outcomes Ref. NIH Swiss mice OEA Agonist 0.44, 30, 30 µM 0.1 µmol/kg, i.p. Increased GSIS ad McKillop et al. (2013) improved glucose tolerance NIH Swiss mice PEA Agonist 4, 30,000, 0.1 µmol/kg, i.p. No significant McKillop et al. (2013) 19,800 nM differences in either GSIS or glucose tolerance STZ-mice Abn-CBD Agonist 2.5, >30, >30 μM 0.1 µmol/kg/day, Reduced food intake, no McKillop et al. (2016) oral changes in body weight, lowered blood glucose and plasma glucagon, increased plasma insulin and pancreatic insulin content, improved glucose tolerance and insulin sensitivity, and decreased cholesterol and triacylglycerol Sprague– O-1602 Agonist 13, >30,000, 0.1–0.5 µg, i.c.v. Increased food intake, Diaz-Arteaga et al. Dawley rats >30,000 nM decreased CART mRNA (2012) and protein levels Sprague– O-1602 Agonist 13, >30,000, 2–200 µg/kg, i.p. Transiently increased Diaz-Arteaga et al. Dawley rats >30,000 nM food intake (2012) Sprague– O-1602 Agonist 13, >30,000, 0.04–0.4 µg/h, Reduced WAT GLUT1 Diaz-Arteaga et al. Dawley rats >30,000 nM i.c.v. and GLUT4 mRNA (2012) levels, increased fat mass change Sprague– O-1602 Agonist 13, >30,000, 0.1 mg/kg/day, i.p. Unchanged food intake Diaz-Arteaga et al. Dawley rats >30,000 nM and body weight gain, (2012) increased fat mass, decreased WAT ATGL and increased WAT IL-6 Journal of Molecular Endocrinology mRNA levels Wistar rats O-1602 Agonist 13, >30,000, 0.2 mg/kg, i.p. Improved glucose Romero-Zerbo et al. >30,000 nM tolerance, increased (2011) GSIS

Endocannabinoids The main endocannabinoids AEA (PEA), virodhamine and oleoylethanolamide (OEA) and 2-AG, that bind to both CB1 and CB2 receptors, are are endogenous lipids that have also been reported to synthesized and released ‘on demand’, a process that modulate GPR55 signaling (Ryberg et al. 2007). Yet, can be regulated by both physiological and pathological even though PEA and virodhamine display high affinity conditions (Fowler et al. 2005). The activation of GPR55 for GPR55 (Ryberg et al. 2007), they failed to elicit Ca2+ by the ‘classical’ endocannabinoids shows controversial responses (Lauckner et al. 2008). results, and there is no consensus in how AEA modulates GPR55 signaling due to the diversity of pathways that Phytocannabinoids and synthetic canna can be activated by this ligand (Ross 2009). In human binoids Phytocannabinoids (cannabinoids naturally embryonic kidney 293 (HEK293) cells transiently occurring in the cannabis plant) do not only exert their expressing GPR55, AEA induces Ca2+ mobilization actions through CB1 and CB2 receptors. Reportedly, (Lauckner et al. 2008, Waldeck-Weiermair et al. 2008). the main pharmacoactive component of cannabis, Δ9- However, the concentration of AEA necessary to activate tetrahydrocannabinol (Δ9-THC), acts as a GPR55 agonist GPR55 is much higher than normally required to activate mediating intracellular Ca2+ transients (Ryberg et al. 2007, the CB1 receptor (Pertwee 2007, Brown & Robin Hiley Lauckner et al. 2008), although another report showed no 2009, Ross 2009). Noladin-ether, palmitoylethanolamine activation of ERK signaling by Δ9-THC (Oka et al. 2007).

