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  • Pharmacol Res. Aug;60(2) doi: /writingdesk.pw Epub Apr The endocannabinoid system: role in glucose and energy. The endocannabinoid system and energy metabolism. actions have been attributed to endocannabinoids, and their involvement in several pathophysiological. PURPOSE OF REVIEW: Growing evidence suggests an important role in metabolic control of the endocannabinoid system, which is composed of cannabinoid.


    Accordingly, the longer the time since the last meal, the greater the activity in relevant endocannabinoid circuits, and consequently the higher the motivation to eat The findings of increased levels of AEA and 2-AG in the fasting condition in the nucleus accumbens and a decline of 2-AG concomitant with the feeding state strongly support this hypothesis Interestingly, unchanged levels of endocannabinoids were shown in the cerebellum, a region not involved in the control of feeding, further confirming the notion that endocannabinoids are produced in situ and on demand With the advent of CB1 receptor-specific antagonists Table 3 , it became clear that, even when injected alone, these compounds are able to modify ingestive behavior.

    An ip injection of SR was found to significantly reduce sucrose or alcohol intake and craving in rodents — and in marmosets , leading to the hypothesis that the activation of the endocannabinoid system may alter the appetitive value of ingested substances.

    This idea is consistent with the evidence in favor of a facilitatory function of the endocannabinoid system on brain reward circuits , In favor of this latter hypothesis, there are several reports indicating the ability of CB1 receptor blockade to decrease the rewarding properties of addictive drugs , — The high expression of CB1 receptor in areas involved in reward constitutes a strong indication that the endocannabinoid system is directly involved in various physiological functions controlled in these brain regions, including feeding This circuit is implicated in the pleasure produced by natural rewards, such as food, addictive drugs, and sex, and it is the neural substrate of drug addiction and addiction-related phenomena, such as craving and dysphoria induced by withdrawal In such a framework, food intake acts on dopamine, opioid, serotonin, and noradrenaline neuronal fibers, which connect the hindbrain and midbrain to the hypothalamus to modulate the action of feeding and satiety factors The most relevant reward pathway is represented by the mesolimbic dopaminergic system.

    It has been shown that increased levels of extracellular dopamine and its metabolites are found within the nucleus accumbens after ingestion of highly palatable food Moreover, administration of a dopamine D1 agonist reduces food intake Both CB1 receptor and endocannabinoids were found in the rat limbic forebrain , in which colocalization with dopamine D1 and D2 and CB1 receptor were described Psychoactive drugs such as marijuana, ethanol, and also pleasant stimuli or palatable food are known to induce the release of dopamine in specific brain regions The endocannabinoid system also provides retrograde control of synaptic transmission onto the VTA dopaminergic neurons, where the postsynaptic synthesis of endocannabinoids is under the control of somatodendritically released dopamine A relevant interplay also exists between the endocannabinoid system and the endogenous opioid peptides Both systems are linked to central reward processes, and there is increasing evidence supporting an important functional cross-talk between the two systems, in relation to a wide range of physiological processes, including appetite.

    Several reports indicate that opioid receptor agonists increase food intake — , whereas opioid antagonists induce anorectic effects Gallate and McGregor found that the facilitatory effects of a cannabinoid agonist on responding to palatable solutions were reversed not only by CB1 receptor antagonism but also by naloxone, an opioid receptor antagonist.

    The existence of cross-talk between the endocannabinoid and opioid systems in controlling food intake was also confirmed by several studies in which naloxone and SR synergistically depress food intake at doses that do not alter food intake on their own , However, a recent finding seems to localize the interaction between opioids and endocannabinoids involved in feeding behavior not at the mesolimbic system level but, preferentially, at the level of the PVN of the hypothalamus.

    In fact, SR was able to attenuate morphine-induced feeding only when the opioid was directly injected in the PVN and not in the nucleus accumbens. According to this last finding, the endocannabinoid system appears to participate in the opioid-mediated enhancement of rewarding properties of food in the hypothalamus and not in the nucleus accumbens According to the involvement of serotonin in the control of feeding behavior , the interaction of the endocannabinoid system with the serotoninergic system has also been investigated.

    However, the administration of a CB1 receptor antagonist in rats combined with dexfenfluramine, an anorectic drug stimulating the release of serotonin, led to additional but not synergistic effects on reducing food intake, which is consistent with the hypothesis that the two pathways work via independent mechanisms of action This notion is important, because it makes it possible to exclude a synergistic effect in a possible future combination of antiobesity drugs such as those inhibiting serotonin reuptake, like sibutramine and CB1 receptor antagonists.

    A complex and redundant neuronal hypothalamic network provides high levels of adaptability of feeding behavior to various central and peripheral stimuli Redundancy in appetite-stimulating signaling is conceivable in view of the vital importance of feeding for survival Whereas defects in anorexigenic signaling pathways almost always lead to obesity, loss of orexigenic signals rarely results in a lean phenotype.

    An example of this redundancy in orexigenic hypothalamic signaling systems is provided by mice lacking neuropeptide Y one of the most important appetite-stimulating neuropeptides where compensatory mechanisms are likely to be activated Signals coming from various peripheral organs, such as the liver, gastrointestinal tract, and adipose tissue, are conveyed mainly at the hypothalamic level to constantly inform the brain about the state of nutrition , An example of such peripheral control is the adipocyte-derived hormone leptin, which acts on receptors located in the hypothalamus A milestone in the identification of the endocannabinoid system as a new player in the regulation of food intake at hypothalamic level was the finding that leptin is a strong modulator of hypothalamic endocannabinoid levels Di Marzo et al.

