ArticleLiterature Review

Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits

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Abstract

The endocannabinoid system has emerged as a key player in the control of eating. Endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), modulate neuronal activity via cannabinoid 1 receptors (CB1Rs) in multiple nuclei of the hypothalamus to induce or inhibit food intake depending on nutritional and hormonal status, suggesting that endocannabinoids may act in the hypothalamus to integrate different types of signals informing about the animal's energy needs. In the mesocorticolimbic system, (endo)cannabinoids modulate synaptic transmission to promote dopamine release in response to palatable food. In addition, (endo)cannabinoids act within the nucleus accumbens to increase food's hedonic impact; although this effect depends on activation of CB1Rs at excitatory, but not inhibitory inputs in the nucleus accumbens. While hyperactivation of the endocannabinoid system is typically associated with overeating and obesity, much evidence has emerged in recent years suggesting a more complicated system than first thought – endocannabinoids promote or suppress feeding depending on cell and input type, or modulation by various neuronal or hormonal signals. This review presents our latest knowledge of the endocannabinoid system in non-homeostatic and homeostatic feeding circuits. In particular, we discuss the functional role and cellular mechanism of action by endocannabinoids within the hypothalamus and mesocorticolimbic system, and how these are modulated by neuropeptide signals related to feeding. In light of recent advances and complexity in the field, we review cannabinoid-based therapeutic strategies for the treatment of obesity and how peripheral restriction of CB1R antagonists may provide a different mechanism of weight loss without the central adverse effects. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”.

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... In this context, endocannabinoids (eCBs) play a pivotal role in both homeostatic and rewarding aspects of feeding (Gatta-Cherifi & Cota, 2015). The two primary eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), by interacting with the cannabinoid type-1 receptor (CB1R), increase food intake by modifying the release of orexigenic and anorectic mediators, as well as by reinforcing the hedonic valuation of food (Lau, Cota, Cristino, & Borgland, 2017). Besides the classical eCBs, the eCB-related lipids, oleoylethanolamine (OEA) and palmitoylethanolamine (PEA), have been increasingly considered to play specific roles in the regulation of feeding (Fu et al., 2003;Romano, Tempesta, Provensi, Passani, & Gaetani, 2015). ...
... As outlined in the introduction, the role of eCBs in the regulation of feeding has been widely established. By activating the CB1Rs within the Hyp and the mesocorticolimbic system, eCBs increase food intake and mediate the hedonic perception of food (Lau et al., 2017;Scherma et al., 2014). Accordingly, when administered into specific areas such as the VMH Hyp, as well as the NAcc, both 2-AG and AEA promote hyperphagia and stimulate the intake of palatable foods (DiPatrizio & Simansky, 2008;Kirkham, Williams, Fezza, & Di Marzo, 2002;Soria-Gómez et al., 2007). ...
... Neuroimaging studies have revealed altered activation patterns within mesocorticolimbic regions in patients with acute AN and once recovered from AN (Frank et al., 2012;Wagner et al., 2007). Moreover, homeostatic and reward-based processes were shown to be under the action of the eCBs (Lau et al., 2017). ...
Article
Objective: Despite the growing knowledge on the functional relationship between an altered endocannabinoid (eCB) system and development of anorexia nervosa (AN), to date no studies have investigated the central eCB tone in the activity-based anorexia (ABA) model that reproduces key aspects of human AN. Method: We measured levels of two major eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), those of two eCB-related lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and the cannabinoid type-1 receptor (CB1R) density in the brain of female ABA rats, focusing on areas involved in homeostatic and rewarding-related regulation of feeding behavior (i.e., prefrontal cortex, nucleus accumbens, caudato putamen, amygdala, hippocampus and hypothalamus). Analysis was carried out also at the end of recovery from the ABA condition. Results: At the end of the ABA induction phase, 2-AG was significantly decreased in ABA rats in different brain areas but not in the caudato putamen. No changes were detected in AEA levels in any region, whereas the levels of OEA and PEA were decreased exclusively in the hippocampus and hypothalamus. Furthermore, CB1R density was decreased in the dentate gyrus of hippocampus and in the lateral hypothalamus. After recovery, both 2-AG levels and CB1R density were partially normalized in some areas. In contrast, AEA levels became markedly reduced in all the analyzed areas. Discussion: These data demonstrate an altered brain eCB tone in ABA rats, further supporting the involvement of an impaired eCB system in AN pathophysiology that may contribute to the maintenance of some symptomatic aspects of the disease.
... They are polyunsaturated fatty acids derived from plasma membrane phospholipid and are increased in the peripheral tissues and brains of obese animals and humans. [76][77][78][79][80] The endocannabinoid system exerts synergistic central and peripheral actions, regulating homeostatic and non-homeostatic feeding, 72,81 as well as energy expenditure, 74 leading to increased fat storage and a net anabolic effect. ...
... 111 Interestingly, eCB-LTD of the NAc is impaired by chronic or acute in vivo exposure to synthetic cannabinoids (eg, Δ9-THC) 112,113 or n-3 polyunsaturated fatty acid deficiency possibly as a result of tolerance and desensitisation of CB1Rs. Thus, diets low in omega-3 polyunsaturated fatty acids can disrupt normal eCB plasticity in the striatum.Endocannabinoids can promote or suppress feeding depending on the dose/concentration, site of action and concurrent neuronal or hormonal signals.81 Application of AEA to the NAc medial shell elicits positive orofacial affective responses to sucrose,114 suggesting that, similar to opioids, eCBs might increase the hedonic impact of foods.115 ...
... Similarly, local administration of both 2-AG and AEA into the NAc elicits hyperphagia, and this is reversed by a CB1R antagonist.116,117 eCBs in the hypothalamus interact with CB1Rs on different hypothalamic neuronal subtypes to modulate neurotransmitter release and endocrine responses and can promote food intake.81 CB1Rs expressed on hypothalamic neuronal subtypes that have opposing action on the regulation of energy balance serve to coordinate behavioural and metabolic changes in response to the diet ingested. ...
Article
Easy access to palatable food and an abundance of food‐related cues exacerbate non‐homeostatic feeding. The metabolic and economical sequelae of non‐homeostatic feeding outweigh those of homeostatic feeding and contribute significantly to the global obesity pandemic. The mesolimbic dopamine system is the primary central circuit that governs the motivation to consume food. Insulin and endocannabinoids (eCBs) are two major, presumably opposing, players in regulating homeostatic and non‐homeostatic feeding centrally and peripherally. Insulin is generally regarded as a postprandial satiety signal, whereas eCBs mainly function as pre‐prandial orexinergic signals. In this review, we discuss the effects of insulin and eCB‐mediated actions within the mesolimbic pathways. We propose that insulin and eCBs have regional‐ and time course‐dependent roles. We discuss their mechanisms of actions in the ventral tegmental area and nucleus accumbens, as well as how their mechanisms converge to finely tune dopaminergic activity and food intake. The most common cause of obesity is overconsumption of energy dense foods due to the ever‐increasing prevalence of an obesogenic food environment. The mesolimbic dopamine circuit underlies the motivational salience of cues predicting food, and thus is an important driver of food intake. This system is modulated by peripheral and central factors that relay information on energy status, including insulin and endocannabinoids. Here, we review the literature on the effects of insulin and endocannabinoid mediated actions within the mesolimbic circuit and propose how their mechanisms converge to tune dopaminergic activity and food‐seeking behaviour.
... Consistent with a key role in the regulation of food intake and energy balance, EC concentrations in the hypothalamus and limbic forebrain of rats, as well as in human plasma, transiently increase after food deprivation, and decrease after feeding (10)(11)(12). These changes have been linked to stimulatory and inhibitory effects of several metabolic hormones whose concentrations also fluctuate with nutritional status, including ghrelin (details in the Supplemental Information) (1,13). This supports the notion of an intricate interplay between the ECS and metabolic hormones in the regulation of both homeostatic and hedonic aspects of food intake (13)(14)(15). ...
... These changes have been linked to stimulatory and inhibitory effects of several metabolic hormones whose concentrations also fluctuate with nutritional status, including ghrelin (details in the Supplemental Information) (1,13). This supports the notion of an intricate interplay between the ECS and metabolic hormones in the regulation of both homeostatic and hedonic aspects of food intake (13)(14)(15). ...
... Finally, animal studies suggest that cannabinoids selectively modulate the motivation to consume palatable food by enhancing its orosensory properties, including taste and smell (16)(17)(18)(19)(20), and thereby its perceived pleasantness (13). As the sensory perception of food is also highly influenced by metabolic status, the ECS may influence appetitive motivation both centrally (in homeostatic and hedonic circuits) and peripherally (by interacting with metabolic hormones as well as food-related sensory information) (8,13,21). ...
