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        PUFA-derived endocannabinoids: an overview
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Abstract

Following on from the discovery of cannabinoid receptors, of their endogenous agonists (endocannabinoids) and of the biosynthetic and metabolic enzymes of the endocannabinoids, significant progress has been made towards the understanding of the role of the endocannabinoid system in both physiological and pathological conditions. Endocannabinoids are mainly n-6 long-chain PUFA (LCPUFA) derivatives that are synthesised by neuronal cells and inactivated via a two-step process that begins with their transport from the extracellular to the intracellular space and culminates in their intracellular degradation by hydrolysis or oxidation. Although the enzymes responsible for the biosynthesis and metabolism of endocannabinoids have been well characterised, the processes involved in their cellular uptake are still a subject of debate. Moreover, little is yet known about the roles of endocannabinoids derived from n-3 LCPUFA such as EPA and DHA. Here, I provide an overview of what is currently known about the mechanisms for the biosynthesis and inactivation of endocannabinoids, together with a brief analysis of the involvement of the endocannabinoids in both food intake and obesity. Owing to limited space, recent reviews will be often cited instead of original papers.

By definition, endocannabinoids are derivatives (amides, esters and ethers) of a long-chain PUFA, specifically arachidonic acid, capable of binding and functionally activating the cannabinoid receptors( Reference Di Marzo, Bifulco and De Petrocellis 1 ). It was 1992 when the first endocannabinoid was isolated from brain and named anandamide (from Sanskrit word ananda ‘supreme joy’)( Reference Devane, Hanus and Breuer 2 , Reference Hanus 3 ). This is the ethanolamide of arachidonic acid, and is thought to be a partial CB1 and CB2 receptor agonist as well as a transient receptor potential vanilloid (TRPV)1 receptor agonist( Reference Devane, Hanus and Breuer 2 , Reference Di Marzo, Bisogno and De Petrocellis 4 Reference Al-Hayani, Wease and Ross 6 ). The other widely investigated endocannabinoid, 2-arachidonoyl-glycerol (2-AG), is the arachidonate ester of glycerol that was isolated from peripheral tissues. This molecule is able to activate CB1 and CB2 receptors with similar potency and efficacy( Reference Mechoulam, Ben-Shabat and Hanus 7 , Reference Sugiura, Kondo and Sukagawa 8 ), and to interact with γ-aminobutyric acid receptors( Reference Sigel, Baur and Rácz 9 ). Other endocannabinoids might be represented by both 2-AG ether (noladin ether), that binds to CB1 receptors with relatively more affinity that to CB2 ( Reference Hanus, Abu-Lafi and Fride 10 ), and virodhamine, that is a CB2 receptor agonist and CB1 receptor partial agonist/antagonist( Reference Porter, Sauer and Knierman 11 ). Other compounds that are thought to be endocannabinoids include N-arachidonoyl dopamine, that like anandamide behaves as an agonist at both CB1 and TRPV1 receptors( Reference De Petrocellis, Cascio and Di Marzo 12 ) and antagonises the melastatin type 8 (TRPM-8) cation channels( Reference De Petrocellis, Starowicz and Moriello 13 ), N-dihomo-γ-linolenoyl ethanolamine and N-oleoyl dopamine( Reference Pertwee 14 ). Besides the n-6 long-chain PUFA, our group recently reported evidence that also the ethanolamides of n-3 fatty acids, docosahexaenoyl-ethanolamide (DHEA) and eicosapentaenoyl-ethanolamide, derived mainly from fish oils in the human diet (DHA and EPA) can be classified as endocannabinoids( Reference Brown, Cascio and Wahle 15 ). Indeed, we found that they both are able to bind to CB1 and CB2 receptors with reasonable potency and they functionally activate both receptors, although with low efficacy( Reference Brown, Cascio and Wahle 15 ). DHEA was first discovered in brain tissue and retina( Reference Bisogno, Delton Vandenbroucke and Milone 16 , Reference Sugiura, Kondo and Sukagawa 17 ). In 2001, Berger et al., demonstrated that brain levels of the ethanolamines of DHA and EPA, DHEA and eicosapentaenoyl-ethanolamide (EPEA), in piglets were modulated by the amount of n-3 long-chain PUFA in the feed( Reference Berger, Crozier and Bisogno 18 ). Other studies have shown an increased formation of DHEA and EPEA in various tissues, including prostate and breast cancer cells, after administering fish oil or individual n-3 long-chain PUFA( Reference Maccarrone, Gasperi and Catani 19 , Reference Brown, Wahle and Cascio 20 ). Interestingly, we have also reported evidence that both DHEA and EPEA show greater anti-proliferative effects than their parent compounds, DHA and EPA, in two prostate cancer cell lines, LNCaP and PC3 cells( Reference Brown, Cascio and Wahle 15 ). However, the mechanisms underlying these effects are not clearly understood yet. Furthermore, when released, endocannabinoids are accompanied by cannabinoid receptor-inactive, saturated and mono- or di-unsaturated congeners, which can influence their metabolism and function. They include palmitoylethanolamide, steaeroylethanolamide, oleoylethanolamide, oleamide, 2-linoeoyl-glycerol and 2-palmitoyl-glycerol. These compounds appear to have cannabimimetic activity but do not bind to the classical cannabinoid receptors. It might be possible that these molecules exert their cannabimimetic effects by acting as ‘entourage molecules’ that prevent anandamide or other true cannabinoids being degraded by specific metabolic enzymes( Reference Brown, Cascio and Rotondo 21 ). This hypothesis is supported by the following observations: (a) oleamide greatly increases the efficiency of anandamide binding to cannabinoid receptors( Reference Mechoulam, Fride and Di Marzo 22 ); (b) both 2-palmitoyl- and 2-linoleoyl-glycerol have a similar facilitatory effect on 2-AG binding to both cannabinoid receptors as well as on the 2-AG inhibitory effect on forskolin-activated adenylate cyclase( Reference Mechoulam, Fride and Di Marzo 22 , Reference Ben-Shabat, Fride and Sheskin 23 ) and (c) these ‘entourage’ effects were less pronounced in the presence of phenylmethylsulphonyl-fluoride, which inhibits the main metabolic enzyme of anandamide and 2-AG, thus suggesting that these effects were due, at least in part, to inhibition of endocannabinoid hydrolysis by the ‘entourage’ compounds( Reference Mechoulam, Fride and Di Marzo 22 ). Other mechanisms potentially involved in the ‘entourage’ effects warrant further investigation.