    They also described the defect in leptin signaling as being constitutively associated with elevated hypothalamic levels of endocannabinoids. In these animals, SR was able to reduce food intake, confirming the anorectic properties of the compound These findings suggest that, at least in genetically modified animal models, obesity is associated with a chronic hypothalamic overactivation of the endocannabinoid system, which may in turn explain the hyperphagic behavior of the animals having leptin signal impairment.

    However, before giving a general value to this assumption, the intrahypothalamic amount of endocannabinoid levels during the development of obesity in normal rodents eating a high-fat diet must be investigated. Nevertheless, endocannabinoids are variably produced in the hypothalamus of normal animals.

    In fact, 2-AG levels increase during acute fasting, decline as the animals are refed, and return to normal values in satiated animals , However, a long period of diet restriction 12 d was found to be associated with reduced levels of 2-AG in the hypothalamus The authors interpreted these data observing that the decrease of 2-AG levels in mice after a prolonged diet may represent a general psychobehavioral strategy for intermittent starvation when food is scarce As mentioned above, the hypothalamus is not the cerebral area where the highest levels of CB1 receptor expression are found 24 , 36 , On the other hand, it is also evident that CB1 receptors are present at a very high density in the brain compared with other receptors.

    Therefore, even regions with a relatively lower density of CB1 receptors, such as the hypothalamus, contain a significant number of receptors. Both these factors thus probably explain the ability of hypothalamic CB1 receptors to strongly affect the functions of this brain region. Interestingly, no changes in CB1 receptor expression have been shown at the level of hypothalamus after diet modification The direct involvement of the hypothalamus in the modulation of food intake operated by endocannabinoids was also demonstrated by the significant hyperphagic effects of AEA directly administered into the ventromedial nucleus and by the inhibition of this effect obtained by the injection of SR via the same route It was only during the last few years that the interaction of CB1 receptor and endocannabinoids in feeding-regulating pathways started to be elucidated in detail.

    The CB1 receptor is expressed in key hypothalamic peptidergic systems, such as those producing CRH in the PVN, cocaine-amphetamine-related transcript in the dorsomedial nucleus, and melanin-concentrating hormone and orexins in the lateral hypothalamus-perifornical area Importantly, these data were recently confirmed by the demonstration that CB1 receptor activation strongly augments the orexin-A-stimulated intracellular pathway This fact confirms that orexigenic pathways are less critical or at least functionally more redundant in the chronic maintenance of energy balance Functional cross-talk between CB1 receptor and melanocortin receptor type 4 MCR4 has been recently highlighted by the finding of the synergistic action of subanorectic doses of SR and of a MCR4 agonist administered together Furthermore, the same authors showed that the orexigenic impulse given by the administration of CB1 receptor agonists is not blocked by the costimulation with MCR4 agonists, whereas CB1 receptor antagonists are able to inhibit the stimulation of food intake induced by MCR4 antagonists.

    Consequently, the authors hypothesized that the melanocortin receptor signaling in the hypothalamic regulation of food intake is upstream of the activation of the endocannabinoid system The mechanism s of action of the endocannabinoids at hypothalamic synaptic level are still a matter of debate.

    Great progress has recently been made by the finding that postsynaptically released endocannabinoids acting at presynaptic CB1 receptors are able to decrease glutaminergic transmission onto CRH-producing neurons, resulting in an inhibition of CRH release This release of endocannabinoids from the parvocellular neurons is stimulated by a nongenomic effect of glucocorticoids. Therefore, it is conceivable that the well-known regulation of food intake by glucocorticoids may partly derive from functional cross-talk with the endocannabinoid system The same inhibitory mechanism mediated by glucocorticoids through an activation of the endocannabinoid system has also been proposed for other hormones and neuropeptides such as oxytocin and vasopressin In this sense, we may speculate that the recently described interaction between endocannabinoid and the oxytocin system in modulating food intake may derive from the same fast feedback mechanism mediated by nongenomic glucocorticoid inhibition.

    Despite the dogma that neurons do not utilize fatty acids for energy, a growing body of evidence points to a critical role for both fatty acid production and utilization in regulating hypthalamic neurons that regulate food intake In fact, inhibitors of fatty acid synthase are capable of greatly affecting appetite in an anorexigenic manner , In such a scenario, it has recently been proposed that via CB1 receptors, endocannabinoids may modulate the fatty acid synthetic pathway in the hypothalamus, and the inhibition of the hypothalamic expression by rimonabant may explain the anorexigenic properties of cannabinoid antagonists Several lines of evidence are currently converging, indicating that the effects of CB1 receptor blockade on food intake and body weight are not limited to a central mode of action.

    An early report describing the effect of CB1 receptor blockade on changes in food intake and in body weight was, in this sense, highly predictive of a mechanism of action not limited to the mesolimibic or hypothalamic circuits. In fact, Colombo et al. Nevertheless, the body weight loss in SRtreated rats persisted for 14 d, well beyond the drug effect on food intake. At that time, the authors were not able to explain this body weight loss that was not related to a decrease in food intake, and they merely hypothesized a stimulatory action of SR on the energy expenditure Indeed, the lack of CB1 receptor in mutant mice causes hypophagia and body fat reduction.

