Introduction
Cannabinoids are psychoactive principles contained in marijuana, and Δ9-tetrahydrocannabinol (Δ9-THC) (Fig. 1) is a representative compound of this class [1]. Pharmacological and molecular biological studies on cannabinoids have evolved into the discovery and characterization of the endocannabinoid system (ECS) in animal tissues. This system is composed of the cannabinoid receptors, their endogenous ligands (the endocannabinoids), represented by N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) (Fig. 1), and the enzyme proteins involved in the biosynthesis and inactivation of endocannabinoids (Fig. 2) [2]. In recent years there has been growing evidence that ECS plays an important role in the regulation of food intake and energy balance. The intention of this short review is to discuss the latest advances in research on the role of ECS in metabolic control, with special reference to the antiobesity effect of the cannabinoid receptor CB1 antagonist rimonabant (Fig. 3). We will also refer to the anorexic effect of N-oleoylethanolamine, an endocannabinoid-related endogenous compound (Fig. 4).
Outline of the endocannabinoid system
In the early 1990s, two G protein-coupled cannabinoid receptors, CB1 and CB2, were cloned and characterized [3,4]. CB1 is predominantly expressed in the central nervous system (CNS) whereas CB2 is primarily expressed in immune and blood cells. CB1 has also been found in various peripheral tissues, however, including adipose tissue [5,6•], liver [7], pancreatic islet [8•], and gastrointestinal tract [9], while CB2 was recently found in brain areas such as brainstem, cortex, cerebellum [10], olfactory bulb, hippocampus and thalamus [11•]. In addition to CB1 and CB2, pharmacological studies strongly suggest the existence of novel cannabinoid receptor subtypes [12,13,14•].
Anandamide [15] and 2-AG [16,17] are the most studied endocannabinoids. Although several other arachidonic acid derivatives were also reported as endocannabinoids [18••], their physiological importance remains unclear. Binding of endocannabinoids as well as cannabinoids to cannabinoid receptors results in the decrease in intracellular cyclic AMP levels and the activation of mitogen-activated protein kinase through the coupled Gi/o proteins. In addition, CB1 activation by endocannabinoids modulates ion channels through Gi/o proteins, leading to the activation of A-type and inwardly rectifying potassium channels and the inhibition of N-type and P/Q-type calcium channels. CB1 can also stimulate the formation of cyclic AMP through Gs under certain conditions [19].
Like other lipid mediators including prostaglandins and leukotrienes, endocannabinoids are not stored in vesicles in the cell. Consequently, the endocannabinoid signaling must be tightly controlled by intracellular enzymes responsible for the biosynthesis and inactivation of endocannabinoids [20,21•]. In general, endocannabinoids are formed from membrane phospholipids by a series of enzyme reactions. The produced endocannabinoids are released outside the cell, and act as ligands of cannabinoid receptors. After reuptake by cells, they are rapidly inactivated by enzymatic hydrolysis. Figure 2 shows outlines of the major pathways through which anandamide and 2-AG are produced and degraded, respectively.
Anandamide is ethanolamide of arachidonic acid, and co-exists in various animal tissues with ethanolamides of other fatty acids, collectively referred to as N-acylethanolamines (NAEs). All NAEs are formed from glycerophospholipids through a common pathway, 'the transacylation-phosphodiesterase pathway', which comprises N-acyltransferase and N-acylphosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D (NAPE-PLD). Since the former enzyme is markedly stimulated by calcium, this reaction is considered to be a rate-limiting step. Although N-acyltransferase has not yet been cloned, we recently cloned a novel enzyme that catalyzes the same reaction calcium-independently [22••]. NAPE-PLD has been cloned and characterized as a member of the metallo-β-lactamase family [23,24•]. The one-step reaction catalyzed by NAPE-PLD may be replaced with two or more consecutive reactions [25,26•,27,28•]. In fact, recent analysis of NAPE-PLD-deficient mice revealed that a NAPE-PLD-independent pathway functions for the formation of anandamide from NAPE [26•].
Among the enzymes involved in the degradation of anandamide and other NAEs, fatty acid amide hydrolase (FAAH) has been most extensively studied [29]. The enzyme hydrolyzes various NAEs to fatty acids and ethanolamine. Analysis of FAAH-deficient mice revealed its central role in the degradation of NAEs especially in the brain. Recently, from humans, but not from rodents, an isozyme of FAAH (FAAH-2) was cloned [30]. We cloned another mammalian NAE hydrolase, termed NAE-hydrolyzing acid amidase (NAAA) [31]. This enzyme is one of the lysosomal hydrolases, and its high expression in macrophages suggests a role of the enzyme in the removal of NAEs accumulating in degenerative or inflammatory tissues [32•].