Article
Background: The endocannabinoid system (ECS) is considered a key player in the neurophysiology of food reward. Animal studies suggest that the ECS stimulates the sensory perception of food, thereby increasing its incentive-motivational and/or hedonic properties and driving consumption, possibly via interactions with metabolic hormones. However, it remains unclear to what extent this can be extrapolated to humans. Objective: We aimed to investigate the effect of oral Δ9-tetrahydrocannabinol (THC) on subjective and metabolic hormone responses to visual food stimuli and food intake. Methods: Seventeen healthy subjects participated in a single-blinded, placebo-controlled, 2 × 2 crossover trial. In each of the 4 visits, subjective "liking" and "wanting" ratings of high- and low-calorie food images were acquired after oral THC or placebo administration. The effect on food intake was quantified in 2 ways: via ad libitum oral intake (half of the visits) and intragastric infusion (other half) of chocolate milkshake. Appetite-related sensations and metabolic hormones were measured at set time points throughout each visit. Results: THC increased "liking" (P = 0.031) and "wanting" ratings (P = 0.0096) of the high-calorie, but not the low-calorie images, compared with placebo. Participants consumed significantly more milkshake after THC than after placebo during oral intake (P = 0.0005), but not intragastric infusion, of milkshake. Prospective food consumption ratings during the food image paradigm were higher after THC than after placebo (P = 0.0039). THC also increased plasma motilin (P = 0.0021) and decreased octanoylated ghrelin (P = 0.023) concentrations before milkshake consumption (i.e., in both oral intake and intragastric infusion test sessions), whereas glucagon-like peptide 1 responses to milkshake intake were attenuated by THC during both oral (P = 0.0002) and intragastric (P = 0.0055) administration. Conclusions: These findings suggest that the ECS drives food intake by interfering with anticipatory, cephalic phase, and metabolic hormone responses. This trial was registered at clinicaltrials.gov as NCT02310347.
... Of course, the ECS is also part of all the integration signals in the hypothalamus that control food intake. Variations in the diet or nutritional status can vary endocannabinoids concentrations within this area of the brain [81]. In the paraventricular nucleus, CB1 receptors modulate the release of serotonin (5-HT) and GABA to stimulate food intake [82], whereas, in the arcuate nucleus, CB1 receptors are expressed in pro-opiomelanocortin (POMC) neurons, where their stimulation causes the release of the orexigenic peptide βendorphin and the inhibition of the release of anorexigenic peptide α-MSH [83]. ...
... In the paraventricular nucleus, CB1 receptors modulate the release of serotonin (5-HT) and GABA to stimulate food intake [82], whereas, in the arcuate nucleus, CB1 receptors are expressed in pro-opiomelanocortin (POMC) neurons, where their stimulation causes the release of the orexigenic peptide βendorphin and the inhibition of the release of anorexigenic peptide α-MSH [83]. Several interactions between leptin, ghrelin, orexin, and the ECS in the hypothalamus have been widely studied and reviewed by Lau et al. [81]. Further investigation is needed to understand the interplay between the mesolimbic DA system and the hypothalamus. ...
... CB1 mediates hypophagia or hyperphagia in ACC, activating respectively, GABAergic or glutamatergic neurons. On the other hand, cannabinoids mediate insulin-induced long-term depression in VTA, which decreases DA release within the mesocorticolimbic system [81], with anorexigenic effects. ...
Article
Full-text available
Obesity is a complex disorder, and the number of people affected is growing every day. In recent years, research has confirmed the hypothesis that food addiction is a determining factor in obesity. Food addiction is a behavioral disorder characterized by disruptions in the reward system in response to hedonic eating. The endocannabinoid system (ECS) plays an important role in the central and peripheral control of food intake and reward-related behaviors. Moreover, both obesity and food addiction have been linked to impairments in the ECS function in various brain regions integrating peripheral metabolic signals and modulating appetite. For these reasons, targeting the ECS could be a valid pharmacological therapy for these pathologies. However, targeting the cannabinoid receptors with inverse agonists failed when used in clinical contexts as a consequence of the induction of affective disorders. In this context, new classes of drugs acting either on CB1 and/or CB2 receptors or on synthetic and degradation enzymes of endogenous cannabinoids are being studied. However, further investigation is necessary to find safe and effective treatments that can exert anti-obesity effects, normalizing reward-related behaviors without causing important adverse mood effects.
... Thus, ECs might induce food overconsumption by amplifying the palatability or orosensory reward of food (Kirkham and Williams, 2001) and also, at post-ingestive and absorptive stages, by the interaction with hormones such as ghrelin, leptin or CCK and by mediation of vagal connections (Di Marzo, 2011;DiPatrizio et al., 2011). Furthermore, short-and long-term feeding with HFD can modulate synaptic plasticity and alter excitability within different brain areas by the regulation of important brain neurotransmitters such as glutamate and γ-Amino butyric acid (GABA) or neurotrophic systems such as brain derived neurotrophic factor (BDNF)/neurotrophic receptor tyrosine kinase (NTRK), inducing changes in FI in which ECs would be also implicated (Lau et al., 2017). ...
... to hypothesize that the mechanisms regulating food intake in fish fed HFD are probably more related to hedonic aspects of feeding, which would be overriding the mechanisms associated with homeostatic control of appetite. This overconsumption motivated only by the rewarding properties of the palatable food, independently of the homeostatic needs, is well known in mammals and is one of the main causes of important metabolic diseases observed in humans like obesity or type 2 diabetes (Lau et al., 2017;Monteleone et al., 2016). In this context, the ECs (together with the endogenous dopamine and opioid systems) are thought to mediate the rewarding aspects of palatable food (La Tellez et al., 2013;Lau et al., 2017). ...
... This overconsumption motivated only by the rewarding properties of the palatable food, independently of the homeostatic needs, is well known in mammals and is one of the main causes of important metabolic diseases observed in humans like obesity or type 2 diabetes (Lau et al., 2017;Monteleone et al., 2016). In this context, the ECs (together with the endogenous dopamine and opioid systems) are thought to mediate the rewarding aspects of palatable food (La Tellez et al., 2013;Lau et al., 2017). Thus, in mammals a clear correlation exists between levels of circulating fatty acid and those of 2-AG and AEA in plasma associated with a preferred consumption of HFD (Higuchi et al., 2012;Joosten et al., 2010;Monteleone et al., 2012Monteleone et al., , 2016Naughton et al., 2013). ...
Article
The endocannabinoid system (ECs) is a well known contributor to the hedonic regulation of food intake (FI) in mammals whereas in fish, the knowledge regarding hedonic mechanisms that control FI is limited. Previous studies reported the involvement of ECs in FI regulation in fish since anandamide (AEA) treatment induced enhanced FI and changes of mRNA abundance of appetite-related neuropeptides through cannabinoid receptor 1 (cnr1). However, no previous studies in fish evaluated the impact of palatable food like high-fat diets (HFD) on mechanisms involved in hedonic regulation of FI including the possible involvement of ECs. Therefore, we aimed to evaluate the effect of feeding a HFD on the response of ECs in rainbow trout (Oncorhynchus mykiss). First, we demonstrated a higher intake over 4 days of HFD compared with a control diet (CD). Then, we evaluated the postprandial response (1, 3 and 6 h) of components of the ECs in plasma, hypothalamus, and telencephalon after feeding fish with CD and HFD. The results obtained indicate that the increased FI of HFD occurred along with increased levels of 2-arachidonoylglycerol (2-AG) and AEA in plasma and in brain areas like hypothalamus and telencephalon putatively involved in hedonic regulation of FI in fish. Decreased mRNA abundance of EC receptors like cnr1, gpr55 and trpv1 suggest a feed-back counter-regulatory mechanism in response to the increased levels of EC. Furthermore, the results also suggest that neural activity players associated to FI regulation in mammals as cFOS, γ-Amino butyric acid (GABA) and brain derived neurotrophic factor (BDNF)/neurotrophic receptor tyrosine kinase (NTRK) systems could be involved in the hedonic eating response to a palatable diet in fish.
... The endocannabinoid system also has a profound regulatory effect on energy balance (Silvestri and Di Marzo, 2013;Piazza et al., 2017). Two endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), have been shown to play important homeostatic roles via the activation of cannabinoid CB 1 receptors in distinct feeding circuits (Lau et al., 2017) and are increased in the brain (Kirkham et al., 2002) and gut (Dipatrizio et al., 2015) following food deprivation, likely due to their role in increasing appetite and motivation to feed. Indeed, manipulations that increase endocannabinoids also stimulate food intake: systemic (Williams and Kirkham, 1999;Hao et al., 2000) and central (Jamshidi and Taylor, 2001;Mahler et al., 2007) AEA administration increases feeding in rodents. ...
... The role of the endocannabinoids in stress-induced changes in feeding remains unclear. A number of studies have investigated how the endocannabinoid system influences the HPA axis (see Hill and Tasker, 2012;Morena et al., 2016), while also modulating homeostatic/hedonic feeding (see Lau et al., 2017). Moreover, stress has a robust effect on modulating both AEA and 2-AG signalling (see Morena et al., 2016 for review), which involves the actions of both CRH and GCs (Evanson et al., 2010;Hill et al., 2011;Wang et al., 2012;Gray et al., 2015Gray et al., , 2016Natividad et al., 2017). ...