    These experiments therefore suggested that the endocannabinoid system might regulate central food intake-related mechanisms at young ages, but that this function diminishes with age These observations converge on the idea that additional peripheral food intake-independent metabolic functions may participate, or even predominate, in the control of energy balance exerted by the endocannabinoid system The expression of CB1 receptor in adipocytes and the ability of SR to block lipogenesis stimulated by cannabinoids represent a first important step forward in understanding the peripheral mechanisms of action of the endocannabinoid system in regulating metabolic processes Moreover, the presence of CB1 receptor is increased in mature adipocytes compared with preadipocytes 59 , 60 , indicating that CB1 receptor activation is likely needed more for metabolic processes than for differentiation.

    Importantly, a recent study shed further light on the mechanisms of action of the endocannabinoid system on adipose tissue. They showed that a major restoration of white adipocyte morphology similar to lean animals occurred in adipocytes derived from obese animals after CB1 antagonist treatment. More importantly, they found that the major alterations in gene expression levels induced by obesity in white adipose tissue were mostly reversed in SRtreated obese mice.

    In particular, in this last context the SRinduced increased expression of glucose transporter 4, the insulin-responsive glucose transporter, appears very important This finding makes it possible to hypothesize that cannabinoid antagonists may also be attractive drugs in fighting diabetes. Altogether, these data confirmed that the endocannabinoid system has a major role in the regulation of energy metabolism in adipocytes. Importantly, CB1 receptor expression has been found to be higher in adipocytes derived from obese animals compared with lean controls Similar to the finding of higher levels of endocannabinoids in the hypothalamus derived from obese animals, the overexpression of CB1 receptor in adipocytes of obese rats seems to confirm the notion that hyperactivity of the endocannabinoid system is associated with the obesity state.

    However, this up-regulation of CB1 receptor expression in fat pads derived from rodents has not been confirmed in adipocytes derived from sc fat of obese women 60 ; on the other hand, a partial limitation of this study is that CB1 receptors have not been measured in visceral fat tissue that is supposed to be more prone to the endocannabinoid action.

    Finally, the increase in levels of adiponectin in Zucker obese rats chronically treated with SR in vivo 59 and in 3T3 FA adipocytes acutely stimulated with the CB1 receptor antagonist in vitro 59 points to a close relationship between CB1 receptor blockade and the production of this antiatherogenic and antidiabetic adipocyte-derived protein The quick and strong improvement of hyperinsulinemia detected after a very short-term treatment with SR 4 d in obese Zucker rats was also attributed to an increase in adiponectin However, the well-known reduction in food intake and the consequent body weight loss displayed at the beginning of SR treatment may be the most obvious explanation for the changes in adiponectin levels.

    The ability of long-term treatment with SR to enhance the circulating levels of adiponectin was further confirmed in DIO mice In the last few years, several studies using different CB1 receptor antagonists confirmed the hypothesis that a potential peripheral mode of action of pharmacological CB1 receptor blockade may play a relevant role in the final weight loss effect. However, the effect on body weight was sustained until the end of the 5-wk experiment compared with DIO mice treated with the vehicle.

    The significant difference in weight of white adipose pads between SR and vehicle-treated animals confirmed that weight loss was accompanied by a decrease in adipose tissue. Similar data showed a rapid tolerance to the anorectic action despite a sustained and prolonged effect on body fat loss also being obtained when obese Zucker rats were treated for 14 d with SR Very recently, Poirier et al. A third group received a dietary switch to standard food after the 5 months on a high-fat diet.

    More importantly, the antiobesity effect of the drug was equivalent both in terms of time course and maximum effect to that achieved by switching obese mice to a normal diet Again, the authors demonstrated that the anorectic effect of the CB1 receptor antagonist vanished with time because the energy intake in the SRtreated animals was equivalent to animals on a high-fat diet during the last 6 wk of the experiment and significantly greater than in the group receiving standard diet.

    Consistent with a previous report , the SRinduced weight loss was accompanied by normalization of leptin, insulin, and glucose levels Notably, SR also normalized triglycerides and low-density lipoprotein-cholesterol. Whether this effect on lipid metabolism is indirectly related to an elevation of adiponectin is still a matter of debate. Moreover, Liu et al.

    The authors were not able to identify the mechanism by which SR treatment is able to affect energy expenditure. A start on clarifying the molecular mechanism by which treatment with SR may favor thermogenesis has been made with the microarray experiment performed by Jbilo et al. These data suggest that the cannabinoid antagonist treatment is able to stimulate the expression of genes favoring energy dissipation through mitochondrial heat production in brown adipose tissue However, it should be mentioned that in vivo microdialysis studies showed that SR increases noradrenaline outflow in rat anterior hypothalamus, suggesting a possible central stimulation of efferent sympathetic activity Importantly, Liu et al.