The major pathway for the biosynthesis of 2-AG comprises hydrolysis of arachidonic acid-containing inositol phospholipids by phospholipase C (PLC) and subsequent hydrolysis of the resultant diacylglycerol by diacylglycerol lipase (DAGL) [33]. Two DAGL isozymes, α and β, have been cloned [34]. The high content of arachidonic acid at the sn-2 position of inositol phospholipids explains predominant production of 2-AG among different monoacylglycerols. Recent studies with gene-disrupted mice and specific inhibitors demonstrated that PLCβ and DAGL are involved in the receptor/Gq-dependent formation of 2-AG acting as a retrograde signaling molecule at synapses [35,36•,37]. 2-AG may also be formed by other routes including that through the combined actions of phospholipase A1 and PLC [38••]. The most ubiquitous mechanism for the degradation of 2-AG is hydrolysis to arachidonic acid and glycerol. Monoacylglycerol lipase (MAGL) is considered to be the major enzyme for this reaction [39,40•].
Metabolic control by the endocannabinoid system in the central nervous system
The ability of recreational marijuana to reliably stimulate appetite generated interest in a role of ECS in metabolic control. CB1 has been detected in various brain regions related to the control of food intake, including hypothalamus, nucleus accumbens, vagus nerve and nodose ganglion [21•]. In mouse hypothalamus, CB1 mRNA was co-localized with several neuropeptides, such as corticotropin-releasing hormone (CRH), cocaine and amphetamine-regulated transcript (CART), preproorexin and melanin-concentrating hormone (MCH) [5]. It was reported that the expression level of CB1 is regulated by feeding behavior and by orexigenic or anorexic peptides. In the limbic forebrain of rats fed a palatable diet, the expression of CB1 mRNA was downregulated [41]. In the nodose ganglion, the mRNA was expressed in the satiety signal cholecystokinin (CCK)-containing neurons, where its expression was upregulated by fasting and was downregulated by refeeding [42]. Moreover, the expression of CB1 in afferent vagal neurons was downregulated by CCK [5,42]. Interestingly, ghrelin, an orexigenic hormone from stomach, counteracted the inhibitory effect of CCK on the induction of CB1 in the nodose ganglion [43]. It is unclear whether or not the CB2 expressed in brain is involved in metabolic control [11•].
In addition to CBs, endocannabinoids were also identified in brain regions, including hypothalamus, limbic forebrain, and brainstem [21•]. Leptin, an anorexic hormone secreted from adipocytes, specifically inhibited the anandamide and 2-AG biosynthesis in hypothalamus. Obese Zucker rats and obese ob/ob and db/db mice, which lack leptin or leptin recptors, showed increased levels of anandamide and 2-AG in the hypothalamus [44]. Glucocorticoids stimulated the biosynthesis and release of endocannabinoids in hypothalamus through nuclear receptors, and leptin blocked this effect [45]. Fasting increased limbic levels of anandamide and 2-AG, whereas in the hypothalamus, only 2-AG was increased [46]. An increased level of ghrelin was also suggested to link to the enhanced endocannabinoid tone [47]. These results revealed the regulation of endocannabinoid levels by appetite-related hormones in the CNS.
More directly, the CB1 antagonist rimonabant decreased the food intake of hyperphagic wild-type mice caused by a brief food deprivation to a level similar to that observed in CB1-disrupted (CB1-/-) mice, but had no effect on the food intake of CB1-/- mice [44]. The knockout mice showed slight anorexia and exhibited a lean phenotype with reduction in fat mass [5]. Injection of anandamide into hypothalamus and that of 2-AG into the nucleus accumbens shell region actually caused hyperphagia in rats, respectively, and this effect was attributed to stimulation of CB1 [46]. Alpha-melanocyte-stimulating hormone (α-MSH) and rimonabant synergistically decreased food intake [48]. Endocannabinoids were also shown to regulate the levels of orexigenic factors such as endogenous opioids, MCH, orexins, neuropeptide Y (NPY) and ghrelin, and anorexic factors including CCK, α-MSH, CRH, and CART [49••,50•]. In CB1-/- mice the expression of CRH was increased and the CART expression was decreased [5]. Recently, endocannabinoids were reported to participate in the brain signaling processes of food reward through the activation of the mesolimbic dopaminergic system [51•,52].