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0253 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 06:40:29PM via free access Journal of Molecular Endocrinology and HEK293 cells expressing human GPR55 ( without inducinganyeffectviaCB1orCB2,inbothyeast synthesized compoundthatselectivelyinhibitsGPR55 Weiermair Ca JWH015 andAEA,whichforinstancetriggerintracellular responses inducedbyotheragonistcompoundssuch as Rimonabant iscapableofblockingtheGPR55signaling ( protein biosensor conferred Rimonabant agonist activity GPR55 ( its structuralanalogueWIN55212failedtoactivate transients ( in different cell types, modulating intracellular Ca CB2 receptoragonistJWH015activatesGPR55signaling receptors alsoseemtomodulatetheGPR55signaling.The cannabinoids withpotenteffectsoverCB1and/orCB2 ( studies suggestedthatCBDmayactasGPR55antagonist Weiermair synthetic analogueO-1602( for thesyntheticΔ Several studies have reported GPR55 agonist activity contribute totherationaldesignofnewGPR55ligands. motifs involvedintheligand–GPR55interactionand & Jagerovic2016 of thosenewsyntheticcompounds(reviewedin 2011 using differentpharmacologicalapproaches( todevelopnewdrugstargetingGPR55 studies trying agonists or antagonists. In this sense, there are some structure andsignaling,itisdifficulttosynthetizespecific different one( Ryberg GPR55 activation by thiscompound ( psychoactive cannabidiol(Abn-CBD);twostudiesreported This discrepancyalsooccurswiththeabnormalnon- AM251-induced GPR55signaling incancercelllines as apotentGPR55inhibitor, blocking both O-1602-and methoxy-1-naphthylfenoterol (AMF),hasbeendescribed 2013 obtained whenusinga affinity for GPR55 ( 2007 of GPR55andmodulatesCa effects throughGPR55.AM251isahigh-affinityligand strong antagonistsoftheCB1receptor, showdiverse 2008 Whyte Kapur DOI: 10.1530/JME-16-0253 http://jme.endocrinology-journals.org Review 2+ Due tothecomplexityofGPR55-bindingpocket transients( , ). Inaddition,a , ). Finally, thesyntheticcannabinoidspyrazoles, Heynen-Genel Henstridge et al et al Oka t al et et al Oka . 2009 . 2007 t al et et al . 2009 Lauckner . 2008 et al . 2007 . 2008 ). However, ithasalsobeenreportedthat ) arehelpingtoelucidatethestructural ), whereasitfailedtomobilizeCa t al et 9 . 2007 Lauckner -THC analogueHU210,CBDandits et al. , , Ryberg Oka Li , . 2009 et al β Ryberg ). CID-16020046isarecently 2-adrenergic agonist,( 2011 , t al et et al Lauckner . 2008 β Ryberg t al et -arrestin–green fluorescent 2+ ), whereasAM281hasno . 2009 , . 2013 t al et et al transients( Morales e . 2007

tudurí ). © 2017SocietyforEndocrinology . 2007 ). However, twoother et al et al . 2008 ). Othersynthetic andothers Johns et al. ). The outcomes . 2008 . 2007 , Printed inGreatBritain Lauckner Ryberg t al. et 2016 , Brown ); however, Kargl , Waldeck- Waldeck- R Morales , ). Most R 2007 2+ et al. et al. ′ t al et )-40- et al ina 2+ , . .