... Activation of the endocannabinoid system and the HPA axis modulates energy balance in opposite ways. Manipulations that increase endocannabinoids or activation of CB 1 receptors stimulate feeding (Lau et al., 2017). In particular, feeding status appears to be regulated by endocannabinoid levels in the brain (Kirkham et al., 2002) and gut (Dipatrizio et al., 2015), suggesting that increased AEA and 2-AG levels drive feeding through separate circuits. ...
Article
Full-text available
Background and purpose: Stress is known to reduce food intake. Many aspects of the stress response and feeding are regulated by the endocannabinoid (eCB) system, but the roles of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in stress-induced anorexia are unclear. Experimental approach: Effects of acute restraint stress on eCBs were investigated in male Sprague Dawley rats. Systemic and central pharmacological inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) was used to determine the potential of elevated AEA and 2-AG to stimulate homeostatic feeding and modulate food consumption after stress. Animals were pretreated with the FAAH inhibitor, PF-04457845, or MAGL inhibitor, MJN110, prior to 2 h acute restraint stress or 2 h homecage period without food. Key results: Restraint stress resulted in a decrease in hypothalamic and circulating AEA, with no effect in the gastrointestinal tract, while 2-AG content in the jejunum (but not duodenum) was reduced. Intracerebroventricular (icv) administration of PF-04457845 (30 μg), attenuated stress-induced anorexia via CB1 receptors, yet reduced homeostatic feeding in unstressed animals through an unknown mechanism. On the other hand, systemic administration of MJN110 (10 mg/kg) reduced feeding regardless of stress/feeding condition and inhibited basal intestinal transit in unstressed rats. The ability of MAGL inhibition to reduce feeding in combination with stress was independent of CB1 signaling in the gut as the peripherally restricted CB1 antagonist, AM6545 did not block this effect. Conclusion and implications: The current study reveals diverse roles for 2-AG and AEA in homeostatic feeding and changes in energy intake following stress.
... In addition to DAergic systems, regulation of food intake and energy balance involves other systems, including the endocannabinoid system [16]. Centrally, this system is composed of two well-characterized G-protein coupled receptors (CB1 and CB2). ...
... The system is expressed both in hypothalamic and mesolimbic brain regions where it regulates both homeostatic and hedonic feeding [17]. In the hypothalamus, endocannabinoid levels are modulated in response to metabolic states with an increase during fasting and a decrease when animals are sated [16]. Endocannabinoids in the NAc and VTA modulate palatable food-evoked DA release [18,19], increasing palatability and the hedonic impact of food [20]. ...
... In the VTA, we observed an opposite regulation of CB1 (decrease) and CB2 (increase) receptor transcripts in fcH-FHS rats, whereas mRNA coding for the synthesis and degradation enzymes for both endocannabinoids were decreased following the diet. CB1 receptors are expressed, primarily, in afferent terminals (excitatory or inhibitory) where they contribute to short-and long-term endocannabinoid-mediated synaptic plasticity [16]. Activation of CB1 receptors on axon terminals of GABAergic neurons in the VTA inhibits GABA transmission, leading to an increase in the firing pattern of DA neurons [49]. ...
Article
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Objectives Increased availability of high-calorie palatable food in most countries has resulted in overconsumption of these foods, suggesting that excessive eating is driven by pleasure, rather than metabolic need. The behavior contributes to the rise in eating disorders, obesity, and associated pathologies like diabetes, cardiac disease, and cancers. The mesocorticolimbic dopamine and homeostatic circuits are interconnected and play a central role in palatable food intake. The endocannabinoid system is expressed in these circuits and represents a potent regulator of feeding, but the impact of an obesogenic diet on its expression is not fully known.Methods Food intake and body weight were recorded in male Wistar rats over a 6-week free-choice regimen of high fat and sugar; transcriptional regulations of the endocannabinoid system were examined post-mortem in brain reward regions (prefrontal cortex, nucleus accumbens, ventral tegmental area, and arcuate nucleus). K-means cluster analysis was used to classify animals based on individual sensitivity to obesity and palatable food intake. Endocannabinoid levels were quantified in the prefrontal cortex and nucleus accumbens. Gene expression in dopamine and homeostatic systems, including ghrelin and leptin receptors, and classical homeostatic peptides, were also investigated.ResultsThe free-choice high-fat -and sugar diet induced hyperphagia and obesity in rats. Cluster analysis revealed that the propensity to develop obesity and excessive palatable food intake was differently associated with dopamine and endocannabinoid system gene expression in reward and homeostatic brain regions. CB2 receptor mRNA was increased in the nucleus accumbens of high sugar consumers, whereas CB1 receptor mRNA was decreased in obesity prone rats.Conclusions Transcriptional data are consistent with observations of altered dopamine function in rodents that have access to an obesogenic diet and point to cannabinoid receptors as GPCR targets involved in neuroplasticity mechanisms associated with maladaptive intake of palatable food.
... Previous work in the cohort has shown that the unmedicated FEP patients consume greater quantities of saturated fat and undertake less highintensity exercise. 11 There is a large body of literature suggesting that the endocannabinoid modulates energy intake 47 and that it may be involved in the development of NAFLD. 48 In line with this, Borgan et al previously showed that 2 independent cohorts of unmedicated patients 49 and medicated patients 50 show reductions in cannabinoid 1 receptor levels. ...
... 49 Cannabinoid receptor type 1 availability may also associate with changes in peripheral endocannabinoid levels in medicated patients. 51 Furthermore, there is a large body of literature suggesting that the ECS modulates energy intake, 47 and that the development of NAFLD is promoted by peripheral activation of the ECS. 48 More studies are clearly needed if one is to elucidate the hypothetical role of ECS as a link between psychosis and the development of metabolic comorbidities. ...
Article
Patients with schizophrenia have a lower than average life span, largely due to the increased prevalence of cardiometabolic comorbidities. There is an unmet public health need to identify individuals with psychotic disorders who have a high risk of rapid weight gain and who are at risk of developing metabolic complications. Here, we applied mass spectrometry-based lipidomics in a prospective study comprising 48 healthy controls (CTR), 44 first-episode psychosis (FEP) patients, and 22 individuals at clinical high risk (CHR) for psychosis, from 2 study centers (Turku, Finland and London, UK). Baseline serum samples were analyzed using lipidomics, and body mass index (BMI) was assessed at baseline and after 12 months. We found that baseline triacylglycerols (TGs) with low double-bond counts and carbon numbers were positively associated with the change in BMI at follow-up. In addition, a molecular signature comprised of 2 TGs (TG[48:0] and TG[45:0]) was predictive of weight gain in individuals with a psychotic disorder, with an area under the receiver operating characteristic curve (AUROC) of 0.74 (95% CI: 0.60-0.85). When independently tested in the CHR group, this molecular signature predicted said weight change with AUROC = 0.73 (95% CI: 0.61-0.83). We conclude that molecular lipids may serve as a predictor of weight gain in psychotic disorders in at-risk individuals and may thus provide a useful marker for identifying individuals who are most prone to developing cardiometabolic comorbidities.
... In this context, the enzyme diacylglycerol lipase α (DAGLα) catalyzes the synthesis of the most abundant EC, 2arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL). Anandamide, another important EC, is mainly synthesized by N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) and is degraded by fatty acid amide hydrolase (FAAH) (Chanda et al., 2019;Lau et al., 2017). The metabolic programming model of maternal supplementation with coconut oil during lactation seems to share similar characteristics to other models. ...
... However, no changes were detected in the proteins related to dopamine signaling in the VTA, NAc and DS, as well as in the μ-opioid receptor in the NAc and DS, indicating that our animals did not have alterations in the reward system related to food behavior. Dopamine synthesis can be modulated by the ECS, which acts to disinhibit the dopaminergic neurons of the VTA, resulting in excitation of these neurons (Lau et al., 2017). Thus, we suppose that the ECS effect in the mesolimbic system is not altered in the CO group. ...
Article
Maternal exposure to coconut oil metabolically programs adult offspring for overweight, hyperphagia and hyperleptinemia. We studied the neuroendocrine mechanisms by which coconut oil supplementation during breastfeeding as well as continued exposure of this oil throughout life affect the feeding behavior of the progeny. At birth, pups were divided into two groups: Soybean oil (SO) and Coconut oil (CO). Dams received these oils by gavage (0.5 g/kg body mass/day) during lactation. Half of the CO group continued to receive CO in chow throughout life (CO + C). Adult CO and CO + C groups had overweight; the CO group had hyperphagia, higher visceral adiposity, and hyperleptinemia, while the CO + C group had hypophagia only. The CO group showed higher DAGLα (endocannabinoid synthesis) but no alteration of FAAH (endocannabinoid degradation) or CB1R. Leptin signaling and GLP1R were unchanged in the CO group, which did not explain its phenotype. Hyperphagia in these animals can be due to higher DAGLα, increasing the production of 2-AG, an orexigenic mediator. The CO + C group had higher preference for fat and lower hypothalamic GLP1R content. Continuous exposure to coconut oil prevented an increase in DAGLα. The CO + C group, although hypophagic, showed greater voracity when exposed to a hyperlipidemic diet, maybe due to lower GLP1R, since GLP1 inhibits short-term food intake.