    This activity might contribute to the improved hyperglycemia seen after SR treatment in previous studies. As shown in Fig. Schematic representation of the main effects of CB1 on intracellular signaling cascades. These last two effects are controlled by protein kinase C PKC , which, after activation, can phosphorylate CB1 in the third cytoplasmatic loop and uncouple the receptor from the ion channels. Stimulation of cytoplasmic kinases could also mediate the CB1-induced expression of the immediate early genes IEG , such as the transcription factors c-fos, c-jun, and zif, and the brain-derived neurotrophic factor BDNF.

    Note that these events were described in different cellular systems and, therefore, they might not occur in the same cell types. Hepatocytes, key players in the metabolic processes, were not considered as a target of endocannabinoid action for a long period of time.

    However, substantial amounts of 2-AG are present in the liver 1. These observations suggested the idea that the liver might be a new target of endocannabinoid action. Very recently, Osei-Hyiaman et al. In fact, probably via inhibition of adenylate cyclase, the cannabinoid agonist HU stimulates the expression of several genes involved in the de novo synthesis of fatty acids, such as lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase.

    However, more importantly, the authors found that the marked increase in the basal rate of hepatic fatty acid synthesis as well as the development of hepatic steatosis observed after the administration of high-fat diet were blunted by SR and absent in CB1 receptor knockout mice. High-fat diet also induces an increase in the number of CB1 receptors and in hepatic levels of AEA, strongly suggesting that the blockade of the endocannabinoid system plays an important protection against the pathological consequences of a fat diet in the liver These data pave the way to hypothesize the clinical use of CB1 antagonists in preventing or reversing the development of fatty liver.

    Another recent report showed that cannabinoids inhibit AMP-activated protein kinase activity in the liver A decrease of AMP-activated protein kinase activity is known to lead to increased storage of energy, particularly in the form of fat, in hepatocytes. This mechanism may contribute to explaining the role of endocannabinoids in promoting the development of hepatic steatosis.

    Based on the whole body result of these data, it has been hypothesized recently that the hepatic endocannabinoid system may represent a target for the treatment of nonalcoholic fatty liver disease A considerable amount of evidence suggests that the endocannabinoid system may regulate food intake by also acting in the gastrointestinal tract.

    Importantly, the concentration of AEA in intestinal tissue increases during food deprivation in rats, reaching levels that are 3-fold greater than those needed to halve maximally activated CB1 receptor and 7-fold higher than the amount detected after refeeding. In general, we can conclude that through multiple interactions, endocannabinoids may modulate food intake also at the level of the gastrointestinal tract.

    Another endogenous lipid, a monounsaturated fatty acid ethanolamide, named oleoylethanolamide OEA , was recently proposed as an important modulator of food intake OEA is an analog of AEA, but the activation of any of the known cannabinoid receptors cannot explain its pharmacological effects.

    Peripheral administration of OEA causes a potent and persistent decrease in food intake, but this compound is completely ineffective when administered centrally — OEA-induced anorexia is not caused by nonspecific behavioral effects, because no aversion or illnesses have been reported after the peripheral administration of the compound However, the mechanisms underlying the reduction in motor activity remain unclear OEA not only acts as a satiety signal, but also reduces body weight gain and serum lipid levels in genetically obese rats and in DIO mice Importantly, these data were recently independently confirmed by another group In conclusion, OEA is a new orally active anorectic agent that may possess potential as a new antiobesity drug.

    The whole body of data mentioned above highlights the role of the endocannabinoid system in feeding and energy balance regulation. Indeed, it was reasonable to hypothesize a therapeutic role for cannabinoid antagonists in the treatment of obesity. SR, also named rimonabant commercialized as Acomplia , is now undergoing multicenter randomized, double-blind phase III trials to assess the effects on weight loss in obese patients with or without comorbidities with dyslipidemia and with type 2 diabetes Moreover, the multitude of patents filed over the last few years claiming the synthesis of novel CB1 receptor antagonists reflects the intense competition in this area However, at present, little is known about the results of these trials.

    The CB1 receptor antagonist rimonabant was initially tested in humans not as an antiobesity drug but for its potential ability to reduce subjective intoxication and tachycardia in healthy subjects with a history of marijuana use or as an antipsychotic agent in schizophrenic patients.

    The first study showed that rimonabant was well tolerated by the participants even at a mg dose single oral dose. A significant dose-dependent blockade of marijuana effects was shown. However, the ability to reduce the intoxication induced by marijuana was very mild The results derived from the clinical trial in which rimonabant was tested to treat schizophrenia and schizoaffective disorders were not very satisfactory, because the effects of the drug in ameliorating clinical symptoms were not different from those obtained by placebo Bearing in mind the function of the endocannabinoid system in the mesolimbic rewarding system, rimonabant is also undergoing clinical trials as an aid to preventing the relapse of smoking cessation The clinical study enrolled smokers who received rimonabant at a dose of 5 or 20 mg or a placebo in a randomized fashion.

    The clinical trial lasted 10 wk, and the smokers were permitted to smoke during the first 2 wk but were asked to abstain from smoking after this period. The quit rate for subjects in the mg rimonabant group was double that of the placebo group.

    In particular, the smokers characterized by overweight and obesity showed a relevant reduction in weight gain over the wk treatment The most promising data seem to derive from rimonabant as a treatment for obesity. Patients taking the mg dose reported a weight loss of 4. No significant adverse effects were noted. At the end of the treatment, weight loss was not maintained. However, the rebound in weight did not reach the pretreatment values Another phase II, 7-d treatment, double-blind, placebo-controlled study was performed to evaluate hunger, calorie and fat intake.