cancer ( cancer cells( asanautocrinefactorin postulated thatLPImightserve and cell migration and proliferation; therefore, it has been and thereisacloserelationbetweentheLPI/GPR55system oncogene arecapableofreleasingLPI( GPR55 ( in patientswhoseglioblastomasexpresshigherlevels of islower and theiraggressiveness,patientsurvival expression in human breast and glioblastoma tumors contrary, thereisanegative correlationbetweenGPR55 content inascitesandserum( between themalignancyofovariancancerandLPI ( main factorsindrivingcellproliferationandmigration effects isanobjectofresearch. Nowadays, howGPR55contributestotheseLPI-mediated endothelial cells ( 1988 D3-modulating Ca release ( associated to LPI such as being an inductor of insulin ligand ofGPR55,relevantbiologicalfunctionshadbeen osteoclasts expressingnativeGPR55( 2009 intracellular Ca 2009 ( a findingthatwascorroboratedinsubsequentstudies Ca ofERKandincreasedintracellular rapid phosphorylation In 2007,OkaandcoworkersdetailedthatLPIinduced recombinant GPR55( have alsobeendescribedincellsexpressinghuman A protein (RhoA) activation and ERK phosphorylation, ligand of GPR55 based on Recently, LPIhasbeenproposedastheendogenous coupled receptors( Lapetina 1982 and Ca action oftheCa generated byphosphatidylinositolhydrolysisviathe ligand ofGPR55 Lysophosphatidylinositol (LPI): theendogenous carcinogenic cells( ( GPR55 andmetabolism Ross 2011 Lauckner Paul Published byBioscientifica Ltd. 2+ Recent evidencerevealsthatbothLPIandGPR55are Previous tothedescriptionofLPIasendogenous inGPR55-expresingHEK293cells( ) andamitogenicmodulatorinbothneuron , , t al. et Oka Oka Tonyali Andradas 2+ Metz 1986 -independent phospholipaseA1( et al et al ). Clinicaldatashowedapositivecorrelation 2014 t al et Ross 2011 . 2008 . 2009 ) andinteractswithspecificG-protein- et al. 2+ . 2009 ) andreducingthechemoresistanceof metabolism,requiring Ras homologue et al. Falasca 2+ Ishii Singh 2+ -dependent phospholipaseA2(19)

2010 ), amediatorofhepaticvitamin metabolism( ) and in cultured human and mouse , Ryberg ). SimilareffectsofLPI/GPR55on 2011 Henstridge LPI isalipidsignalingmolecule et al. ), withspecialrelevancein bone et al. Downloaded fromBioscientifica.com at09/27/202106:40:29PM et al. , Pineiro ). Cellstransformedbytheras 2004 in vitro et al Sutphen 2016 1995 . 2007 , et al et al. Arifin &Falasca2016 ). Baran &MarieKelly and , Whyte et al. 58 . 2009 Corda Falasca 2011 , : Oka 3 Henstridge in vivo 2004 et al. , et al , et al. et al Kapur Ross 2011 Billah & ). Onthe . 2009 studies. . 2007 2002 1998 R196 et al et al ). via freeaccess ). ), ). ), ). . . Review e tudurí and others GPR55 and metabolism 58:3 R197

Given the increasing evidence linking LPI/GPR55 and obesity. In addition, the chronic i.c.v. infusion of O-1602 obesity and cancer (Calle & Kaaks 2004, Basen-Engquist increases adiposity in rats by inhibiting lipolytic genes & Chang 2011), it will be important to know the precise and independently of food intake (Diaz-Arteaga et al. mechanisms regulated by the GPR55 pharmacology in 2012), although it remains unclear whether this effect is both diseases. mediated by GPR55 or by another unidentified receptor.

Metabolic actions of GPR55 Metabolic actions of GPR55 in WAT

Metabolic actions of GPR55 in the CNS Due to the high activity of the ECS in VAT of T2D patients (Di Marzo 2008), the LPI/GPR55 system has Given its extensive distribution in the brain, GPR55 been studied in detail in WAT. Reportedly, LPI induced participates in a number of physiological processes that the expression of lipogenic genes and peroxisome include movement coordination and motor activity proliferator-activated receptor γ (PPARγ) in human VAT (Wu et al. 2013, Bjursell et al. 2016), nociception (Deliu et al. explants, and further experiments with differentiated 2015), modulation of anxiety-like behaviors (Rahimi et al. adipocytes from VAT of obese patients displayed 2015), as well as energy expenditure (Bjursell et al. 2016, increased intracellular Ca2+ in response to LPI (Moreno- Meadows et al. 2016) (Fig. 1). Energy homeostasis is Navarrete et al. 2012), which could be related to mainly determined by the balance between energy intake increased lipogenic activity (Gericke et al. 2009). All (from food ingestion) and energy expenditure (from basal these results suggest that GPR55 signaling is positively metabolic rate, thermogenesis and physical activity). To associated with human obesity; hence, pharmacological decipher the effects of central GPR55 signaling on food blockade of GPR55 could be a therapeutic approach to consumption, a number of pharmacological studies control excessive weight gain. have been performed in animal models; however, many In contrast to the observations made in humans, of them employed cannabinoid receptor/lipid biased studies performed in animal models show a different compound libraries, which lead to lack of receptor participation of GPR55 in adipose tissue metabolism selectivity (Kotsikorou et al. 2013). For instance, rats (Table 1). Genetic GPR55 ablation leads to increased that followed a treatment with CBD displayed reduced adiposity (Meadows et al. 2016) and, accordingly, obese body weight gain and food intake; however, those effects rodent models including mice lacking leptin (ob/ob mice) were not detected when animals also received AM630, a and rats fed a high-fat diet (HFD) showed decreased WAT