Cannabinoid receptors

Cannabinoid CB1 ( Reference Devane, Dysarz and Johnson 24 , Reference Matsuda, Lolait and Brownstein 25 ) and CB2 ( Reference Munro, Thomas and Abu-Shaar 26 ) receptors belong to the G-protein-coupled receptor superfamily. Their activation inhibits adenylate cyclase and Ca2+ (N- and P/Q-type) channels, activates K+ channels and mitogen-activated protein kinase cascades( Reference Pertwee 27 ), specifically extracellular signal-regulated kinases and p38 mitogen-activated protein kinase cascades( Reference Derkinderen, Ledent and Parmentier 28 , Reference Gertsch, Schoop and Kuenzle 29 ). Cannabinoid CB1 receptors are mainly expressed in the central nervous system where they mediate inhibition of ongoing release of various neurotransmitters (acetylcholine, noradrenaline, dopamine, 5-hydroxytryptamine, γ-aminobutyric acid, glutamate, d-aspartate and cholecystokinin)( Reference Howlett, Barth and Bonner 30 , Reference Pertwee and Ross 31 ), and at lower levels in testis, heart, vascular tissue and in immune cells. Within the central nervous system, CB1 receptors are highly expressed in the cerebral cortex, hippocampus, lateral caudate-putamen, substantia nigra pars reticulate, globus pallidus, entopeduncular nucleus and cerebellum as well as in the pain pathways in brain and spinal cord. In these areas endocannabinoids control processes such as cognition, memory, motor function and analgesia( Reference Pertwee 32 ). Unlike CB2, CB1 receptors are associated with special membrane microdomains, named ‘lipid rafts’( Reference Battista, Di Tommaso and Bari 33 ). This association is greatly affected by cholesterol content; indeed, membrane cholesterol enrichment in both primary and immortalised cell lines reduces the binding to CB1; instead cholesterol depletion modifies anandamide-induced endocytosis of CB1, which apparently loses the ability to be directed towards the lysosomal compartment( Reference Battista, Di Tommaso and Bari 33 ). Importantly, the existence on the CB1 cannabinoid receptors of an allosteric binding site that can be recognised by synthetic small molecules was reported for the first time by our group( Reference Price, Baillie and Thomas 34 ). Whether the CB2 receptor, such as CB1, possesses an allosteric binding site, warrants further investigation. Cannabinoid CB2 receptors are mainly expressed in immune cells, and recently they have also been detected in microglia, astrocytes and in central neurons( Reference Onaivi, Ishiguro and Gong 35 , Reference Viscomi, Oddi and Latini 36 ). Finally, the existence of a third type of cannabinoid receptor, GPR55, is still a subject of debate( Reference Gasperi, Dainese and Oddi 37 ).

