The endocannabinoid system has been recently recognized as an important modulatory It appears to play a very important regulatory role in the secretion of . The endocannabinoid system, including its receptors (CB(1) and CB(2)), During foetal life, the cannabinoid CB(1) receptor plays a major role in brain. The endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role.
System Plays a Role Vital Endocannabinoid The
However, it was recently proposed that the endocannabinoid system might control hormonal balance also through a direct effect at the level of the peripheral target organs.
An overview of the cannabinoid actions on endocrine axes is given in Table 1. Stimulation of the hypothalamic-pituitary-adrenal HPA axis is a crucial neuroendocrine response to stress. Psychological or physiological stressors are known to induce CRH production in the PVN of the hypothalamus, eventually leading to a release of this hypothalamic peptide onto the anterior pituitary gland.
In turn, this leads to increased circulating levels of ACTH and, finally, to an increase of corticosteroids secreted by the adrenal gland. Until a few years ago, the impact of the cannabinoids on the HPA axis was considered as an exception. Whereas the commonly accepted view attributes the cannabinoid system with a general inhibitory role on neuroendocrine functions, it was suggested that cannabinoids are, on the contrary, able to stimulate the HPA axis.
In fact, many studies in animals point to a CB1 receptor-dependent increase of circulating ACTH and glucocorticoid levels after pharmacological administration of plant-derived , synthetic , , or endogenous cannabinoid agonists , In agreement with this, a simultaneous elevation of CRH in the PVN and of proopiomelanocortin in the anterior pituitary after chronic treatment 18 d with the CB1 receptor agonist CP, was observed in rats However, this concept was recently challenged by several reports showing a different function of endocannabinoids on the HPA axis.
In fact, some studies showed that administration of the CB1 receptor antagonist SR in rats is able to induce ACTH and corticosterone release and to produce anxiety-like behavior , It is well known that this behavior represents part of the physiological response to stressful stimuli and is, indeed, associated with the hyperactivation of the HPA axis Moreover, compounds able to increase endocannabinoid tone by inhibiting FAAH activity were recently proposed as treatment for anxiety-related disorders because they were shown to reduce restraint-induced corticosterone release and to diminish the anxiety-like response in different tasks Therefore, a novel view seems to attribute the endocannabinoid system with a critical inhibitory action on HPA functions.
A recent elegant report by Patel et al. The authors confirmed previous studies showing that systemic treatment with SR is able to increase serum corticosterone concentrations in basal conditions; more importantly, they found that pretreatment of mice with the same CB1 receptor antagonist before acute restraint stress provokes a potentiation of the restraint-induced rise in serum corticosterone concentrations. In addition, endogenous cannabinoids and, in particular 2-AG, were found to be decreased after a short period of restraint stress, whereas a condition of prolonged stress was associated with an increase in 2-AG concentrations Accordingly, they concluded that endocannabinoid signaling negatively modulates the stress-induced activation of the HPA axis, confirming the notion that a pharmacological increase in endocannabinoid signaling activity may constitute a novel approach to the treatment of anxiety-related disorders Besides the hypothalamus, peripheral sites of action, such as pituitary and adrenal glands, could participate in the endocannabinoid modulation of the HPA functions.
Therefore, in the corticotroph cells, an endocannabinoid tone could interfere with the normal regulation of the adenylate cyclase activity and, thus, with the secretion of ACTH. As mentioned above, a pending question regards CB1 receptor expression and endocannabinoid production at the level of cortical adrenal gland and their putative role in the secretive function of this gland.
Further efforts are needed to solve this important issue. GH secretion is mainly stimulated by hypothalamic GHRH and by the recently discovered peptide ghrelin 69 , whereas somatostatin is the most important negative regulator.
Other neurotransmitters such as serotonin, dopamine, and catecholamines can affect GH secretion through modulation of GHRH release. Few data are available concerning the effects of marijuana on GH in humans. Four days of marijuana consumption were shown to inhibit the GH-counteracting response provoked by insulin-induced hypoglycemia However, compared with other hormones, it is still questionable whether cannabinoids are able to decrease GH secretion acting exclusively at the hypothalamic level or whether they also directly influence GH pituitary output.