    All these parameters were significantly reduced at the end of the short treatment, and the resulting average loss in body weight was 0. The drug showed a good safety profile A large phase III trial named as RIO rimonabant in obesity was initiated in August including more than overweight or obese patients All studies have already been concluded, and some of them are already reported in the literature , Two of these studies, named RIO-North America and RIO-Europe, recruited obese and overweight patients with or without comorbidities who were treated for 2 yr with 5 or 20 mg rimonabant vs.

    The primary endpoints of the RIO-North America study were the absolute change in weight from baseline to 1 yr and the prevention of weight regain after rerandomization second year , whereas the main endpoint of the RIO-Europe study was the assessment of weight reduction by using the same dosages. RIO-Lipids and RIO-Diabetes are the other two clinical trials with rimonabant aimed at investigating the amelioration, after treatment with the CB1 receptor antagonist, of specific comorbidity factors associated with obesity or overweight such as hyperlipidemia and diabetes.

    All patients were required to follow a reduced calorie diet. After 1 yr of therapy, patients in the mg dose group showed a loss of 8.

    Rimonabant was associated with an important and significant reduction in waist circumference, tryglicerides, and C reactive protein, whereas a significant increase in HDL-cholesterol was found in the mg treatment group compared with the group of patients undergoing placebo treatment. Rimonabant was generally well tolerated, and the most frequently reported side effects were gastrointestinal and upper respiratory tract symptoms Similar data have been obtained by the ad interim analysis of the first year treatment in the RIO-Europe study , The pattern of weight loss appeared to be sustained for up to 36—40 wk.

    A concomitant reduction in waist circumference of about 9 cm was observed in patients treated with 20 mg rimonabant. As expected by studies in the animals described above, the study of Van Gaal et al. Although Van Gaal et al. Full understanding of these still unknown modes of action is urgently needed to better characterize the ideal phenotype of obese patients to be targeted with CB1 receptor antagonist drugs.

    Rimonabant treatment was well tolerated, and the most common adverse events experienced with 20 mg rimonabant were gastrointestinal symptoms such as nausea and diarrhea and mood disorders such as anxiety and depression. However, the effects were found to be mild, and the discontinuation rate due to these events was similar between patients taking 20 mg rimonabant or placebo.

    The genesis of these adverse events might be explained by bearing in mind that, as explained above, CB1 receptor plays a role in gastrointestinal motility and in HPA axis activation. Nausea and diarrhea on the one hand and anxiety and depression on the other hand might be due to CB1 receptor pharmacological blockade. Concerning studies in humans, a very recent report confirms, on a genetic basis, the possible association between the chronic pathological overactivation of the endocannabinoid system and the development of obesity.

    In fact, in a large cohort of Caucasian and black subjects, overweight and obesity have been found to be associated with a polymorphism in FAAH. This genetic variant predicts a substitution of threonine for a highly conserved proline residue PT. It has been observed that patients carrying this polymorphism may have approximately half the enzymatic activity of FAAH.

    This may lead to a reduced inactivation of AEA and, eventually, to an inappropriate chronic increase of endocannabinoid tone In such a context, a recent work 60 showed increased circulating levels of AEA and 2-AG in obese women when compared with a lean control group.

    Moreover, in the same study, a marked down-regulation of FAAH gene expression in adipose tissue of obese women has been found, suggesting that the increased endocannabinoid levels may be secondary to decreased enzymatic degradation A number of studies show that the endocannabinoid system profoundly influences both hormone secretion and metabolic processes. Animal models have represented the ideal tool for advancing the understanding of the mechanisms of these functions.

    However, the data derived from early studies were not always straightforward in the conclusions. The contradictory results had to be largely attributed to the heterogeneous variety of substances, dosages, and routes of administration used in each experimental model. Actions of CB1 antagonists on the target organs involved in food intake and metabolic control. Schematic drawing illustrating the main sites of action of CB1 antagonists in the control of energy balance. As a general conclusion, the endocannabinoid system appears to play a very important regulatory role in the secretion of hormones related to reproductive functions and to stress responses.

    These observations have led to some important clinical considerations. High levels of endocannabinoids seem to negatively affect reproduction by acting at different sites. It is therefore possible to speculate about a clinical use of CB1 receptor antagonists to ameliorate gonadotropin pulsatility or to improve fertilization capability.

    On the other hand, endocannabinoids are important modulators in the physiological response of the HPA axis during repetitive stress conditions and in pathological conditions, such as anxiety, phobias, depression, and posttraumatic stress disorders 16 , Moreover, the endocannabinoid system has been proposed as playing an important role in protection against neurotoxicity and, possibly, certain forms of epilepsy , , Drugs presumed to increase endocannabinoid tone are therefore currently proposed as a new therapeutical frontier to treat anxiety-related disorders and neurodegenerative diseases The use of drugs acting as antagonists of CB1 receptor should thus be carefully monitored when administered, for instance, to patients with anxiety traits, epilepsy, or neurodegenerative disorders.