Endocannabinoids biosynthesis and uptake

Although the biosynthetic and metabolic pathways have been largely studied for the n-6 endocannabinoids, it is probably that similar routes can occur for the n-3 endocannabinoids. Endocannabinoids are not stored in cells such as classical neurotransmitters waiting to be released after cell stimulation, but instead they are rapidly formed from membrane phospholipids ‘on demand’, where and when needed, and immediately released to target cannabinoid receptors mainly locally. Although anandamide and 2-AG are similar in structure, these endocannabinoids exhibit some differences in terms of biochemical and metabolic pathways. Both endocannabinoids are produced at post-synaptic neurons. For anandamide, the main biosynthetic pathway consists of a two-step process: (1) formation of N-acyl-phosphatidyl-ethanolamine (NAPE) from phosphatidyl-ethanolamine by a calcium-dependent N-acyltransferase, and (2) hydrolysis of NAPE to form N-acylethanolamines in a process that is catalysed by NAPE-hydrolysing phospholipase D( Reference Schmid, Schmid and Natarajan 38 Reference Hansen, Lauritzen and Moesgaard 40 ) (Fig. 1). Since cells lacking NAPE-phospholipase D are also able to synthesise anandamide, alternative pathways have been proposed( Reference Sun, Tsuboi and Okamoto 41 Reference Katayama, Ueda and Katoh 47 ) and they are summarised in Fig. 1. The main biosynthetic pathway for 2-AG consists of hydrolysis by phospholipase C of inositol phospholipids containing arachidonic acid at the sn-2 position and further hydrolysis by diacylglycerol lipase (DAGL) of the arachidonic acid-containing DAG to 2-AG( Reference Ueda, Tsuboi and Uyama 48 ) (Fig. 2). In 2003, human DAGL was cloned and further characterised( Reference Bisogno, Howell and Williams 49 ). It exists as two closely related genes designated α and β( Reference Bisogno, Howell and Williams 49 ). Pharmacological studies have revealed that during neuronal development, localisation of DAGLα and DAGLβ changes from pre- to post-synaptic elements, i.e. from axonal tracts in the embryo to dendritic fields in the adult, suggesting a different need for 2-AG synthesis from pre- to the post-synaptic compartment during brain development( Reference Bisogno, Howell and Williams 49 , Reference Williams, Walsh and Doherty 50 ). Furthermore, several studies suggest that DAGLα plays an essential role in the regulation of retrograde synaptic plasticity and neurogenesis. In support of this hypothesis two recent studies suggest that: (1) DAGLα-knockout mice show marked (up to 80%) reductions in 2-AG levels in brain and spinal cord with concomitant decrease in arachidonic acid levels, whereas DAGLβ-knockout animals exhibited either no( Reference Tanimura, Yamazaki and Hashimotodani 51 ) or up to 50% reduction( Reference Gao, Vasilyev and Goncalves 52 ) in brain 2-AG levels; (2) several forms of retrograde endocannabinoid-mediated synaptic suppression, such as depolarisation-induced suppression of excitation and depolarisation-induced suppression of inhibition, were absent in hippocampus, cerebellum and striatum in DAGLα-knockout, but not in DAGLβ-knockout mice( Reference Tanimura, Yamazaki and Hashimotodani 51 Reference Savinainen, Saario and Laitinen 53 ). Like anandamide, also 2-AG can be synthesised by alternative pathways. However, the physiological meaning of these proposed pathways is not yet clear. Endocannabinoids function as retrograde messengers. Indeed, after their biosynthesis, they are released from post-synaptic neurons upon post-synaptic depolarisation and/or receptor activation and act on presynaptic CB1 receptors to induce transient suppression of transmitter release. Two forms of short-term synaptic plasticity have been identified so far, named depolarisation-induced suppression of inhibition, which involves GABAergic transmission, and depolarisation-induced suppression of excitation, which involves glutamatergic transmission( Reference Wilson and Nicoll 54 , Reference Diana and Marty 55 ). These processes were found mainly in the hippocampus and cerebellum, where it seems they play an important role in physiological processes such as memory and motor coordination( Reference Wilson and Nicoll 56 Reference Diana, Levenes and Mackie 58 ). Additional forms of synaptic transmission involve the induction of long-term synaptic plasticity, named long-term potentiation and long-term depression( Reference Rodríguez de Fonseca, Del Arco and Bermudez-Silva 59 ). After targeting their receptors, the endocannabinoids are inactivated by a two-step process. The first process is the endocannabinoid transport from the extracellular to the intracellular space, followed by their metabolism. Whether this cellular uptake depends on the presence of an ‘endocannabinoid membrane transporter’ is currently a subject for debate as no such transporter has yet been cloned. Recently, Fowler has elegantly reviewed the current state of the art of endocannabinoid uptake( Reference Fowler 60 ).