Metabolic control by the endocannabinoid system in peripheral tissues
Action of endocannabinoids is not confined to the CNS, but they rather function as local mediators in peripheral tissues, including white adipose tissue [5,53•,54•], liver [7], skeletal muscle [18••,55], gut [56], and pancreas [8•,53•]. Through CB1 expressed in these peripheral tissues, the endocannabinoid stimulation promotes lipogenesis and fat accumulation, induces glucose intolerance, and diminishes thermogenesis [50•,57]. The hyperactivity of peripheral endocannabinoids has been related to obesity [53•,58,59•].
White adipose tissue is involved in lipid synthesis, storage, and release, while brown adipose tissue is responsible for energy consumption through uncoupled mitochondrial respiration. The CB1 activation increased the activity of lipoprotein lipase in adipocytes, and rimonabant blocked this action [5]. Very recently, it was found that the adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression levels in adipose tissue [60•]. This CB1 expression was directly regulated by peroxisome proliferator-activated receptor (PPAR)-δ. One of the major roles of adipose tissue in metabolic control is the secretion of metabolism-related hormones such as adiponectin and leptin [61]. Adiponectin increases insulin sensitivity and thereby contributes to the decrease in levels of blood glucose and plasma insulin, and the loss of body weight [50•]. The administration of rimonabant increased adiponectin expression in the cultured adipocytes of mice [5,62] and in Zucker (fa/fa) rats [62]. The reduction of adipose mass by rimonabant resulted from an enhanced lipolysis, an increased energy expenditure, and a tight regulation of glucose homeostasis [57]. Recently, rimonabant was also found to inhibit the proliferation of preadipocyte cells and to increase adipocyte maturation without lipid accumulation [63•]. Moreover, in obese rats, rimonabant increased the low level of adiponectin with concomitant decrease in the high level of tumor necrosis factor-α [64•]. These results clearly suggest the involvement of ECS in the function of adipose tissue. Although CB2 was also found in human adipocytes [54•], its role in adipose tissue remains unknown.
In liver, endocannabinoids induced the expression of a cluster of genes which stimulated hepatic fat synthesis, including the lipogenic transcription factor sterol regulatory element-binding protein (SREBP)-1c and the key lipogenic enzymes acetyl coenzyme A carboxylase-1 and fatty acid synthase. As a result, CB1 activation significantly increased fatty acid synthesis with normal mice, whereas the effect by CB1 agonist was not observed with CB1-/- mice or with rimonabant-administered normal mice [7]. The treatment with rimonabant also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDL-cholesterol/LDL-cholesterol ratio [64•]. The soleus muscle derived from obese mice expressed a higher CB1 level compared with lean controls [18••]. A significant increase in glucose uptake by isolated soleus muscle and oxygen consumption was observed in obese mice when treated with rimonabant for seven days [55]. Recently, endocannabinoids were reported to suppress fatty acid oxidation in skeletal muscle by affecting the expression of energy metabolism-regulating genes including AMP-activated protein kinases α1 and α2, pyruvate dehydrogenase kinase 4, and PPAR-γ co-activator-1α [65•]. In small intestine, the anandamide levels increased after starvation and returned with refeeding [56].
Pancreatic islet is recently noted to be a new peripheral target of endocannabinoids. High glucose levels accelerated the production of endocannabinoids in the pancreatic β-cells of rat [53•]. In rats, the administration of anandamide and its stable analog arachidonyl-2′-chloroethylamide resulted in glucose intolerance after a glucose load, which may be due to the reduction of glucose-dependent insulin secretion [66•]. Rimonabant ameliorated hyperinsulinemia in obese animals [62]. Interestingly, activation of CB2 improved glucose tolerance, and blockade of CB2 counteracted this effect [67•], which suggested the involvement of CB2 in glucose homeostasis.