Journal of Molecular Endocrinology selective CB2 antagonist, suggesting that the CB2 receptor GPR55 expression (Moreno-Navarrete et al. 2012). Such might be involved in the outcomes previously observed potentiation of adiposity may result, at least in part, from (Ignatowska-Jankowska et al. 2011). Similarly, although reduced physical activity (Meadows et al. 2016); however, the intracerebroventricular (i.c.v.) administration of the other factors might also be involved. Díaz-Arteaga and atypical cannabinoid O-1602 acutely stimulates food coworkers showed decreased mobilization of fatty acids intake in rats, a parallel experiment performed in GPR55−/− after either central or peripheral sub-chronic O-1602 mice revealed that effect of O-1602 on food consumption treatment in rats (Diaz-Arteaga et al. 2012). In agreement, was independent of GPR55 (Diaz-Arteaga et al. 2012). O-1602 increased the intracellular Ca2+ levels and lipid Moreover, Gpr55−/− mice did not exhibit different food accumulation in 3T3-L1 cells (Diaz-Arteaga et al. 2012). intake compared to their control littermates (Bjursell et al. Given that O-1602 is capable of triggering signals through 2016, Meadows et al. 2016). Nonetheless, the fact that a various receptors, it remains to be determined whether dysfunctional alteration of the Gpr55 gene is associated GPR55 mediated such effects. to increased vulnerability to anorexia nervosa in Japanese women, suggests that Gpr55 plays a role in the regulation Metabolic actions of GPR55 in the of feeding behavior (Ishiguro et al. 2011). gastrointestinal (GI) tract Although the extent to which GPR55 modulates food consumption is unclear, phenotyping studies using Physiological studies show that activation of GPR55 Gpr55−/− mice showed decreased energy expenditure resulted in the inhibition of the neurogenic contractions and spontaneous locomotor activity, which results in in the mouse intestine (Ross et al. 2012) and are also increased fat mass and leptin levels, as well as in insulin involved in colon motility (Lin et al. 2011, Li et al. 2013). resistance (Meadows et al. 2016) (Table 1), a trend toward For instance, O-1602 reduced contractions in muscle