Fig. 1. Schematic representation of anandamide and 2-arachidonoyl-glycerol biosynthesis routes. AEA, anandamide; NAPE, N-acylphosphatidyl-ethanolamine; NArPE, N-arachidonoylphosphatidylethanolamine; PLC, phospholipase C; PTPN22, protein tyrosine phosphatase; PLA2, phospholipase A2; PE, phosphatidyl-ethanolamine; PLD, phospholipase D; Abhd4, α/β-hydrolase 4; DAG, diacylglycerol.

Fig. 2. Schematic representation of anandamide and 2-arachidonoyl-glycerol metabolic routes. HETE, hydroxyeicosatetraenoic acid; HPETEA, hydroxyperoxyeicosatetraenoylethanolamide; LOX, lypoxygenase; COX, cyclooxygenase; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAAA, N-acylethanolamine-hydrolysing acid amidase; ABHD, α/β-hydrolase domain.

Endocannabinoid metabolism

Whatever is the mechanism by which endocannabinoids are taken up by cells, after the uptake, they are metabolised by hydrolysis or oxidation (Fig. 2).

Hydrolysis

Fatty acid amide hydrolase (FAAH) is the main enzyme involved in anandamide hydrolysis, and it is able to recognise as substrates also other N-acyl-ethanolamines such as oleamide( Reference Giang and Cravatt 61 , Reference Maurelli, Bisogno and De Petrocellis 62 ), and N-acyl-taurines( Reference Saghatelian, Trauger and Want 63 ). FAAH is a membrane-associated serine hydrolase belonging to the amidase signature family( Reference Cravatt, Giang and Mayfield 64 ). The catalytic triad is composed of Lys142, Ser217 and Ser241 ( Reference McKinney and Cravatt 65 ). This enzyme is widely distributed in various tissues of rat( Reference Cravatt, Giang and Mayfield 64 , Reference Desarnaud, Cadas and Piomelli 66 , Reference Katayama, Ueda and Kurahashi 67 ), mouse( Reference Sun, Tsuboi and Zhao 68 , Reference Reilly, O'Shea and Andersson 69 ) and human subjects( Reference Giang and Cravatt 61 , Reference Wei, Mikkelsen and McKinney 70 ), and its optimal pH lies within the range 8·5–10. Other enzymes involved in anandamide hydrolysis are N-acylethanolamine acid amidase( Reference Ueda, Yamanaka and Terasawa 71 ) and FAAH-2( Reference Wei, Mikkelsen and McKinney 70 ), this latter being an isozyme of FAAH-1 with about 20% sequence identity at the amino acid level, mainly expressed in human subjects, but not in rodents( Reference Wei, Mikkelsen and McKinney 70 ). N-acylethanolamine acid amidase is an N-glycosylated protein, localised in the lysosomes or the Golgi apparatus with an optimal pH of 4·5–5( Reference Ueda, Yamanaka and Terasawa 71 Reference Wang, Zhao and Uyama 74 ). FAAH-2 is more effective at metabolizing oleamide than anandamide or other N-acyl-ethanolamines. FAAH-1 and FAAH-2 are located in the cytosolic and luminal sides of intracellular membranes, respectively. FAAH is also able to metabolise, although to a lesser extent, 2-AG( Reference Blankman, Simon and Cravatt 75 , Reference Goparaju, Ueda and Taniguchi 76 ). Recently, three ‘guardians’ of 2-AG signalling have been reported: monoacylglygerol lipase, α/β-hydrolase domain (ABHD)-6 and ABHD-12. As recently reviewed( Reference Savinainen, Saario and Laitinen 53 ), MAG lipase is a serine hydrolase belonging to the α/β-hydrolase superfamily, whose catalytic triad is composed of Ser122, Asp239 and His269 ( Reference Labar, Wouters and Lambert 77 , Reference Bertrand, Auge and Houtmann 78 ). It was originally purified, and subsequently cloned from adipose tissue( Reference Labar, Wouters and Lambert 77 , Reference Karlsson, Contreras and Hellman 79 ), and it is detected in both cytosol and membrane preparation( Reference Labar, Bauvois and Borel 80 ). This enzyme accounts for about 80–85% of 2-AG hydrolysis, but it is also involved in the hydrolysis of other 2-monoacylglygerols and 1-monoacylglygerols. Its localisation is mainly presynaptic, where it often co-localises with CB1 receptors in the axon terminals( Reference Kano, Ohno-Shosaku and Hashimotodani 81 ). ABHD-6 and ABHD-12 belong to the α/β-hydrolase family with the postulated catalytic triad serine-aspartic acid-histidine( Reference Savinainen, Saario and Laitinen 53 , Reference Navia-Paldanius, Savinainen and Laitinen 82 ). ABHD-6 is mainly post-synaptic where it regulates 2-AG levels at the site of its generation( Reference Marrs, Blankman and Horne 83 ). This enzyme is also expressed in the mouse microglial cell line BV-2, in which monoacylglygerol lipase is not expressed( Reference Marrs, Blankman and Horne 83 ). The ABHD-6 catalytic triad has not been resolved yet, but it is predicted to face the cytosol/intracellular membrane( Reference Savinainen, Saario and Laitinen 53 , Reference Blankman, Simon and Cravatt 75 ). ABHD-12 is highly expressed in microglia, macrophages and osteoclasts. Its catalytic triad is not resolved yet but it is predicted to face the luminal/extracellular side( Reference Savinainen, Saario and Laitinen 53 , Reference Blankman, Simon and Cravatt 75 ). Inactivating ABHD-12 mutations have been causally linked to neurodegenerative conditions, known as polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract( Reference Savinainen, Saario and Laitinen 53 , Reference Fiskerstrand, Brahim and Johanssond 84 ).