Rimonabant as antiobesity drug
As mentioned above, in animal models rimonabant successfully suppressed food intake. It should be noted, however, that weight loss by rimonabant outlasted the reduction of food intake [5,44,68], suggesting that the compound also effectively acts on energy metabolism in peripheral organs. Among drugs so far developed as new therapeutic options for obesity, rimonabant is considered to be by far the most exciting drug in human applications [69,70]. Since 2006 rimonabant has been available in Europe as a clinical drug for antiobesity and smoking cessation. Very recently, however, the committee of outside advisers of the US Food and Drug Administration (FDA) rejected the clinical treatment of rimonabant for obesity because of safety concerns. Sanofi-Aventis soon withdrew its application to the FDA.
As a large phase III trial of rimonabant, Rimonabant in Obesity (RIO) was initiated in August 2001 and enrolled more than 6600 overweight (body mass index higher than 27 kg/m2) or obese patients (body mass index no less than 30 kg/m2). The RIO program consisted of four phase III randomized controlled trials: RIO-Europe, RIO-North America, RIO-Lipids, and RIO-Diabetes. In addition to a diet and lifestyle therapy, all subjects received 5 or 20 mg/day rimonabant or only placebo. RIO-Europe and RIO-North America were 2-year trials, whereas RIO-Lipids and RIO-Diabetes were performed for 1 year [71,72,73••,74••,75]. As compared with the placebo group, the treatment with the 20 mg dose of rimonabant led to a mean weight loss of 3.9-5.4 kg and a mean waist circumference reduction of 3.3-4.7 cm. In RIO-North America, the weight loss was maintained with the patients treated for 2 years, whereas the patients, who were treated with rimonabant in year 1 but received placebo in year 2, regained their weight [73••]. In addition, a reduction (12-16%) in triglycerides and an increase (7-9%) in HDL-cholesterol level were consistently observed. Reductions in total cholesterol and LDL-cholesterol were not observed in all trials, however, and the blood pressure was either unchanged [71,73••,74••] or slightly reduced [72]. Rimonabant also induced favorable changes in fasting insulin level and insulin resistance, and decreased the proportion of patients who fulfilled the criteria for the metabolic syndrome. Moreover, an increase in plasma adiponectin level was observed [72,74••]. In patients with type 2 diabetes, rimonabant improved atherogenic dyslipidemia and reduced the levels of HbA1c and high-sensitivity C-reactive protein [74••]. After rimonabant treatment (20 mg/day) for 1 year, improvement in the levels of HDL-cholesterol, triglycerides, and HbA1c surpassed weight loss, which suggested that beneficial effects of rimonabant on risk factors are probably derived not only from the weight loss due to appetite suppression, but also from its peripheral action on energy metabolism [71,72,73••,74••]. The discontinuation rates in the trials were relatively high, but similar between the drug-treated and placebo groups. The most frequent adverse effect was nausea, and others included dizziness, diarrhea, and insomnia. It should be noted that the discontinuation was mainly due to psychiatric disorders, mostly depression and anxiety [71,72,73••,74••]. In Europe, rimonabant was marketed with the precautions for the application to patients with serious psychiatric illness, such as major depression, and patients receiving antidepressants [76]. Because of no beneficial effects on LDL-cholesterol and blood pressure, it remains uncertain whether monotherapy of rimonabant is valuable for obese patients with dyslipidemia or diabetes [69].
Preclinical and clinical researches also revealed multifunction of rimonabant in relation to a broad range of diseases [77•]. For example, rimonabant showed hepatoprotective [64•], anti-inflammatory and antihyperalgesic effect [78] on obese animals. Furthermore, the drug was reported to exhibit antiproliferative [79], antitumor [80], and penile erection-inducing effects [81,82]. Recently, several novel CB1 antagonists, such as LH 21, MK-0364 (Fig. 3), and AM1387 have been developed and used in animal experiments, which might be promising for clinical applications [83•,84•,85]. CB1 was reported to contain an allosteric-binding site, which can be recognized by synthetic small molecule ligands [86]. The allosteric modulation may supply a new strategy in the therapeutic exploitation of cannabinoid receptors. A class of allosteric CB1 antagonists was recently discovered, and the optimized prototype in this class, PSNCBAM-1, was shown to decrease food intake and body weight in an acute rat feeding model [87].