Recent data point to a functional cross-talk between CB1 receptor and the ghrelinergic system. In fact, hyperphagia associated with intracerebroventricular administration of ghrelin is blocked by pretreating the rats with SR Unfortunately, no data have been provided concerning GH release in this experimental setting.
Altogether, these data seem to indicate that the effect of exogenous cannabinoids on GH secretion is located at a suprapituitary level. However, the cannabinoid agonist WIN 55, inhibited GH secretion in human GH-producing adenomas in culture, and this effect was reversed by the specific CB1 receptor antagonist SR, suggesting that cannabinoids are able to directly influence basal GH secretion through CB1 receptor activation, at least in tumoral tissues No data are available on the physiological modulation made by the endocannabinoid system on GH secretion.
Pioneer studies showed that marijuana is able to decrease TSH and thyroid hormones in rats , and iodine accumulation in the isolated rat thyroid The lack of changes in TRH secretion in the hypothalamus led the authors to conclude that the cannabinoid effect could be attributed to a direct action at the level of the pituitary or the thyroid gland Recently, Porcella et al.
TSH levels were unaffected, indicating that the thyroid gland itself may be the direct target of cannabinoid action On the other hand, the lack of TSH changes may also be explained by an action of cannabinoids on the levels of thyroid binding protein or on the metabolism of thyroid hormones.
More studies are needed to verify these hypotheses. Concerning the physiological roles of the endocannabinoid system, an inhibitory action on TRH neurons through a glucocorticoid-induced inhibition of glutamate transmission was recently proposed There is no general consensus regarding the effect of exogenous cannabinoids on PRL secretion. Early studies in rodents and primates favor an inhibitory role of cannabinoids on PRL release , — through a CB1 receptor-mediated effect Conversely, some reports showed that cannabinoids may also have either a stimulatory effect , or no effect on PRL release.
As often occurs in the field of cannabinoids, this controversy may be largely due to the different experimental settings used. In the same study, the antagonist SR was only able to block the inhibitory effect, whereas no effect was seen toward the cannabinoid stimulatory effect on PRL There is a general agreement that cannabinoid activation of the tuberoinfundibolar dopaminergic neurons controlling PRL secretion is the main mechanism responsible for the inhibition of this pituitary hormone , Similar conclusions were drawn from similar models by other authors Recently, exogenous AEA was shown to inhibit PRL release from male rats by acting on the CB1 receptor on dopaminergic neurons located in the medial basal hypothalamus However, like other hormones, it has also been hypothesized that cannabinoids may also affect PRL secretion directly in the pituitary.
The direct effect of cannabinoids at pituitary level was also confirmed by the demonstration that WIN 55, does not affect basal secretion, but inhibits vasoactive intestinal peptide- and TRH-stimulated PRL release in tumoral pituitary GH 4 C 1 cells In conclusion, we can assume that the biphasic action on PRL secretion of exogenous cannabinoids is mediated by an initial activation of CB1 receptor located at the level of the pituitary and followed by a persistent inhibitory action mediated by the activation of the release of dopamine from hypothalamic structures.
While FSH secretion seems to be unaffected by administration of exogenous or endogenous cannabinoids , several pieces of evidence attribute cannabinoids with a strong ability to down-regulate blood LH levels 49 , , , This effect is due to a complete suppression of the secretory pulse of LH , However, the same animals developed tolerance to the antireproductive effect of the drug after a few months of treatment The sustained use of marijuana at least four times per week may cause alterations of the menstrual cycle, such as oligomenorrea; however, no changes were shown in hormonal parameters in a group of 13 pregnant women who continued to smoke marijuana during pregnancy An excess of cannabinoids may also impair regular ovulation, not only acting at the hypothalamic level but also directly affecting ovarian granulosa layers A general consensus attributes the LH-inhibitory action of cannabinoids to a suprapituitary site of action.
However, a report showed that cannabinoids are not able to block the basal GnRH secretion from hypothalami in vitro This last finding suggests that cannabinoids indirectly modify GnRH secretion by negatively modulating the activity of neurotransmitters known to facilitate GnRH secretion, such as norepinephrine and glutamate , and by stimulating those modulators known to down-regulate GnRH secretion, such as dopamine , GABA , opioids , and CRH The stimulatory effect of cannabinoids on dopaminergic neurons is well known , however their impact on the brain dopaminergic activity varies as a function of the gonadal status, as demonstrated by several lines of evidence Moreover, in the same study Mani et al.