Oxidation

Both endocannabinoids can also be metabolised by oxidation involving enzymes such as cytochrome P-450, cyclooxygenase-2 (COX-2) and by the 12- and 15-lipoxygenases, 12-LOX and 15-LOX( Reference Yates and Barker 85 ) (Fig. 2). Specifically, anandamide can undergo oxidation by several human cytochrome P-450 isoenzymes, including CYP3A4, CYP4F2, CYP4X1 and the polymorphic CYP2D6 resulting in a number of structurally diverse epoxy derivatives that are still able to act on both cannabinoid receptors, CB1 and CB2, and on vanilloid TRPV4 receptors( Reference Piscitelli and Di Marzo 86 ). Little evidence exists for the oxidation of 2-AG by any P-450 enzymes from different tissue preparations( Reference Brown, Cascio and Rotondo 21 ). Lipoxygenases generate hydroxyl-endocannabinoids that activate both cannabinoid receptors and vanilloid TRPV1 receptors( Reference Piscitelli and Di Marzo 86 ). Finally, Yu et al. ( Reference Yu, Ives and Ramesha 87 ) showed that COX-2 but not COX-1 oxygenates anandamide, indicating substrate specificity for the two isoforms. The catalysis mediated by COX-2 induces the formation of both prostamides and PG-glycerol esters, that do not appear to act as ligands for CB1 and CB2 cannabinoid receptors or of any of the EP1-4 eicosanoid receptors, but that have been shown to act through other receptors such as PPAR and NF-κB receptors( Reference Brown, Cascio and Rotondo 21 ).

The physiological and pathological roles of the endocannabinoids

Under physiological conditions, the endocannabinoid system has been reported to modulate several other systems that range from the central and autonomic nervous systems to the endocrine system, the gastrointestinal tract and the reproductive, immune and cardiovascular systems( Reference Pertwee 14 , Reference Di Marzo 88 ). Furthermore, there is convincing evidence too that the endocannabinoid system plays a crucial role also in several pathological conditions. An up-regulation of the endocannabinoid system has already been observed in a wide range of disorders such as multiple sclerosis, cancer, schizophrenia, post-traumatic stress disorders, certain types of pain, some intestinal and cardiovascular diseases, excitotoxicity and traumatic head injury. On the one hand, this up-regulation may play an ‘autoprotective’ role with consequent reduction of the severity of symptoms or a slowing of disease progression( Reference Pertwee 14 , Reference Pertwee 27 ). However, there are also disorders in which up-regulation of the endocannabinoid system contributes to the production or exacerbation of unwanted effects, and so is ‘auto-impairing’( Reference Pertwee 14 , Reference Pertwee 27 ). These disorders include obesity, impaired fertility, stroke, cystitis, ileitis and paralytic ileus. It will be really important to understand which are the mechanisms underlying the alterations in the endocannabinoid levels and to explore whether these are due to an increase in their biosynthesis or a decrease in their enzymatic degradation. Here, I will briefly describe the role played by the endocannabinoid system in the control of food intake (physiological role) and in obesity (pathological role).