... The physiological mechanisms that lead an organism to eat or not are modulated by a complex system of central and peripheral signals where neurotransmitters and neuropeptides interact to stimulate or inhibit food intake. 1 These mechanisms respond to different motivations related to energetic and/or reward needs involving homeostatic and hedonic components in the regulation of appetite. 2 The endocannabinoid system (ECs) has been reported to be involved in hedonic and homeostatic regulation of food intake and energy balance in mammals with forebrain and hypothalamus being the main regions involved. 3 The ECs is composed by the ligands N-arachidonylethanolamine (Anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the enzymes involved in synthesis (Fatty acid hydrolase, FAAH) and degradation (N-acetylphosphatidylethanolamine-hydrolysing phospholipase D, NAPE-PLD) of endocannabinoids, and the endocannabinoid receptors 1 (CNR1) and 2 (CNR2). ...
... 29,34,35 Furthermore, the levels of these endocannabinoids can be modulated in mammals by the effects of some important endocrine signals as leptin and ghrelin. 2 In fish, a recent study reported increased levels of endocannabinoids in plasma and brain of rainbow trout after feeding a palatable diet suggesting a role of the ECs in the hedonic regulation of food intake also in fish. 28 As far as we are aware, this is the first study in which endocannabinoid levels are reported in fish related to their feeding condition. ...
Article
Background The mechanisms that regulate food intake are very complex since they comprise several neuroendocrine and metabolic signals responding to energetic or reward requirements. Previous studies in mammals indicate that cannabinoid system is implicated in homeostatic and hedonic regulation of food intake. In fish, several studies describe the components of this system, but only a little information is available regarding their role in food intake and energy balance regulation. Objectives The objective of this study was to evaluate the main components of cannabinoid system related to feeding conditions in fish. Methods Samples of blood and different brain areas (telencephalon and hypothalamus) were taken from rainbow trout under different nutritional status (fasted, fed and refed) at different periprandial times (−30, 0, +30 and +180 min). Results Changes in AEA and 2-AG levels were observed in plasma related to the nutritional status and the sampling times assessed. At central levels, changes in endocannabinoids levels were observed in hypothalamus and in mRNA abundance of cnr1 and tprv1 in telencephalon and faah, gpr55 and fos in both brain areas. Discussion The results obtained suggest a role of endocannabinoid system in the regulation of food intake in fish at central level but further studies are required to fully elucidate the mechanisms involved.
... The endogenous cannabinoid (endocannabinoid) system plays an important role in regulating appetite and food intake (Di Marzo and Matias, 2005). Both exogenous and endogenous cannabinoids induce hyperphagia by activating cannabinoid type 1 (CB1) receptors within hypothalamic, mesolimbic and gustatory brain regions to respectively enhance hunger, desire and taste for food (Kirkham et al., 2002;Lau et al., 2017;Di Marzo, 2011;Soria-Gómez et al., 2014). Furthermore, obesity is typically associated with elevated levels of the major endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA) in both the brain and periphery (Gatta-Cherifi and Cota, 2016). ...
... We found that the frequency, but not amplitude, of mIPSCs onto lOFC pyramidal neurons from extended access rats was significantly decreased compared to chow or restricted access rats ( Figure 1C,D), consistent with a presynaptic mechanism of action reported previously (Thompson et al., 2017). Given that obesity is associated with an overactive endocannabinoid system (Gatta-Cherifi and Cota, 2016; Lau et al., 2017), we hypothesized that elevated levels of endocannabinoids may mediate the suppression of inhibition observed in the lOFC of extended access rats. If endocannabinoids are tonically present under basal conditions to suppress GABAergic transmission, then blockade of CB1 receptors should unmask a facilitation of inhibitory transmission. ...
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S ummary Overconsumption of palatable, energy dense food is considered a key driver of the obesity pandemic. The orbitofrontal cortex (OFC) is critical for reward valuation of gustatory signals, yet how the OFC adapts to obesogenic diets is poorly understood. Here we show that an impairment of astrocyte glutamate clearance following extended access to a cafeteria diet reduces GABA release onto layer II/III pyramidal neurons in the lateral OFC in rats. This decrease in GABA tone is due to an increase in extrasynaptic glutamate, which activates metabotropic glutamate receptors (mGluR5) and liberates endocannabinoids. In obese rats, these synaptic impairments were rescued by the nutritional supplement, N-acetylcysteine, which restores glutamate homeostasis. Together, our findings indicate that obesity targets astrocytes to disrupt the delicate balance between excitatory and inhibitory transmission in the lateral OFC. H ighlights Synaptic plasticity within the OFC is disrupted with diet-induced obesity. Diet-induced obesity induces hypertrophic astrocytes in the OFC. Failure of astrocytes to clear synaptic glutamate drives endocannabinoid-mediated inhibitory long-term depression of OFC neurons. Astrocytic glutamate transporter function is restored with NAC, which rescues synaptic plasticity.
... A regulação do balanço energético consiste em uma complexa rede de sistemas de feedback, envolvendo controle hormonal e neural da energia ingerida e da energia gasta. Assim, o desequilíbrio energético leva a mudanças bruscas no metabolismo dos adipócitos 2,3 . Da mesma forma o Sistema Endocanabinóide (SE), descoberto na década de 90, é também um sistema de sinalização que controla o comportamento alimentar e que, na obesidade, parece estar hiperativo 4 . ...
... Possui ações neuromodulatórias, por influenciar a atividade de outros sistemas neurotransmissores. No entanto, ao contrário dos neurotransmissores clássicos os endocanabinóides são sintetizados sob demanda em resposta a estimulação aguda 3 . ...
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O objetivo do estudo foi investigar os efeitos da dieta hiperlipídica e do treinamento de natação e força sobre o tecido adiposo, perfil lipídico e sistema endocanabinóide de ratos obesos exógenos. Para isso, utilizamos sessenta ratos adultos machos divididos em seis grupos: Sedentário Padrão (SP); Sedentário Hiperlipídico (SH); Natação Padrão (NP); Natação Hiperlipídica (NH); Força Padrão (FP); Força Hiperlipídica (FH). Após três semanas recebendo dieta padrão ou hiperlipídica, os animais iniciaram os protocolos de exercício. Os grupos NP e NH nadaram 60 minutos/dia, 5 dias/semana com carga de 5% do peso corporal atada ao corpo, em tanques de 50x30 cm, durante 8 semanas. Os grupos FP e FH realizaram exercício de subida em escada com pesos atados às suas caudas, uma vez a cada três dias, durante 8 semanas. Os animais dos grupos SP e SH continuaram sedentários e alimentados com suas respectivas dietas. A dieta hiperlipídica aumentou o ganho de massa corporal, peso relativo dos tecidos adiposos (epididimal, retroperitoneal, visceral e subcutâneo) e área de adipócitos (epididimal, retroperitoneal e visceral). Também aumentou o percentual de gordura de todos os tecidos adiposos e fígado, além de aumentar a expressão gênica do receptor CB1. Os grupos treinados apresentaram menores valores de área de adipócitos, melhora do perfil lipídico, menores valores no percentual de gordura dos tecidos adiposos e fígado, menores ganhos de massa corporal, além de menores expressão gênica do receptor CB1. Assim nossos resultados indicam os potenciais benefícios do treinamento força e natação, como alternativas não farmacológicas para controlar os efeitos deletérios da dieta hiperlipídica sobre o tecido adiposo, perfil lipídico, conteúdo lipídico e controle do desequilíbrio do sistema endocanabinóide provocado pela dieta hiperlipídica.
... Food intake in vertebrates is under control of homeostatic mechanisms to maintain a balanced energy status (Lau et al., 2017). Even when this balance is not negative, other processes related to motivation, memory or emotion can also influence appetite regulation (Berthoud et al., 2017). ...
... The endocannabinoids also relate to feeding-related neuronal circuitry, affecting the release of appetite-related neurotransmitters like GABA and glutamate (Haspula and Clark, 2020). Furthermore, synaptic plasticity plays an important role in endocannabinoids action (Cota, 2007) through its interaction with the transcription factor cAMP response element-binding protein (CREB), the neural molecular marker cFOS, and the neurotrophic system brain-derived neurotrophic factor (BDNF)/Neurotrophic Receptor Tyrosine Kinase 1 (NTRK) (Castillo et al., 2012;Lau et al., 2017). ...