However, although pharmacological studies have helped to explain the relevant role of the cannabinoids in modulation of the hypothalamus-pituitary-gonadal axis and sexual behavior, it is not yet known how, where, and under what circumstances the endocannabinoids are produced to do so. The recent findings of fluctuation during the ovarian cycle of AEA in both hypothalamus and pituitary 49 allowed some authors to speculate that endocannabinoids may influence hormonal secretion and sexual behavior by directly targeting the CB1 receptor Furthermore, an important production of endocannabinoids was found in the ovary, in particular at the time of ovulation, making it possible to hypothesize that the endocannabinoids may help to regulate follicular maturation and development of the ovary This observation, together with the expression of CB1 receptors in preimplantation embryos 80 , recently prompted strong efforts focused on the role of the endocannabinoid system during early pregnancy and in the modulation of embryo-uterine interactions.
High levels of AEA adversely affect embryo development and implantation through CB1 receptor activation , whereas low levels of AEA promote embryonic growth and differentiation , , Notably, a strong inverse correlation was described between levels of FAAH activity in maternal peripheral blood mononuclear cells and spontaneous miscarriage in women In addition, FAAH activity is lower, and consequently AEA higher, in patients who fail to achieve pregnancy during in vitro fertilization embryo transfer in comparison to patients who become pregnant Furthermore, AEA levels in the mouse uterus are inversely related to uterine receptivity for implantation, being higher with uterine refractoriness to blastocyst implantation , , and lower at implantation sites We can therefore conclude that high levels of maternal AEA are detrimental to early placental and fetal development.
In favor of this hypothesis, it was recently shown that high levels of FAAH are present in the cytotrophoblast, presumably to prevent the transfer of AEA from maternal blood to the embryo A series of studies by Maccarrone et al. Importantly, by using genetic or pharmacological blockade of the CB1 receptor, it was very recently demonstrated that an impairment in endocannabinoid signaling leads to a retention of a large number of embryos in the mouse oviduct, leading to pregnancy failure.
This is due to a profound impairment of a coordinated oviductal smooth muscle contraction and relaxation The authors propose that their findings may have strong implications for ectopic pregnancy in women because one major cause of tubal pregnancy is embryo retention in the fallopian tube Consistently, both endogenous and exogenous cannabinoids exert a CB1 receptor-mediated relaxant effect, not only on the oviductal smooth muscle but also on the human pregnant myometrium, highlighting a possible role of endocannabinoids during human parturition and pregnancy In fact, pregnancy also seems to be tightly controlled by the endocannabinoid system In summary, all the steps starting with fertilization up to pregnancy seem to be tightly modulated by endocannabinoids, reinforcing the concept that the endocannabinoid system should be considered not only as a central neuromodulator but also as a physiological actor in a wider scenario.
Cannabinoids also were shown to decrease LH in males , Although there is still no general consensus, chronic cannabinoid use in several species seems to decrease testosterone production and secretion , , to suppress spermatogenesis, and to reduce the weight of testes and accessory reproductive organs The important effects of cannabinoids on the gonadal system are mainly attributed to CB1 receptor activation, as demonstrated by using specific CB1 receptor agonists and antagonists , Interestingly, the testis is known to express CB1 receptor 70 and to synthesize endocannabinoids Studies with sea urchin gametes provided the first evidence that cannabinoids, in particular AEA, are able to directly inhibit achrosome reaction and sperm fertilization capacity On the other hand, seminal plasma contains high amount of AEA, and this may contribute to maintaining sperms in a quiescent metabolic condition The content of AEA decreases progressively in the uterus, oviduct, and follicular fluid, and this change in endocannabinoids may render sperms suitable for capacitation and fertilizing ability 74 , Furthermore, as shown in sea urchin, the eggs may have the capacity to release AEA after activation by the fertilizing sperm , inducing a CB1 receptor activation that might be able to prevent polyspermic fertilization by blocking the acrosome reaction in other sperm In humans, CB1 receptor activation by AEA was also shown to reduce sperm mobility by affecting mitochondrial activity, and to inhibit capacitation-induced acrosome reaction.