    The anecdotes regarding the orexigenic properties of marijuana have nowadays been substantiated by an impressive number of reports that make it possible to definitively include cannabinoids in the large family of orexigenic signals. This large body of data provided the basis to establish a novel approach to tackle obesity and related disorders by means, as strongly suggested by the clinical trials with rimonabant, of a CB1 receptor antagonist. During the last few years, it has become evident that multiple mechanisms of action, not solely limited to the CNS, are involved in the endocannabinoid-mediated control of food intake and energy balance.

    The full understanding of these modes of action may lead to the identification of the particular types of obesity where treatment with CB1 receptor antagonists work most efficiently. The potential clinical use of rimonabant will also help us to clarify how the endocannabinoid system affects the physiological functions and the pathological diseases related to hormonal secretion and energy balance.

    Close mobile search navigation Article navigation. Endocannabinoid System in the Modulation of Energy Balance. Note Added in Proof. View large Download slide. Overview of the cannabinoid action by CB1 activation in the various endocrine axes. Summary of the effect of CB1 antagonist treatment on food intake in different rodent models.

    Isolation, structure and partial synthesis of an active constituent of hashish. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

    Isolation and structure of a brain constituent that binds to the cannabinoid receptor. The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: The endogenous cannabinoid system controls extinction of aversive memories. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. Cannabinoid system as a potential target for drug development in the treatment of cardiovascular disease.

    Targeting the endocannabinoid system in cancer therapy: International Union of Pharmacology. Classification of cannabinoid receptors. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Characterization and localization of cannabinoid receptors in rat brain: Cannabinoid receptor binding and messenger RNA expression in human brain: Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain.

    The gastrointestinal tract is a site for the production of EC, and along with its associated organs, it is influenced by the ECS during the digestion and absorption of macronutrients. Muscle and liver are sites for glucose storage, as glycogen and adipose are for fat deposition. Furthermore, biochemical pathways of glucose, amino acids, and lipid metabolism link the muscle, liver, and adipose to cooperatively sustain the supply of intermediates that maintain energy balance in the fed and fasting state, as well as for growth and maintenance.

    It is clear that the ECS is a key player in macronutrient metabolism between the organs involved in food intake and systemic energy balance Di Marzo and Matias, ; Viveros et al. At the gene level, sensitivity of muscle to insulin and glucose uptake appears to be influenced by the ECS Kim et al. Aspects of the involvement of the ECS in obesity, with specific studies in adipocyte cell cultures and adipose tissues, are described in the literature Naughton et al.

    The change in expression of ECS genes also indicated differences between muscle and adipose in mice. Furthermore, epididymal fat mass was lower in mice fed the DHA containing semi-purified diet, as compared to mice fed the control diet.

    If the action of DHA is as the EC, docosahexaenoyl ethanolamide, it may alter cannabinoid downstream signaling to improve glucose uptake in myoblasts Kim et al. In support of these findings and the link to macronutrient metabolism, these initial studies in mice show that DHA, most likely through the ECS, alters metabolite profiles to favor fatty acid oxidation and reduce fat accretion Kim et al. At the least, mechanistic research in rodent models and clinical investigations on dietary PUFA in glucose metabolism and fat accretion are warranted to understand the relationships of fat intake and the ECS.

    High circulating levels of AA-derived EC and excessive endocannabinoid production by adipocytes are associated with human obesity and fat accretion in rodents Engeli et al. The ECS works through many anorexigenic and orexigenic pathways where ghrelin, leptin, adiponectin, endogenous opioids, and corticotropin-releasing hormones are involved Viveros et al. Taken together, with the emerging role played by the ECS in obesity and with over production of the AA-derived EC prolonging stimulation of CB1 that leads to dysregulation Matias et al.

    Systemic macronutrient metabolism of carbohydrates, amino acids, and fatty acids now places the ECS as a target to redirect the fate of energy metabolism in the gastrointestinal tract, liver, muscle, and adipose.

    Emerging evidence of the phylogenic and developmental aspects of the ECS can be useful in understanding this complex system Viveros et al. As described in this review, the ECS plays an important role in eating, and specifically, when activated, CB1 leads to stimulation of food intake, which includes the behavioral aspects observed in fasted mice Soria-Gomez et al.

    The mechanisms and actions of the ECS in the full array of the drive to eat are not well understood. Mechoulam and Parker recently reviewed several behavioral aspects of the ECS in the brain, suggesting that the brain contains numerous EC-like compounds that activate the cannabinoid receptors to influence mood, depression, cognition, and learning; however, further study is needed to advance the knowledge of the CNS and brain functions.

    Interestingly, the distribution of the CB1 receptors, which is a primary receptor in the brain Wilson and Nicoll, and CNS, differs in neonatal and adult brains. Moreover, since cannabinoid receptor distribution and expression are influenced by aging, research should determine how the ECS functions during aging and especially with the loss of appetite in older adults. These findings underscore the complex nature of the ECS, which is a comprehensive component that ultimately impacts all aspects of eating behavior.

    It is well known that the ECS and the endogenously produced EC are crucial components for inducing food intake and controlling macronutrient metabolism Di Marzo and Matias, The flux through metabolic pathways for glucose, fatty acids, and amino acids is largely dependent on rate regulating enzymes of metabolic pathways in major organs, such as muscle, liver, and adipose, which are all impacted by the ECS.