Endocannabinoids in the control of food intake and energy expenditure

In mammals, the need for feeding is governed by endogenous controllers that include signals released from the gastrointestinal tract after meals, such as ghrelin, cholecystokinin, and peptide YY, as well as signals more strictly related to metabolism, such as the circulating hormones insulin and leptin( Reference Maccarrone, Gasperi and Catani 19 ). All stimuli involved in feeding are centrally integrated by the hypothalamus, a brain area known to play an important role in homoeostatic control, thus maintaining an adequate body weight( Reference Maccarrone, Gasperi and Catani 19 ). There is now convincing evidence that the endocannabinoid system is involved in the regulation of food intake and energy expenditure. This is supported by the following observations: (i) Δ9-tetrahydrocannabinol, the main psychotropic ingredient of Cannabis sativa, has been found to induce signs of hyperphagia by activating cannabinoid CB1 receptors( Reference Williams, Rogers and Kirkham 89 , Reference Williams and Kirkham 90 ). Indeed, tetrahydrocannabinol was found to improve appetite and increase body weight in advanced cancer patients or in anorexic patients with AIDS or Alzheimer's disease( Reference Gamage and Lichtman 91 ). Moreover, (ii) cannabinoid CB1 receptors are activated after brief food deprivation in a manner that increases the levels of orexigenic and anorexigenic mediators and induces food intake( Reference Matias and Di Marzo 92 ); (iii) the levels of endocannabinoids in the hypothalamus are higher in rodents deprived of food for several hours v. ad libitum-fed animals( Reference Matias and Di Marzo 92 ); and (iv) when directly injected into the hypothalamus or the nucleus accumbens shell, endocannabinoids induce food intake in satiated animals( Reference Matias and Di Marzo 92 ). The fact that all these effects are attenuated by CB1 receptor antagonists strongly supports a role of the endocannabinoid system in the regulation of food intake. Accordingly, cannabinoid CB1 receptors have been found to exert both central and peripheral effects on food intake and energy homoeostasis( Reference Li, Jones and Persaud 93 ). In the central nervous system, cannabinoid CB1 receptors have been found in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus and amygdala) and several parts of the basal ganglia, thalamic and hypothalamic nuclei, cerebellar cortex, brainstem nuclei as well as in areas involved in reward/reinforcement circuitry( Reference Li, Jones and Persaud 93 ). Furthermore, cannabinoid CB1 receptors have been found to co-localise with other receptors in the central nervous system whose activities are essential in the processes of feeding and satiety. For example, the dopaminergic system, which is involved in reward regulation, interacts with CB1 receptors and co-localisation between dopamine receptors (D1 and D2) and CB1 receptors was reported in mouse hippocampus (CB1 and D2), and striatum and olfactory tubercle (CB1, D1 and D2)( Reference Li, Jones and Persaud 93 ). In addition, it has been found that cannabinoid CB1 receptor antagonists, such as SR141716 (also known as rimonabant), AM251 or AM1387, suppress food intake and disrupt food-reinforced behaviour( Reference Salamone, McLaughlin and Sink 94 ); that food-deprived CB1 −/− mice eat less than their wild-type littermates (SR141716 does not affect the food intake of these animals)( Reference Di Marzo, Goparaju and Wang 95 , Reference Wiley, Burston and Leggett 96 ) and that levels of endocannabinoids are elevated in leptin-deficient mice and rats, suggesting that endocannabinoids form part of the leptin-regulated neural circuitry that is involved in appetite regulation( Reference Di Marzo, Goparaju and Wang 95 ). In periphery, the endocannabinoid system acts directly to regulate processes such as gastric emptying, lipogenesis and glucose intake( Reference Cota 97 ) through cannabinoid receptors expressed by peripheral cells and tissues controlling energy homoeostasis, including the gut, the liver and hepatocytes, white adipose tissue, and adipocytes, skeletal muscle and the pancreas( Reference Matias and Di Marzo 92 ). In this way, signals from these peripheral organs can be collectively converged and fed back centrally, allowing the brain to constantly monitor the metabolic state of an organism( Reference Li, Jones and Persaud 93 ).