Anorexic effect of N-oleoylethanolamine
N-Oleoylethanolamine (oleylethanolamide or oleoylethanolamide) is a monounsaturated NAE widely present in mammalian tissues, including small intestine and adipose tissue. In contrast to polyunsaturated NAEs such as anandamide, this compound does not bind to or activate cannabinoid receptors. In the past decade, however, the compound has attracted attention as an anorexic mediator that modulates feeding and energy homeostasis [18••,88]. This finding was particularly interesting since the structurally related anandamide shows orexigenic activity as an endocannabinoid. Administration of N-oleoylethanolamine to rodents caused reduction of food intake, activation of lipolysis, and decrease in body weight gain [88-90]. Both intraperitoneal and oral administrations were effective. N-Oleoylethanolamine had a high affinity for PPAR-α, and its biological activity was not observed with mice that lack this nuclear receptor [88,91,92]. The compound was shown to regulate body weight by altering peripheral lipid metabolism through PPAR-α. For example, the compound lowered tissue triglyceride levels, enhanced fatty acid uptake, and induced the expression of PPAR-α-regulated genes, including fatty acid binding protein, fatty acid translocase (FAT/CD36), and uncoupling protein-2 [93,94]. Furthermore, N-oleoylethanolamine was reported to affect glucose metabolism by impairing glucose tolerance and inhibiting insulin-stimulated glucose uptake in rat adipocytes [95] and showed cardioprotective effect on doxorubicin-induced cardiomyopathy [96].
Enzymatic hydrolysis-resistant analogs of N-oleoylethanolamine were recently developed, and the most potent analog, termed KDS-5104 (Fig. 4), was more potent than N-oleoylethanolamine in enhancement of transcriptional activity of PPAR-α and reduction of food intake [97•]. Thus, derivatization of N-oleoylethanolamine may lead to development of new antiobesity drugs. The treatment of obese Zucker rats with a combination of rimonabant and N-oleoylethanolamine markedly decreased food intake, body weight gain, and plasma cholesterol levels [98•]. In addition to PPAR-α, N-oleoylethanolamine and other 18-carbon NAEs were shown to function as ligands of the vanilloid receptor TRPV1 [99,100]. Importantly, N-oleoylethanolamine was recently reported to be a ligand of the orphan G protein-coupled receptor GPR119, which was expressed predominantly in pancreas and gastrointestinal tract of human and rodent [101••]. Oral administration of a novel selective nonlipophilic agonist of this receptor, PSN632408 (Fig. 4), resulted in suppression of food intake and reduction of body weight gain in rat models. This finding suggested the involvement of GPR119 in modulating feeding and energy homeostasis [101••].
It is of interest to know whether or not N-oleoylethanolamine is a physiological regulator of appetite. Its endogenous level in the intestine was reported to vary during feeding and fasting [89]. This finding was recently reproduced by another group, who showed that food deprivation in rat caused significant decrease in the intestinal level of N-oleoylethanolamine together with N-palmitoylethanolamine and N-linoleoylethanolamine [102•]. Re-feeding quickly increased their levels to those of free-feeding animals. Levels of their corresponding NAPEs as precursors also changed in parallel with the NAE levels. Interestingly, the levels of anandamide and its precursor N-arachidonoylphosphatidylethanolamine were increased by food deprivation, and were decreased by refeeding, suggesting the existence of different pathways for production of individual NAEs [102•]. Moreover, a recent study [103•] showed that the feeding-induced formation of N-oleoylethanolamine is restricted to the lumen of rat proximal small intestine. Food intake also enhanced the activity and mRNA level of NAPE-PLD, and decreased the FAAH activity, suggesting the regulation of N-oleoylethanolamine level by these enzymes. As another example of its physiological regulation, acute cold exposure stimulated the N-oleoylethanolamine mobilization in rodent white adipose tissue, but not in small intestine, liver, or skeletal muscle [104]. Furthermore, acute alcohol exposure diminished the N-oleoylethanolamine level in hypothalamus and some other regions of rat brain [105].
Conclusion
In the past several years, ECS has been revealed to play an important role in the regulation of appetite, energy balance, and lipid metabolism through central and peripheral mechanisms. In preclinical and clinical studies, the CB1 antagonist rimonabant showed a significant antiobesity effect on overweight and obese patients, and ameliorated dyslipidemia and diabetes. Considering its multiple beneficial effects, more extensive applications of this drug are expected. Development of other CB1 antagonists with different pharmacological properties is also anticipated. N-Oleoylethanolamine also attracted attention due to its anorexic effects. Since the mechanism is largely different from that of CB1 antagonists, its stable analogs may supply new therapeutic strategies against obesity. Concerning physiological significance of N-oleoylethanolamine as well as other NAEs, further studies will be required.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 106-107).
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