Article
The endocannabinoid system (ECs) is known to participate in several processes in mammals related to synaptic signaling including regulation of food intake, appetite and energy balance. In fish, the relationship of ECs with food intake regulation is poorly understood. In the present study, we assessed in rainbow trout Oncorhynchus mykiss the effect of intracerebroventricular administration (ICV) of low and high doses of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on food intake. We assessed endocannabinoid levels in hypothalamus, telencephalon and plasma as well as the effect of AEA and 2-AG administration at central level on gene expression of receptors involved in ECs (cnr1, gpr55 and trpv1) and markers of neural activity (fos, ntrk2 and GABA-related genes). The results obtained indicate that whereas high doses of endocannabinoids did not elicit changes in food intake levels, low doses of the endocannabinoids produce an orexigenic effect that could be due to a possible inhibition of gabaergic neurotransmission and the modulation of neural plasticity in brain areas related to appetite control, such as hypothalamus and telencephalon.
... However, in zebrafish both receptors can be likely expressed in the same or adjacent cell, and future studies can help to elucidate this aspect. Several studies have reported the involvement of orexins/Ecs interactions in the physio-pathological control of homeostasis, food intake and energy balance in mammals (Lau et al., 2017). Indeed, co-localization of these receptors in the hypothalamic area of zebrafish could affect alertness associated to hyperphagic behavior, possibly through the same molecular mechanism described in obese mice, by blunting Pomc gene expression and POMC/α-MSH production . ...
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Hypocretins/Orexins neuropeptides are known to regulate numerous physiological functions, such as energy homeostasis, food intake, sleep/wake cycle, arousal and wakefulness, in vertebrates. Previous studies on mice have revealed an intriguing orexins/endocannabinoids (ECs) signaling interaction at both structural and functional levels, with OX-A behaving as a strong enhancer of 2-arachydonoyl-glycerol (2-AG) biosynthesis. In this study, we describe, for the first time in the brain of zebrafish, the anatomical distribution and co-expression of orexin (OX-2R) and endocannabinoid (CB1R) receptors, suggesting a functional interaction. The immunohistochemical colocalization of these receptors by confocal imaging in the dorsal and ventral telencephalon, suprachiasmatic nucleus (SC), thalamus, hypothalamus, preoptic area (PO) and cerebellum, is reported. Moreover, biochemical quantification of 2-AG levels by LC-MS supports the occurrence of OX-A-induced 2-AG biosynthesis in the zebrafish brain after 3 h of OX-A intraperitoneal (i.p.; 3 pmol/g) or intracerebroventricular (i.c.v.; 0.3 pmol/g) injection. This effect is likely mediated by OX-2R as it is counteracted by i.p./i.c.v administration of OX-2R antagonist (SB334867, 10 pmol/g). This study provides compelling morphological and functional evidence of an OX-2R/CB1R signaling interaction in the brain of adult zebrafish, suggesting the use of this well-established vertebrate animal model for the study of complex and phylogenetically conserved physiological functions.
... Brain CB1R availability, as measured by PET imaging, associates with changes in peripheral endocannabinoid levels [39]. Furthermore, there is a large body of literature suggesting that the ECS modulates energy intake [40], and that the development of NAFLD is promoted by peripheral activation of the ECS [41]. More studies are clearly needed if one is to elucidate the hypothetical role of ECS as a link between psychosis and the development of metabolic comorbidities. ...
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Patients with schizophrenia have a lower than average life span, largely due to the increased prevalence of cardiometabolic co-morbidities. Identification of individuals with psychotic disorders with a high risk of rapid weight gain, and the associated development of metabolic complications, is an unmet need as regards public health. Here, we applied mass spectrometry-based lipidomics in a prospective study comprising 48 controls (CTR), 44 first-episode psychosis (FEP) patients and 22 individuals at clinical-high-risk (CHR) for psychosis, from two study centers (Turku/Finland and London/UK). Baseline serum samples were analyzed by lipidomics, while body mass index (BMI) was assessed at baseline and after 12 months. We found that baseline triacylglycerols with low double bond counts and carbon numbers were positively associated with the change in BMI at follow-up. In addition, a molecular signature comprised of two triacylglycerols (TG(48:0) and TG(45:0)), was predictive of weight gain in individuals with a psychotic disorder, with an area under the receiver operating characteristic curve (AUROC) of 0.74 (95% CI: 0.60-0.85). When independently tested in the CHR group, this molecular signature predicted said weight change with AUROC = 0.73 (95% CI: 0.61-0.83). We conclude that molecular lipids may serve as a predictor of weight gain in psychotic disorders in at-risk individuals, and may thus provide a useful marker for identifying individuals who are most prone to developing cardiometabolic co-morbidities.
... In spite of the fact that we are unable to determine the magnitude of the glutamatergic contribution on the hyperphagic effects of CB1R activation in our experiments, convincing evidence suggests that orexigenic effects of cannabinoids and endocannabinoids depend in part on actions at CB1R located at the terminals of glutamatergic cells Lafourcade et al., 2007;Lau et al., 2017 ). Furthermore, CB1R can also be expressed postsynaptically, and many studies have evidenced that CB1R can form heterodimers with other GPCR ( e.g. ...
Article
Endocannabinoids and their receptors not only contribute to the control of natural processes of appetite regulation and energy balance but also have an important role in the pathogenesis of obesity. CB1 receptors (CB1R) are expressed in several hypothalamic nuclei, including the paraventricular nucleus (PVN), where induce potent orexigenic responses. Activation of CB1R in the PVN induces hyperphagia by modulating directly or indirectly orexigenic and anorexigenic signals; however, interaction among these mediators has not been clearly defined. CB1R mRNA is expressed in serotonergic neurons that innervate the PVN, and activation of 5-HT receptors in the PVN constitutes an important satiety signal. Some GABAergic terminals are negatively influenced by 5-HT, suggesting that the hyperphagic effect of CB1R activation could involve changes in serotonergic and GABAergic signaling in the PVN. Accordingly, the present study was aimed to characterize the neurochemical mechanisms related to the hyperphagic effects induced by activation of CB1R in the PVN, studying in vitro and in vivo changes induced by direct activation these receptors. Here, we have found that the neurochemical mechanisms activated by stimulation of CB1 receptors in the PVN involve inhibition of 5-HT release, resulting in a decrease of serotonergic activity mediated by 5-HT1A and 5-HT1B receptors and inducing disinhibition of GABA release to stimulate food intake. In conclusion, these neurochemical changes in the PVN are determinant to the cannabinoid-induced stimulation of food intake. Our findings provide evidence of a functional connection among CB1R and serotonergic and GABAergic systems on the control of appetite regulation mediated by endocannabinoids.
... The endocannabinoid (eCB) system is a central regulator of metabolism and energy homeostasis in mammals [8][9][10][11]. The eCB system is involved in many physiological and pathological conditions; its role in metabolism and energy homeostasis in humans and in many murine models for obesity, insulin resistance, and glucose homeostasis, as well as fatty liver is well defined and documented [12][13][14]. The main eCBs, N-arachidonoylethanolamide (anandamide, AEA)[15] and 2-arachidonoylglycerol (2-AG) [16,17], are essential regulators of the rapid (non-genomic) and stress-related fine tuning of energy intake due to their fast and adaptive mechanisms of synthesis, release, and degradation [18][19][20]. ...
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Adipose tissue (AT) plays a major role in metabolic adaptations in postpartum (PP) dairy cows. The endocannabinoid (eCB) system is a key regulator of metabolism and energy homeostasis; however, information about this system in ruminants is scarce. Therefore, this work aimed to assess the eCB system in subcutaneous AT, and to determine its relation to the metabolic profile in peripartum cows. Biopsies of AT were performed at 14 d prepartum, and 4 and 30 d PP from 18 multiparous peripartum cows. Cows were categorized retrospectively according to those with high body weight (BW) loss (HWL, 8.5 ± 1.7% BW loss) or low body weight loss (LWL, 2.9 ± 2.5% BW loss) during the first month PP. The HWL had higher plasma non-esterified fatty acids and a lower insulin/glucagon ratio PP than did LWL. Two-fold elevated AT levels of the main eCBs, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were found 4 d PP compared with prepartum in HWL, but not in LWL cows. AT levels of the eCB-like molecules oleoylethanolamide, palmitoylethanolamide, and of arachidonic acid were elevated PP compared with prepartum in all cows. The abundance of monoglyceride lipase (MGLL), the 2-AG degrading enzyme, was lower in HWL vs. LWL AT PP. The relative gene expression of the cannabinoid receptors CNR1 and CNR2 in AT tended to be higher in HWL vs. LWL PP. Proteomic analysis of AT showed an enrichment of the inflammatory pathways’ acute phase signaling and complement system in HWL vs. LWL cows PP. In summary, eCB levels in AT were elevated at the onset of lactation as part of the metabolic adaptations in PP dairy cows. Furthermore, activating the eCB system in AT is most likely associated with a metabolic response of greater BW loss, lipolysis, and AT inflammation in PP dairy cows.