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0253 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 06:40:29PM via free access Journal of Molecular Endocrinology diabetic mice( and pancreaticinsulincontent instreptozotocin-induced glucose andplasmaglucagon andincreasedplasmainsulin agonist forGPR55( daily oraladministrationof Abn-CBD,apotentselective GPR55 antagonist( insulin secretionisdetectedafterexposureofthecellsto a display greaterinsulinrelease,whereasinhibition of with arangeofGPR55agonistsatdifferentconcentrations agreement, glucose-responsiveBRIN-BD11cellsstimulated both the first and second phases ( with GPR55ligandsalsopotentiatesinsulinlevelsduring 2011 increases intracellularCa such effect.TheexposureofrodentisletstoGPR55agonists but onlyrecentlyitwasdemonstratedthatGPR55mediates insulin secretionhadbeenpreviouslyreported( consequently, inglucosehomeostasis.Infact,LPI-induced of GPR55intheregulationinsulinsecretion,and The presenceofGPR55in Metabolic actionsofGPR55intheisletsLangerhans human GIisstillunknown. boweldisease,thefunctionofGPR55in inflammatory for thedevelopmentofnewtherapeuticstrategiestotreat GPR55 ininflammation( fromrodentstudiessuggestingaroleof the observations receptors ( effects wereindependentlyoftheCB1,CB2andGPR55 experimentally inducedcolitis,itwasdeterminedthatits O-1602 hasbeenshowntobeprotectiveagainst recruitment tothecolon( cytokinesandleukocyte and todecreaseproinflammatory 16020046 was showntoimprove intestinal inflammation the administrationofGPR55antagonistCID- their controllittermates( susceptibility tointestinalinflammationcompared that from theobservations of GPR55inGIinflammationhasalsobeenproposed independently ofCB1andCB2( neurogenic contractionsinthegutthroughGPR55and ( bead expulsioninWTmicebutnot injections ofO-1602slowedwholeguttransitandcolonic ( reversed byCBDanddidnotoccurinmicelackingGPR55 gut transitandcolonicbeadexpulsion;effectsthatwere strips fromthecolonandileum,whichslowedwhole resulting inenhancedinsulinsecretion( Li Li DOI: 10.1530/JME-16-0253 http://jme.endocrinology-journals.org Review t al et t al et , McKillop . 2013 . 2013 Schicho ). Moreover, O-1602wasfoundtoreduce et al ). Inaddition,intraperitonealandi.c.v. McKillop . 2013 McKillop McKillop t al et 2+ ). The stimulation of human islets ). Thestimulationofhumanislets . 2011 Stan Table 1 concentration and cAMP levels, concentrationandcAMPlevels, t al et Stan β -cells suggest a potential role -cells suggestapotentialrole et al Gpr55 č t al et i ć č 2016 . ). Unfortunately, despite

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normal glucosetolerancein ( lacking GPR55 onglucosemetabolism( studies employing ( glucose loadandimprovedtoleranceinrodents of GPR55agonistsstimulatedinsulinsecretionaftera 2011 after stimulation with O-1602 ( to increase glucose-stimulated insulin secretion (GSIS) was confirmedinisletsfrom detected ( consumption, thoughnoeffectonoverallbodyweightwas 2016 and triacylglycerolweredecreased( sensitivity weremarkedlyimproved,andtotalcholesterol administration ofAbn-CBD,glucosetoleranceandinsulin show differentresults( -independent manner. GPR55, mayplayactionsin both aGPR55-dependentand not all, the compounds that are assumed to be specific for been madeduringthelastyears,butitseemsthatmost, if great progressinthedevelopmentofnewcompoundshas mechanisms may be independent of GPR55. Indeed, a even thoughsometimestheyaffecttheseparameters,the food intake,gastrointestinalmotilityorbodyweightand, agonists/antagonists donotshowaconsistentactionon are reflectedbythefactthatsupposedspecificGPR55 potential translationofpreclinicaldata.Thesedifficulties dependent manner, makesitdifficulttounderstandthe and second,thefactthatitisregulatedinaspecies- that first,hasanextremelycomplicatedpharmacology because wearefacingaG-protein-coupledreceptor GPR55. Themainreasonsforthisarelikelyexplained being challengedbythedifficultiesthatimplytargeting aroused greatinterest.However, theinitialenthusiasmis of analternativecannabinoidreceptorhaslogically system intermsofmetabolicsyndrome,thediscovery Given theclinicalrelevanceofendocannabinoid Future perspectives differences reportedintheseanimals. factor/s (i.e. age, gender, strain…) responsible for the methodological informationimpedestodecipherthe differences inGSIS( Song GPR55 andmetabolism Song Romero-Zerbo Published byBioscientifica Ltd. The participationofGPR55intheoutcomesobtained Although findingsobtained inmice lacking ). In this report, the GPR55 agonist decreased food ). Inthisreport,theGPR55agonistdecreasedfood ). Inaddition,acuteintraperitonealadministration et al et al Gpr55 . 2012 McKillop . 2012 showedslightlyimpairedglucosetolerance , et al McKillop ), whereasamorerecentreportshowed Gpr55 et al . 2011 Meadows . 2016 −/− Downloaded fromBioscientifica.com at09/27/202106:40:29PM , et al McKillop micereportdifferenteffectsof Romero-Zerbo ). . 2013 Gpr55 t al et Gpr55 al 1 Table , −/− Romero-Zerbo et al . 2016 2016 mice,whichfailed 58 −/− . 2013 : McKillop micewithno 3 ). Miceglobally ), themostsolid ). Thelackof t al et ). However, . 2011 R198 t al et Gpr55 t al et via freeaccess . . ,