Importantly, these effects are inhibited by the CB1 receptor antagonist SR It is therefore reasonable to hypothesize that AEA levels might be increased in different pathological conditions of the male reproductive tract. In these cases, the pharmacological blockade of the endocannabinoid system might be helpful in the treatment of some forms of male infertility In conclusion, it appears that the endocannabinoid system plays an important role in the regulation of the hypothalamus-pituitary-gonadal axis both in females and in males, and fertility may be affected by cannabinoid drugs.
This evidence may represent an important issue in clinical endocrinological praxis. In the light of the widespread use of marijuana as a recreational drug among young people, subtle alterations of the gonadal hormonal profile or in fertility may therefore be attributed to a concomitant use of cannabis derivatives. On the other hand, the results of human epidemiological studies have not always been clear in confirming this negative impact , and more detailed research on this topic is needed in the future before drawing definitive conclusions.
Two notions highlight the importance of the endocannabinoid system in the regulation of food intake and energy metabolism. The first is the finding of a high degree of evolutionary conservation of the role of this system in the regulation of feeding responses The second is the observation that high levels of endocannabinoids in maternal milk are critically important for the initiation of the suckling response in newborns Animal models are ideal tools for elucidating the putative mechanism s of cannabinoids in the control of energy metabolism.
From a general point of view, one can say that rather contradictory results were obtained in these experiments. The ambiguous data could likely be attributed to differences in the animal model and in the experimental procedures used.
Moreover, in early studies using marijuana extracts, comparisons between various experimental data sets are extremely difficult due to the variability of the activity of cannabis derivatives, the dosages, and the routes of administration. In general, early studies using low doses of cannabinoids showed a reliable increase in food intake. This is also the reason why, in reviewing the studies published between and , Abel reported an increased food intake after cannabinoid administration only in 3 of 25 experiments In , Williams et al.
The authors maximized the ability to detect hyperphagia by adopting a prefed paradigm in which the animals were characterized by low baseline food intake before drug administration. The authors observed that the maximum effect of the drug 1. Abel also critically reviewed the studies aimed at proving the stimulating effect of cannabis on hunger in humans.
However, the lack of scientific thoroughness of these earlier studies led Abel to conclude that the putative cannabis-induced hunger effect was still far from being proven Both parameters increased after the first few days of the experiment. However, after this period, body weight continued to rise, averaging 2.
This pioneer study already suggested that the ability of cannabinoids to stimulate hunger may vanish with time, whereas a possible metabolic effect of the drug may remain active longer Nonetheless, later studies did not investigate the metabolic idea further, preferring to concentrate interest on the ability of cannabis to stimulate hyperphagia and overconsumption of highly palatable food at the central level.
In , Foltin et al. This hypothesis was further substantiated by the same group a few years later when increased total food intake particularly related to consumption of palatable food sweet solid snacks was observed as a main effect of smoked marijuana The stimulating effect of cannabinoids on appetite observed in healthy subjects promoted assessment of the efficacy of a cannabinoid treatment for clinical syndromes featuring loss of appetite or weight, such as cancer or AIDS-associated anorexia — , or as adjuvant therapy to limit nausea and vomiting symptoms associated with most chemotherapeutic drugs In , the U.
In , Dronabinol was approved for the treatment of patients with HIV-induced wasting syndrome. The most comprehensive data are those obtained when Dronabinol was administered in HIV patients with wasting syndrome , — To varying degrees, the drug was able to mildly increase appetite and energy intake in all studies.
However, a marked improvement in mood was also documented, raising the question of whether the positive effect in energy balance may derive from a specific action of cannabinoids in the brain areas controlling food intake or may be simply due to a generalized change in the sense of well-being.
Intriguingly, in some reports, a significant gain was found in body fat mass associated with minimal changes in appetite rating and food intake , At that time, this finding remained unexplained. In this context, it is still unknown, and it would be of great relevance to investigate whether the administration of Dronabinol can improve the pathological changes in fat distribution induced by the concomitant retroviral therapy in patients with AIDS The authors speculated that administration of AEA may represent an amplification of endocannabinoid activity associated with the normal, episodic pattern of meal-taking in rats Importantly, the effect of AEA was completely blocked by pretreating the animals with SR, confirming the pivotal role of CB1 receptor activation in the hyperphagic effects of endocannabinoids , Similar conclusions were derived from other studies in which AEA was able to exert an appetite-stimulating effect even at very low doses in mice 0.