... Activation of the CB1 receptor by exogenous substances, such as marijuana, have long been known to promote feeding behavior and an understanding of the complex neural circuits that underlie this behavior is an area of active research (for recent review: Lau et al., 2017). 2arachidonoyl glycerol (2-AG) is one endogenous ligand for the CB1 receptor, the primary endocannabinoid receptor in neurons, where it acts as a full agonist (Soethoudt et al., 2017). ...
Article
The compulsive, habitual behaviors that have been observed in individuals diagnosed with substance use disorders may be due to disruptions in the neural circuits that mediate goal‐directed actions. The endocannabinoid system has been shown to play a critical role in habit learning, but the role of this neuromodulatory system in habit expression is unclear. Here, we investigated the role of the endocannabinoid system in established habitual actions using contingency degradation in male C57BL/6 mice. We found that administration of the endocannabinoid transport inhibitor AM404 reduced habitual responding for food and that antagonism of cannabinoid receptor type 1 (CB1), but not transient receptor potential cation subfamily V (TRPV1), receptors produced a similar reduction in habitual responding. Moreover, pharmacological stimulation of CB1 receptors increased habitual responding for food. Co‐administration of an enzyme inhibitor that selectively increases the endocannabinoid 2‐arachidonoyl glycerol (2‐AG) with AM404 partially restored habitual responding for food. Together, these findings demonstrate an important role for the endocannabinoid system in the expression of habits and provide novel insights into potential pharmacological strategies for reducing habitual behaviors in mental disorders. This article is protected by copyright. All rights reserved.
... The hypothalamus is the main brain region included in the control of metabolism and energy intake according to physical status. It is necessary to note the mechanisms regulating homeostatic eating but these will not be explained in detail as this research focuses on the association of the hedonic pathway to the food intake behavior (Lau et al., 2017). The hedonic pathway relates to feeding for pleasure in the absence of physiological status. ...
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Obesity and overweight are frequently prescribed for dysfunction in food-intake behavior. Due to the widely prevalence of obesity in last year’s, there is demand for more studies which are aimed to modify the food-intake behavior. For the past decades many researches has applied in modify food-intake by brain training or stimulation. This review for neuroscience studies in modifying food-intake behavior, it’s involved three sections; The first section explained the role of brain activity in food-intake regulation, general ideas about biomedical devices in food-intake behavior are discussed in second section and third section focused on brain-stimulation systems. Finally, this paper concluded with main points that need to be taken into account when designing experimental study for modification food-intake behavior by brain stimulation according to previous studies recommendation and challenges.
... This molecule originated from gram (-) bacteria prevails during conditions such as the prolonged use of antibiotics, unbalanced diets leading to obesity and metabolic disorders, or the chronic consumption of dietary supplements affecting the integrity of the intestinal mucus (29)(30)(31). Additionally, since OX-A is increased in the plasma of obese individuals due to excessive release from the lateral hypothalamus (32,33), our findings also raise the possibility that the effects found in this study may represent a negative feedback mechanism to counteract the increased intestinal permeability and systemic inflammation typical of obesity. Several studies have emphasized the interactions between the CNS and the gastrointestinal system (34)(35)(36)(37). ...
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In states of intestinal dysbiosis, a perturbation of the normal microbiome composition, the intestinal epithelial barrier (IEB) permeability is increased as a result of the disruption of the epithelial tight junction protein network, in which occludin is mostly affected. The loss of IEB integrity promotes endotoxemia, that is, bacterial lipopolysaccharide (LPS) translocation from the intestinal lumen to the circulatory system. This condition induces an enhancement of pro-inflammatory cytokines, which leads to neuroinflammation through the gut-brain axis. Orexin-A (OX-A), a neuropeptide implicated in many physiological functions and produced mainly in the brain lateral hypothalamic area, is expressed also in several peripheral tissues. Orexin-producing neurons have been found in the myenteric plexus to project to orexin receptor 1 (OX-1R)-expressing enterocytes of the intestinal villi. In the present study we investigated the protective role of OX-A against LPS-induced increase of IEB permeability and microglia activation in both an in vivo and in vitro model of the gut-brain axis. By exploiting biochemical, immunocytochemical, immunohistochemical, and functional approaches, we demonstrate that OX-A preserves the IEB and occludin expression, thus preventing endotoxemia and subsequent neuroinflammation.
... L'importance de ce système dans le contrôle de la balance énergétique ne fait plus de doute. Ce système jouerait d'ailleurs un rôle à la fois dans le contrôle homéostatique de la prise alimentaire et dans ses aspects hédoniques et motivationnels (Lau et al. 2017). ...
Thesis
En 2015, la revue Nature a publié la plus grande étude d’association pangénomique à ce jour reliant des variants génétiques à l’indice de masse corporelle. Cette étude a mis en avant le rôle du système nerveux central dans la vulnérabilité à l’obésité, et soutient un concept original selon lequel la plasticité cérébrale jouerait un rôle important dans le contrôle de la balance énergétique. Ainsi, des capacités de plasticité cérébrale réduites pourraient favoriser des comportements alimentaires inadaptés, ce qui augmenterait le risque de prise de poids sous pression calorique. Les neurones anorexigènes POMC et les neurones orexigènes AgRP qui composent le système à mélanocortine et qui contrôlent la balance énergétique, conservent effectivement des propriétés de plasticité synaptique dans le cerveau adulte. Celles-ci se manifestent en réponse à des fluctuations hormonales intenses, induites par des manipulations génétiques, chirurgicales ou nutritionnelles drastiques. Cependant le rôle physiologique de cette plasticité synaptique au sein du système à mélanocortine n’a pas encore été démontré. Nos résultats montrent que des phénomènes de plasticité cérébrale sont récapitulés à l’échelle des repas chez la souris, en fonction de l’état prandial, en réponse à des changements métaboliques et hormonaux modérés. En effet, une exposition à 1h de régime standard augmente l’activité électrique des neurones POMC, ce qui est corrélé à une rétractation de la couverture astrocytaire autour des somas POMC, sans changement de configuration synaptique par rapport à l’état préprandial. A l’opposé, une exposition à 1h de régime riche en lipides ne modifie pas l’activité électrique des neurones POMC et n’entraine pas de rétractation de la couverture astrocytaire. De plus, par blocage pharmacologique de l’hyperglycémie post-prandiale, nous avons montré que le glucose était nécessaire pour initier la rétractation gliale post-prandiale. Enfin, par une approche pharmacogénétique, nous avons montré que l’inactivation des astrocytes modifie le comportement alimentaire et diminue la couverture astrocytaire autour des neurones POMC. Ces résultats suggèrent que l’astrocyte jouerait un rôle inhibiteur sur l’activité électrique des neurones POMC et que la rétractation astrocytaire post-prandiale, autour des somas POMC lèverait l’inhibition des neurones POMC et favoriserait la sensation de satiété. Ce mode de régulation ne serait pas déclenché lors d’un repas riche en graisses, ce qui expliquerait le faible pouvoir satiétogène de ce type de repas.
... The ARC neurons as a whole project to both orexin and MCH neurons (González et al. 2016). Studies in rodents have demonstrated that HFD induced leptinresistance in the ARC contributes to the remodelling of inputs to orexin neurons from predominately excitatory to predominantly inhibitory (Cristino et al. 2013, Lau et al 2017. ...
Article
Emerging evidence from human imaging studies suggests that obese individuals have altered connectivity between the hypothalamus, the key brain region controlling energy homeostasis, and cortical regions involved in decision making and reward processing. Historically, animal studies have demonstrated that the lateral hypothalamus is the key hypothalamic region involved in feeding and reward. The lateral hypothalamus is a heterogeneous structure comprised of several distinct types of neurons which are scattered throughout. In addition, the lateral hypothalamus receives inputs from a number of cortical brain regions suggesting it's uniquely positioned to be a key integrator of cortical information and metabolic feedback. In this review, we summarize how human brain imaging can inform detailed animal studies to investigate neural pathways connecting cortical regions and the hypothalamus. Here, we discuss key cortical brain regions that are reciprocally connected to the lateral hypothalamus and are implicated in decision making processes surrounding food. This article is protected by copyright. All rights reserved.
... Two primary ECs, the fatty acid ethanolamide anandamide (AEA) and the monoacylglycerol 2-arachidonoyl-sn-glycerol (2-AG), act through cannabinoid type 1 receptors (CB 1 Rs) to stimulate palatable food intake (4,5,13,14,22). This is in contrast to oleoylethanolamide (OEA), a related fatty acid ethanolamide analog of AEA that does not interact with the CB receptors and plays a role in suppressing food intake (11,12,18,19,34). ...