Review e tudurí and others GPR55 and metabolism 58:3 R199

data are probably coming from the pancreas, where GPR55 Balenga NA, Aflaki E, Kargl J, Platzer W, Schroder R, Blattermann S, is expressed in both human and rodent -cells and GPR55 Kostenis E, Brown AJ, Heinemann A & Waldhoer M 2011 GPR55 β regulates cannabinoid 2 receptor-mediated responses in human agonists have an insulinotropic action. This consistency neutrophils. Cell Research 21 1452–1469. (doi:10.1038/cr.2011.60) is strengthened by the fact that the LPI/GPR55 system Baran DT & Marie Kelly A 1988 Lysophosphatidylinositol: a potential has a potential role in human type 2 diabetes (Moreno- mediator of 1, 25-dihydroxyvitamin D-induced increments in hepatocyte cytosolic calcium. Endocrinology 122 930–934. Navarrete et al. 2012). Thus, the therapeutic potential of (doi:10.1210/endo-122-3-930) agonizing GPR55 for the treatment of T2D is currently Basen-Engquist K & Chang M 2011 Obesity and cancer risk: recent very attractive. However, we must take these emerging review and evidence. Current Oncology Reports 13 71–76. (doi:10.1007/s11912-010-0139-7) data with caution because even if GPR55 agonists have Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J positive effects on insulin secretion and sensitivity, those & Kunos G 2005 Evidence for novel cannabinoid receptors. compounds will target many different tissues due to the Pharmacology and Therapeutics 106 133–145. (doi:10.1016/j. pharmthera.2004.11.005) wide expression of GPR55. For instance, GPR55 agonists Billah M & Lapetina E 1982 Formation of lysophosphatidylinositol in will reach a large number of brain areas, and therefore, platelets stimulated with thrombin or ionophore A23187. Journal of it is plausible to hypothesize that these compounds will Biological Chemistry 257 5196–5200. Bjursell M, Ryberg E, Wu T, Greasley PJ, Bohlooly YM & Hjorth S 2016 exert off-target effects. Thus, the design and validation Deletion of Gpr55 results in subtle effects on energy metabolism, of GPR55 agonists with tissue-specific action might be motor activity and thermal pain sensation. PLoS ONE 11 e0167965. an important issue to investigate in further studies. In (doi:10.1371/journal.pone.0167965) Brown AJ & Robin Hiley C 2009 Is GPR55 an anandamide receptor? any case, the full characterization of the different actions Vitamins and Hormones 81 111–137. (doi:10.1016/s0083- of GPR55 in energy balance and glucose metabolism 6729(09)81005-4) is prompting a new and exciting, but also complex, Brown AJ, Daniels DA, Kassim M, Brown S, Haslam CP, Terrell VR, Brown J, Nichols PL, Staton PC, Wise A, et al. 2011 Pharmacology of pharmaceutical target. GPR55 in yeast and identification of GSK494581A as a mixed- activity glycine transporter subtype 1 inhibitor and GPR55 agonist. Journal of Pharmacology and Experimental Therapeutics 337 236–246. 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29 (1Supplement) andothers Printed inGreatBritain Zeng Y, Irvine R & Hiley C 2015Biasedsignallingmightbetheanswer &Hiley C Zeng Y, Irvine R Accepted Preprint published online 14 February 2017 Accepted Preprintpublishedonline14February 2017 Accepted 14February 2017 Received infinalform30January GPR55 andmetabolism Published byBioscientifica Ltd. content/29/1_Supplement/772.7 (1 Supplement)772.7.(availableat: to theinconsistentpharmacologyofGPR55. pone.0060314) coordination. coupled receptorforlysophosphatidylinositol,playsaroleinmotor PLoS ONE

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