Endocannabinoids in obesity

Besides its role in the regulation of food intake, there is also evidence that the endocannabinoid system is overactivated and dysregulated in human obesity. Obesity is a pathological condition whose incidence continues to increase as a global nutrition and health problem. One of the key factors leading to obesity is a significant imbalance between energy intake and expenditure. In addition, the high amount of n-6 PUFA, such as linolenic acid and arachidonic acid, over the n-3 PUFA, in the Western diet has hugely contributed to the onset of obesity. Unfortunately, the mechanisms by which different fatty acids contribute to obesity are not well-understood yet and further research is needed. The involvement of the endocannabinoid system in obesity is supported by the following observations: (i) CB1 receptor antagonists are significantly more efficacious in reducing caloric intake and body weight in rodents with diet-induced or genetic obesity than in their respective lean controls( Reference Di Marzo, Goparaju and Wang 95 , Reference Ravinet Trillou, Arnone and Delgorge 98 , Reference Vickers, Webster and Wyatt 99 ); (ii) CB1 −/− mice are resistant to diet-induced obesity( Reference Ravinet Trillou, Delgorge and Menet 100 , Reference Osei-Hyiaman, Harvey-White and Batkai 101 ); and (iii) both an up-regulation of CB1 receptors and elevated endocannabinoid levels have been detected in the adipose tissue of obese compared with lean patients( Reference Bensaid, Gary-Bobo and Esclangon 102 , Reference Matias, Gonthier and Orlando 103 ). Importantly, CB1 receptor antagonists show significant anti-obesity effects. Rimonabant, which is a CB1 receptor inverse agonist/antagonist, has been found (i) to reduce food intake in both lean and obese rodents and to lower body weight both in experimental models of obesity and in clinical trials( Reference Fernandez and Allison 104 ); (ii) to decrease fat intake as well as hunger ratings( Reference Fernandez and Allison 104 ); and (iii) to improve waist circumference, plasma TAG, HDL cholesterol and blood pressure( Reference Fernandez and Allison 104 ). Rimonabant was approved in 2006 as a weight loss medication in the European Union. Unfortunately, however, the use of this drug in the clinic has been suspended because of serious psychiatric side effects, particularly an increased incidence of depression and suicidality.

In this regard, the use of CB1 receptor antagonists that do not cross the blood–brain barrier might provide a novel pharmacological approach to controlling obesity without the psychiatric side-effects observed with rimonabant and its analogues. In addition, the development of ‘neutral’ CB1 antagonists, that do not show any significant signs of inverse agonism, has provided very promising results at the preclinical level, particularly in terms of their reversal of insulin and leptin resistance( Reference Silvestri and Di Marzo 105 ). Furthermore, in the light of the fact that the increased endocannabinoid tone observed in metabolic disorders can be attributed to increased endocannabinoid biosynthesis, an alternative strategy to regulate dysregulated endocannabinoid tone in obesity might be to use DAGL inhibitors with consequent reduction in 2-AG biosynthesis( Reference Bisogno, Burston and Rai 106 ). Finally, changes in diet can be beneficial in preventing the onset of both obesity and other metabolic disorders. Indeed, several data reported in the literature suggest that dietary intake can modulate the endocannabinoid system. Thus, high-fat diets increase intestinal motility and the levels of the endocannabinoids, probably due to decreased monoacylglygerol lipase and FAAH activity and increased NAPE-phospholipase D action( Reference Naughton, Mathai and Hryciw 107 ). Interestingly, the role of dietary fish oil n-3 fatty acids, EPA and DHA, in modulating endocannabinoid biosynthesis has been widely studied. Indeed, increased intake of EPA and DHA, that are able to displace arachidonic acid from phospholipid membranes, not only contributes to a marked decrease in endocannabinoid biosynthesis, but also causes a decrease in NAPE-phospholipase D, FAAH and CB1 mRNA expression with a consequent reduction of receptor stimulation( Reference Naughton, Mathai and Hryciw 107 ). However, such a change in diet should be considered with caution in newborn since it can cause long-lasting alterations in brain phospholipid composition and function( Reference Silvestri and Di Marzo 105 ).

Conclusions and future directions

It is now generally accepted that the endocannabinoid system plays a crucial role in several physiological processes and pathological conditions in both central and peripheral tissues. One challenge now is to develop: (a) new peripherally restricted CB1 receptor agonists and/or antagonists that while maintaining the sought-after therapeutic effect do not show the unwanted side-effects that have been observed with direct CB1 ligands which cross the blood–brain barrier; (b) new medicines that affect the tissue level of endocannabinoids at their receptors for the treatment of a range of disorders, such as, to mention just a few, pain, multiple sclerosis, hypertension and cancer.

Acknowledgements

I wish to thank Professor Roger G. Pertwee (University of Aberdeen) for his continuing support and advice.

Financial Support

This was provided by GW Pharmaceuticals and Otsuka. No one from GW Pharmaceuticals or Otsuka had a role in the design, analysis or writing of this article.

Conflicts of Interest

None.

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