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Epidemiological and clinical research studies have provided ample evidence demonstrating that consumption of sugar-sweetened beverages (SSB) increases risk factors involved in the development of obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD). Our previous study demonstrated that when compared to aspartame (Asp), two weeks of high-fructose corn syrup (HFCS)-sweetened beverages provided at 25% of daily energy requirement (Ereq) was associated with increased body weight, postprandial (pp) triglycerides (TG), and fasting and pp CVD risk factors in young adults. The fatty acid ethanolamide, anandamide (AEA), and the monoacylglycerol, 2-arachidonoyl-sn-glycerol (2-AG), are two primary endocannabinoids (ECs) that play a role in regulating food intake, increasing adipose storage, and regulating lipid metabolism. Therefore, we measured plasma concentrations of ECs and their analogs, oleoylethanolamide (OEA), docosahexaenoyl ethanolamide (DHEA), and docosahexaenoyl glycerol (DHG), in participants from our previous study who consumed HFCS- or Asp-sweetened beverages to determine associations with weight gain and CVD risk factors. Two-week exposure to either HFCS- or Asp-sweetened beverages resulted in significant differences in the changes in fasting levels of OEA and DHEA between groups after the testing period. Subjects who consumed Asp, but not HFCS, displayed a reduction in AEA, OEA and DHEA after the testing period. In contrast, there were significant positive relationships between AEA, OEA, and DHEA versus ppTG, ppApoCIII and ppApoE in those consuming HFCS, but not in those consuming Asp. Our findings reveal previously unknown associations between circulating ECs and EC-related molecules with markers of lipid metabolism and CVD risk after HFCS-consumption.
... The endocannabinoid system is a physiologically omnipresent regulatory system which comprises endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes involved in synthesising and metabolising endocannabinoids [12]. The system plays an important role in neuro-and immunomodulatory effects which impact upon the homeostasis of processes relating to appetite [13], motor function [14], fertility [15] and pain sensation [16]. ...
Article
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The endocannabinoid system is involved in many areas of physiological function and homeostasis. Cannabinoid receptors are expressed in the peripheral and central nervous system and on immune cells, all areas ideally suited to modulation of pain processing. There are a wealth of preclinical data in a number of acute, chronic, neuropathic and cancer pain models that have demonstrated a potent analgesic potential for cannabinoids, especially in patients with cancer. However, although there are some positive results in pain of cancer patients, the clinical evidence for cannabinoids as analgesics has not been convincing and their use can only be weakly recommended. The efficacy of cannabinoids seems to have been 'lost in translation' which may in part be related to using extracts of herbal cannabis rather than targeted selective full agonists at the cannabinoid CB1 and CB2 receptors.
... The endocannabinoid system has been implicated in numerous aspects of eating-related behaviors and disorders. 1,2 Previous studies have demonstrated that CB1R agonists can induce overeating, 3 while CB1R antagonists suppress food intake and weight gain in rodents, 4,5 suggesting potential use of CB1R antagonists in treatment of body overweight and obesity. However, the related clinical trials have been terminated worldwide because of the depressive and anxiogenic properties of CB1R antagonists. ...
Article
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A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)–approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood. Here, we examined the effects of CBD on oral sucrose self‐administration in rodents and explored the receptor mechanisms underlying CBD‐induced behavioral effects using pharmacological and transgenic approaches. Systemic administration of CBD (10, 20, and 40 mg/kg, ip) produced a dose‐dependent reduction in sucrose self‐administration in rats and in wild‐type (WT) and CB1−/− mice but not in CB2−/− mice. CBD appeared to be more efficacious in CB1−/− mice than in WT mice. Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD‐induced reduction in sucrose self‐administration, suggesting the involvement of CB1 and CB2 receptors. Furthermore, systemic administration of JWH133, a selective CB2R agonist, also produced a dose‐dependent reduction in sucrose self‐administration in WT and CB1−/− mice, but not in CB2−/− mice. Pretreatment with AM251 enhanced, while AM630 blocked JWH133‐induced reduction in sucrose self‐administration in WT mice, suggesting that CBD inhibits sucrose self‐administration likely by CB1 receptor antagonism and CB2 receptor agonism. Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity. Cannabidiol is a recently U.S. FDA approved medication for the treatment of epilepsy. In this study, we found that it is also effective in controlling food‐taking behavior in rats and mice largely by activation of cannabinoid CB2 receptor.
... Notably, the eCB system is involved in the regulation of food intake as well as the sensory and hedonic processing of food (Mahler et al. 2007;Soria-Gomez et al. 2014;Lau et al. 2017). CB1 agonists generally induce hyperphagia and locally modulate neurotransmission in the VTA and NAc to influence dopamine release in response to the consumption of palatable foods (Mahler et al. 2007). ...
Article
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Rationale Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking. Objectives Here, we determine whether systemic injections of rimonabant, a CB1 receptor inverse agonist, during Pavlovian lever autoshaping impair the expression of sign-tracking. We next examine whether rimonabant blocks the reinforcing properties of the Pavlovian lever cue in a conditioned reinforcement test. Methods In Exp. 1, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1, 3 mg/kg) during early and late Pavlovian lever autoshaping sessions. In Exp. 2, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1 mg/kg) during a conditioned reinforcement test. Results Rimonabant dose-dependently decreased lever contact and probability, and increased sign-tracker’s latency to approach the lever cue early in Pavlovian training. With extended training, many previously goal-tracking and intermediate rats shifted to lever approach, which remained dose-dependently sensitive to rimonabant. Rimonabant attenuated cue-evoked food cup approach early, but not late, in conditioning, and did not affect pellet retrieval or consumption. The inserted lever cue served as a robust conditioned reinforcer after Pavlovian lever autoshaping, and 1 mg/kg rimonabant blocked conditioned reinforcement. Conclusions Together, our results suggest that CB1 signaling mediates two critical properties of incentive stimuli; their ability to attract (Exp. 1) and their ability to reinforce (Exp. 2) behavior.
... Notably, the exposure to stress may mediate feeding via the effect of endocannabinoids and stress hormones (e.g., corticotropin-releasing factor), or by modulating the influence of appetitive hormones on the VTA [84,87]. In mice, endocannabinoids have been shown to promote the hedonic value of palatable food by increasing dopaminergic release from the VTA to the NAcc [88]. While insulin in the VTA has been reported to suppress preference and anticipatory behaviors to food-related cues in mice, this inhibitory effect was contingent on endocannabinoid-mediated inhibition on presynaptic glutamate release [89]. ...
Article
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Functional neuroimaging has become a widely used tool in obesity and eating disorder research to explore the alterations in neurobiology that underlie overeating and binge eating behaviors. Current and traditional neurobiological models underscore the importance of impairments in brain systems supporting reward, cognitive control, attention, and emotion regulation as primary drivers for overeating. Due to the technical limitations of standard field strength functional magnetic resonance imaging (fMRI) scanners, human neuroimaging research to date has focused largely on cortical and basal ganglia effects on appetitive behaviors. The present review draws on animal and human research to highlight how neural signaling encoding energy regulation, reward-learning, and habit formation converge on hypothalamic, brainstem, thalamic, and striatal regions to contribute to overeating in humans. We also consider the role of regions such as the mediodorsal thalamus, ventral striatum, lateral hypothalamus and locus coeruleus in supporting habit formation, inhibitory control of food craving, and attentional biases. Through these discussions, we present proposals on how the neurobiology underlying these processes could be examined using functional neuroimaging and highlight how ultra-high field 7-Tesla (7 T) fMRI may be leveraged to elucidate the potential functional alterations in subcortical networks. Focus is given to how interactions of these regions with peripheral endocannabinoids and neuropeptides, such as orexin, could be explored. Technical and methodological aspects regarding the use of ultra-high field 7 T fMRI to study eating behaviors are also reviewed.
... While effective in reducing appetite and weight gain, this drug was discontinued because of psychiatric side effects. Hence, with respect to the efficacy of omega-3 PUFA in modulating ECS, a diet-based approach may be a potential alternative in targeting the ECS [71]. ...
Article
Increased levels of endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA) have a pathophysiological role in the setting of cardiometabolic diseases. This systematic review was carried out to appraise the effect of omega-3 on cardiometabolic risk factors by highlighting the mediating effect of endocannabinoids. SCOPUS, PubMed, Embase, Google Scholar and ProQuest databases were searched until January 2020. All published English-language animal studies and clinical trials that evaluated the effects of omega-3 on cardiometabolic diseases with a focus on endocannabinoids were included. Of 1407 studies, 16 animal studies and three clinical trials were included for analysis. Eleven animal studies and two human studies showed a marked reduction in 2-AG and AEA levels following intake of omega-3 which correlated with decreased adiposity, weight gain and improved glucose homeostasis. Moreover, endocannabinoids were elevated in three studies that replaced omega-3 with omega-6. Omega-3 showed anti-inflammatory properties due to reduced levels of inflammatory cytokines, regulation of T-cells function and increased levels of eicosapentaenoyl ethanolamide, docosahexaenoyl ethanolamide and oxylipins; however, a limited number of studies examined a correlation between inflammatory cytokines and endocannabinoids following omega-3 administration. In conclusion, omega-3 modulates endocannabinoid tone, which subsequently attenuates inflammation and cardiometabolic risk factors. However, further randomized clinical trials are needed before any recommendations are made to target the ECS using omega-3 as an alternative therapy to drugs for cardiometabolic disease improvement.