    Hence, understanding these intermediary pathways, endocrine factors, and gene expression will encourage important areas of research to determine the role of the ECS on eating behavior Richard et al. As previously stated, one research approach should be to characterize how the different PUFA families integrate in the processes of metabolic flux of macronutrient pathways in major organs where the ECS is of consequence. In this review, we described the current research on the ECS and food intake, macronutrient metabolism, and the participating dietary PUFA that serve as substrate for the biosynthesis of EC.

    The evidence clearly indicates that the activation of the cannabinoid receptors in the brain stimulates food intake and overstimulation of the ECS contributes to overeating and obesity. In this regard, the ECS participates in macronutrient metabolism and energy status in adipose and muscle that appears to be highly dependent on the type of EC derived from dietary PUFA.

    Future studies should focus on the underlying aspects of how the n-6 and n-3 dietary PUFA families affect the ECS, alter the types of EC synthesized, change gene expression of the ECS, and direct the signaling pathways downstream of receptor activation. These investigations will potentially impact obesity risk and metabolic syndrome. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    Retrograde signaling in the regulation of synaptic transmission: Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity. Obesity Silver Spring 20, — Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Cannabinoids and the skeleton: Endocannabinoids may mediate the ability of n-3 fatty acids to reduce ectopic fat and inflammatory mediators in obese Zucker rats.

    The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period. Pubmed Abstract Pubmed Full Text 3. The endocannabinoid system in normal and pathological brain ageing. Brain regional distribution of endocannabinoids: The endocannabinoid signalling system: Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity.

    Functionally selective cannabinoid receptor signalling: Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. The neutral cannabinoid CB 1 receptor antagonist AM regulates body weight through changes in energy intake in the rat.

    The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. An introduction to the endocannabinoid system: Determination and characterization of a cannabinoid receptor in rat brain. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: CB1 antagonists for obesity—what lessons have we learned from rimonabant?

    Leptin-regulated endocannabinoids are involved in maintaining food intake. Endocannabinoid control of food intake and energy balance. Activation of the peripheral endocannabinoid system in human obesity. Effects of the cannabinoid antagonist SR rimonabant and d-amphetamine on palatable food and food pellet intake in non-human primates. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner.

    CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages.

    Gynecomastia in marihuana users. Endocannabinoids and the regulation of body fat: Feeding and body-weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats.

    Docosahexaenoyl ethanolamide improves glucose uptake and alters endocannabinoid system gene expression in proliferating and differentiating C2C12 myoblasts. Endocannabinoid signaling and energy metabolism: Fat to treat fat: Prostaglandins Other Lipid Mediat.

    Cannabinoid receptor antagonists and fatty acids alter endocannabinoid system gene expression and COX activity. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.

    Bone mineral content is positively correlated to n-3 fatty acids in the femur of growing rats. Cannabinoid agonist WIN, partially restores neurogenesis in the aged rat brain. Alterations in the hippocampal endocannabinoid system in diet-induced obese mice.

    The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

    Regulation of food intake and obesity. Care and feeding of the endocannabinoid system: Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. The endocannabinoid system and the brain. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa.

    Cannabis, the mind and society: The endocannabinoid system is implicated in both homeostatic and hedonic food intakes [ 9 ], with activation of the system resulting in an increase in hunger [ 10 , 11 ]. Specifically, anandamide AEA and 2-arachidonoyl glycerol 2-AG , which are derivatives of arachidonic acid AA [ 7 , 12 , 13 ], bind to the main two receptors, cannabinoid receptor 1 CB 1 and cannabinoid receptor 2 CB 2 , leading to activation of pathways to initiate food intake in the limbic system [ 14 ], hypothalamus [ 15 , 16 ] and hindbrain [ 17 ].

    CB 1 and CB 2 belong to the GPCR class of receptors, generally signalling through proteins, though chronic low level stimulation triggers a shift to signalling through G s proteins [ 18 ].

    Though there are structural differences between the glycerol-based and the N -acylethanolamine- NAE- based endocannabinoids, they share common receptor pathways and functions, with all compounds involved in appetite and modulation of metabolism signalling through GPCR or altering GPCR signalling [ 21 , 23 , 24 ].

    Endocannabinoids are products of dietary fatty acids FA and were originally thought to be generated on demand [ 25 — 27 ], though it is now known that AEA can be stored in intracellular lipid droplets [ 28 ]. As such, modulation of cannabinoid receptor function can occur via modification of dietary FA intake. Current dietary guidelines recommend a shift away from animal-derived fats in favour of plant fats, in an effort to reduce saturated fat intake and cardiovascular disease risk, which has resulted in an increased intake of polyunsaturated fatty acids PUFA , especially that of linoleic acid [ 29 , 30 ].

    AA can then be converted to AEA via several pathways as shown in Figure 1 , including the condensation of AA and ethanolamide due to the reverse activity of fatty acid amide hydrolase FAAH , as reviewed by Sugiura [ 32 ]. As FAAH is also the main enzyme responsible for AEA breakdown, its action is also capable of decreasing cannabinoid receptor activation through a reduction in the availability of agonists [ 33 ]. Similarly there are several pathways through which 2-AG can be synthesised, as shown in Figure 2.

    One of these pathways involves the conversion of diacylglycerol to 2-AG via diacylglycerol lipase, with diacylglycerol being produced from phosphatidylinositol, phosphatidylcholine, or phosphatidic acid, with the latter two being synthesised by phospholipase C and phosphatases, respectively [ 36 , 37 ]. Phospholipase C is also capable of converting phosphatidylinositol bisphosphate to diacylglycerol and lysophosphatidylinositol to 2-AG, though this requires a specific phospholipase C isoform [ 38 ].