These data therefore make it possible to attribute the endocannabinoid system with an important role in the processes underlying the motivation to obtain food. It is suggested that endocannabinoids gradually increase during intermeal intervals, reaching a critical level where motivation to eat is triggered.
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. The research that has been done, however, shows us that the ECS is an essential regulator of bodily function in its many facets. There are three components to the endocannabinoid system: The interactions of these three components in different areas of the body are responsible for a wide range of biological processes and health outcomes.
Our bodies produce many endocannabinoids, and two of them have been well-studied: Both are synthesized on demand for homeostatic functions.
Many other endocannabinoids exist, and when interacting with anandamide, 2-AG, and each other they provide significant increase in function. It appears that endocannabinoids use the entourage effect, similar to the entourage effect observed with phytocannabinoids, where they work better within the whole ECS rather than as isolated chemicals. The two main cannabinoid receptors are CB1 and CB2. The most abundant G protein-coupled receptor in the brain, suggesting it plays an important role in brain function, health, and disease;.
Largely present in the basal ganglia, hippocampus, cerebral cortex, cerebellum, and amygdaloid nucleus areas of the brain;. Unlike opioid receptors, largely absent from the brain stem, accounting for the lack of cannabis-related fatalities;. Receptors in the brain where THC exerts its effects by modulating short-term memory, pain, emotion, and hunger;.
Abundantly occurring in the spinal cord and peripheral nervous system;. Occurs in the gastrointestinal tract and modulates propulsion and excretion;. Anandamide and 2-AG are produced on demand by nerve cells as a response to stimulation. They can also block the release of other neurotransmitters e. Enzymes are substances that the body produces to create biochemical reactions. Within the endocannabinoid system, there are enzymes that synthesize anandamide and 2-AG as well as enzymes that break down both anandamide and 2-AG.
The most active endocannabinoid breakdown enzyme is fatty acid amide hydrolase FAAH which breaks down anandamide. Manipulation of FAAH can increase the activity of anandamide, much like selective serotonin reuptake inhibitors SSRIs increase serotonin activity to treat depression.
The ECS interacts with many different systems and functions of the body, however its general role is to maintain homeostasis, or balance. A person with a fully functioning ECS would, in theory, have no pain, a healthy appetite with good digestion, and normal mental function. In the absence of serious trauma or disease, the ECS fulfills many functions related to healthy growth and homeostasis: Cannabinoid receptors are present from the blastocyst period of gestation days.
Embryonal implantation on the uterine wall requires a temporary and localized reduction in anandamide, development of the fetal nervous system is regulated and protected from trauma by anandamide, and newborn suckling is critically dependent on activation of the CB1 receptors.
Similar to the role the ECS plays in embryonic brain development, the ECS also moderates adult neurogenesis, or the development of new neurons in the brain. The ECS modulates cell metabolism. Central Nervous System Feedback: The ECS is involved in regulating the release of classical neurotransmitters, the chemical messengers that transport signals across the synapses.
Cannabinoids, again functioning to create balance, suppress the production of some immune system cells and increases the secretion of others.
In addition, CB2 receptors and endocannabinoids are integral to the functioning of B cell lymphocytes defender cells and other killer cells.
Cannabinoids have been noted to cause antitumor effects by various mechanisms, including the induction of cell death, inhibition of cell growth, and inhibition of tumor metastasis. Cannabinoids also inhibit tumor angiogenesis the growth of blood and lymphatic systems that support tumors.
Both CB1 and CB2 receptors play a role in bone health, and protect against age-related bone loss as well as bone resorption.
The Endocannabinoid System
Due to the fact that it is such an important part of human health, Humboldt more information about the role that this system plays in our body. Abstract: A few years ago the endocannabinoid system has been recognized as a major .. seal system plays an important role in maintaining homeostasis. The main endocannabinoid system's function is the regulation of body homeostasis. The endocannabinoid system plays an important role in multiple aspects of.