    With dietary fats being the only source of FA required for synthesis of endocannabinoids, it is possible that what is being consumed is capable of modulating circulating endocannabinoid levels, thus influencing GPCR signalling in an acute time frame and affecting appetite and subsequent food intake.

    Also, specific FA, such as AA, are favourably incorporated into phospholipids as opposed to triglycerides [ 41 ], further affecting their fate in regard to endocannabinoid synthesis due to their cellular location; however, the role of storage in the acute effects of dietary fats and later endocannabinoid synthesis requires further investigation. Clear associations between body weight and modulation of the endocannabinoid system have been found.

    The most common of these is that circulating 2-AG levels are significantly increased in obese individuals compared to lean controls [ 42 , 43 ].

    This increase in 2-AG may also be a result of increased diacylglycerol lipase in obesity, which has been demonstrated in both animal [ 48 , 49 ] and human adipocytes [ 50 , 51 ], though this may be site specific [ 50 ] and influenced by dietary composition [ 52 ]. An increase in FAAH has been found to result in decreased subcutaneous adipose tissue 2-AG levels in obese subjects when compared to lean controls [ 53 ], with 2-AG also being positively correlated with visceral CB 1 gene expression [ 42 ].

    Body weight has also been found to influence cannabinoid receptor expression, with significant correlations found between CB 1 expression and BMI [ 54 ], percentage body fat [ 42 ], and the presence of the metabolic syndrome independent of BMI [ 54 ].

    A correlation in obese individuals has also been found between circulating insulin and increased visceral adipose tissue CB 1 expression, compounded by the presence of the metabolic syndrome, perpetuating visceral lipogenesis due to the role of CB 1 in promoting energy storage in adipose tissue [ 54 ]. Overweight and obese individuals often have a dysregulation of the endocannabinoid system in peripheral tissues, affecting glucose and lipid metabolism [ 50 , 55 , 56 ].

    Demonstrating this, a study using paired adipose tissue samples found greater CB 1 mRNA expression in visceral adipose tissue than subcutaneous, with a negative correlation between visceral fat mass and FAAH mRNA expression [ 42 ].

    Similarly, other studies have found that genes involved in 2-AG, CB 1 , and MGL synthesis are downregulated in gluteal and upregulated in abdominal adipose tissue of obese individuals [ 50 , 55 ].

    As activation of CB 1 results in increased glucose uptake [ 57 ], this may indicate preferential energy storage in abdominal adipose tissue. Supporting this, glucose uptake in adipocytes is increased by treatment with 2-AG [ 58 ] or AEA which increased glucose uptake 2-fold [ 59 ] with insulin resistant adipocytes from obese mice showing increased expression of endocannabinoid synthesising enzymes and decreased degrading enzymes [ 48 ].

    Thus, chronic stimulation of CB 1 may lead to a cycle of increased adipocyte differentiation and thus further CB 1 expression. Similarly CB 1 agonism with arachidonoylchloroethylamide in lean rat muscle significantly reduces both basal and insulin stimulated glucose uptake [ 64 ].

    Research on acute modulation of the endocannabinoid system by dietary intake in humans is extremely limited and has generally focused on macronutrient ratios rather than specific FA intakes. These studies tested different meal compositions with Gatta-Cherifi et al. Both studies showed obese subjects to have increased fasting plasma AEA and 2-AG concentrations, indicating potential chronic cannabinoid receptor overstimulation [ 61 , 65 ], with Gatta-Cherifi et al.

    A positive correlation was also found between AEA and insulin levels in the obese group [ 65 ], demonstrating CB 1 overactivity in insulin resistant individuals. This study also found that in the hour after meal consumption AEA levels decreased only in lean subjects, indicating greater orexigenic stimulus in the obese individuals [ 65 ], possibly leading to short term hedonic food intake and therefore excess energy intake. Meal consumption by normoglycaemic participants in the Matias et al.

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    Involvement of the Endocannabinoid System in Metabolism and Fertility. Potential Implication in the Polycystic Ovary Syndrome. Authors; Authors and affiliations. In general, the endocannabinoid system is involved in many different physiological functions, many of which relate to stress‐recovery systems. The endocannabinoid system (ECS) has emerged as one of the most relevant regulators of energy balance. The ECS acts through two.

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    Involvement of the Endocannabinoid System in Metabolism and Fertility. Potential Implication in the Polycystic Ovary Syndrome. Authors; Authors and affiliations.


    In general, the endocannabinoid system is involved in many different physiological functions, many of which relate to stress‐recovery systems.


    The endocannabinoid system (ECS) has emerged as one of the most relevant regulators of energy balance. The ECS acts through two.


    Overview of the Endocannabinoid System in the Brain and Peripheral Organs the role of the ECS in systemic macronutrient metabolism and fat accretion.


    This knowledge may help in the design of future therapies for the metabolic .. The role of the endocannabinoid system in skeletal muscle and metabolic.


    The Endocannabinoid System and Peripheral Organs Involved in Control of of endocannabinoids in the regulation of food intake and energy metabolism, and.

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