... A role for mitochondrial CB1 receptors in neurons and astrocytes in the control of the respiratory chain of these cells, and hence of mouse brain function and, subsequently, behaviour is also emerging (Jimenez-Blasco et al. 2020). Indeed, one of the major functions of brain CB1 receptors is to control behaviour, including the motivational, homeostatic and sensory aspects of feeding (Lau et al. 2017, Tarragon & Moreno 2017, Coccurello & Maccarrone 2018. These latter functions are usually stimulated by CB1 receptors through a plethora of neural pathways in several brain areas, thus resulting in increased food intake. ...
Article
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Two complex systems are emerging as being deeply involved in the control of energy metabolism. The intestinal microbiota, with its warehouse of genes, proteins and small molecules, i.e. the gut microbiome; and the endocannabinoid system, with its recent extension to a more complex signalling apparatus including more than one hundred lipid mediators and fifty proteins, i.e. the endocannabinoidome. Both systems can become perturbed following bad dietary habits and during obesity, thus contributing to exacerbating this latter condition and its consequences in both peripheral organs and the brain. Here we discuss some of the multifaceted aspects of the regulation and dysregulation of the gut microbiome and endocannabinoidome in energy metabolism and metabolic disorders, with special emphasis on the emerging functional interactions between the two systems. The potential exploitation of this new knowledge for the development of new pharmacological and nutritional approaches against obesity and its consequences is also briefly touched upon.
... CB1R are also highly expressed in the PCx and are required for the expression of appetitive olfactory memory (Terral et al., 2019). Moreover, the endocannabinoid system is involved in the regulation of food intake in connection with the mechanisms of reward (Lau et al., 2017). The deletion of CB1 in dorsal telencephalic excitatory neurons regulating hedonic feeding behavior protects against pathological effects of DIO (Ruiz de Azua et al., 2021). ...
Article
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The olfactory system is at the crossroad between sensory processing and metabolic sensing. In addition to being the center of detection and identification of food odors, it is a sensor for most of the hormones and nutrients responsible for feeding behavior regulation. The consequences of modifications in body homeostasis, nutrient overload and alteration of this brain network in the pathological condition of food-induced obesity and type 2 diabetes are still not elucidated. The aim of this review was first to use both humans and animal studies to report on the current knowledge of the consequences of obesity and type 2 diabetes on odorant threshold and olfactory perception including identification discrimination and memory. We then discuss how olfactory processing can be modified by an alteration of the metabolic homeostasis of the organism and available elements on pharmacological treatments that regulate olfaction. We focus on data within the olfactory system but also on the interactions between the olfactory system and other brain networks impacted by metabolic diseases.
... The control and regulation of food intake is a complex process involving central and peripheral signals that are integrated at the brain level [1,2]. Endocannabinoids (ECs) may act at both peripheral and central sites, thus exerting a pivotal role in regulating energy homeostasis [3,4]. The endocannabinoid system (ECS) consists of the G protein-coupled cannabinoid receptors 1 (CB 1 ) and 2 (CB 2 ) [5], their endogen ligands N-arachidonylethanolamide (anandamide; AEA) and 2-arachidonoylglyerol (2-AG) [6,7] and specific enzymes for their synthesis and degradation [8]. ...
Article
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The endocannabinoid system (ECS) plays a pivotal role in the complex control and regulation of food intake. Pharmacological ECS activation could improve health in energy-deficient stages by increasing food intake, at least in intermittent feeders. However, knowledge of the mechanism regulating appetite in species with continued nutrient delivery is incomplete. The objectives of this pilot study were to investigate the effect of the intraperitoneal (i.p.) administration of the endocannabinoids (ECs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on food intake, plasma EC concentrations and hypothalamic orexigenic signaling, and to study how the circulatory EC tone changes in response to short-term food deprivation in dairy cows, a species with continuous nutrient delivery. The administration of EC resulted in higher food intake during the first hour after treatment. Plasma AEA concentrations were significantly increased 2.5 h after AEA injection, whereas plasma 2-AG concentrations remained unchanged 2.5 h after 2-AG injection. The hypothalamic immunoreactivity of cannabinoid receptor 1, agouti-related protein, and orexin-A was not affected by either treatment; however, neuropeptide Y and agouti-related protein mRNA abundances were downregulated in the arcuate nucleus of AEA-treated animals. Short-term food deprivation increased plasma 2-AG, while plasma AEA remained unchanged. In conclusion, i.p.-administered 2-AG and AEA increase food intake in the short term, but only AEA accumulates in the circulation. However, plasma 2-AG concentrations are more responsive to food deprivation than AEA.
... Brain AEA and 2-AG levels peak before food consumption and gradually decrease after food intake (Kirkham et al. 2002). These signals and those from the peripheral tissues converge in the lateral hypothalamus to regulate food motivation (Cristino et al. 2014;Lau et al. 2017). Furthermore, AEA-related compounds such as palmitoleoylethanolamide (POEA) may have a role in nutrient sensing and energy intake regulation through insulin release (Syed et al. 2012). ...
Article
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RationaleEndocannabinoids are well poised to regulate crosstalk between energy sensing of hunger and satiety and reward-driven motivation.Objectives Here, we aimed to unravel associations between plasma endocannabinoids and brain connectivity in homeostatic and reward circuits across hunger and satiety states.Methods Fifteen participants (7 females) underwent two counter-balanced resting-state functional magnetic resonance imaging scans, one after overnight fasting and one after consumption of a standardized filling meal (satiety). Before each scan, we drew blood to measure plasma endocannabinoid concentrations (anandamide [AEA], anandamide-derived POEA, and 2-arachidonoylglycerol [2-AG]), analyzed with liquid chromatography tandem mass spectrometry.ResultsWe found that AEA levels were associated with increased connectivity between the lateral hypothalamus and the ventral striatum during satiety. Furthermore, fasting AEA levels correlated with connectivity between the ventral striatum and the anterior cingulate cortex and the insula.Conclusions Altogether, results suggest that peripheral AEA concentrations are sensitive to homeostatic changes and linked to neural communication in reward and salience networks. Findings may have significant implications for understanding normal and abnormal interactions between homeostatic input and reward valuation.
... Herein, CB 1 R mainly controls food preferences, e.g., digestion of fat rich palatable food [37]. Several experimental findings already pointed to CB 1 R as therapeutic target to treat altered feeding behavior and obesity [30,34,41,42], due to the hyperphagic role of this receptor, and the possible exploitation of its pharmacological blockade, as recently reviewed [43]. It should be recalled that rimonabant, a CB 1 R antagonist/inverse agonist [44], entered the European mass market, showing weight loss benefits but it was soon withdrawn due to the significant side effects [45]. ...
Article
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Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies.
... CBD treatment was also associated with reduced appetite in the epilepsy studies. The endocannabinoid system contributes to the regulation of food intake and moderates the hedonic effect of food consumption [35]. Previous studies have suggested that CBD in cannabis may reduce the appetitive effects of food stimuli [36], but its molecular mechanism of action in this context remains unclear. ...
Article
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Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting ≥7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal for any reason (OR 2.61, 95% CI: 1.38-4.96) or due to adverse events (OR 2.65, 95% CI: 1.04-6.80), any serious adverse event (OR 2.30, 95% CI: 1.18-4.48), serious adverse events related to abnormal liver function tests (OR 11.19, 95% CI: 2.09-60.02) or pneumonia (OR 5.37, 95% CI: 1.17-24.65), any adverse event (OR 1.55, 95% CI: 1.03-2.33), adverse events due to decreased appetite (OR 3.56, 95% CI: 1.94-6.53), diarrhoea (OR 2.61, 95% CI: 1.46-4.67), somnolence (OR 2.23, 95% CI: 1.07-4.64) and sedation (OR 4.21, 95% CI: 1.18-15.01). Associations with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhoea (OR 5.03, 95% CI: 1.44-17.61). In summary, the available data from clinical trials suggest that CBD is well tolerated and has relatively few serious adverse effects, however interactions with other medications should be monitored carefully. Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed to assess whether the conclusions drawn from clinical trials can be applied more broadly.
... and anandamide (AEA) are able to modulate not only homeostatic hypothalamic systems but also the dopaminergic mesolimbic circuitry thus affecting reward systems (Lau et al. 2017). Available studies showed that AEA regulates feeding levels (Valenti et al. 2005, Piccinetti et al. 2010) but again there are no studies on reward systems. ...
Article
Evidence indicates that central regulation of food intake is well conserved along the vertebrate lineage, at least between teleost fish and mammals. However, several differences arise in the comparison between both groups. In this review, we describe similarities and differences between teleost fish and mammals on an evolutionary perspective. We focussed on the existing knowledge of specific fish features conditioning food intake, anatomical homologies and analogies between both groups as well as the main signaling pathways of neuroendocrine and metabolic nature involved in the homeostatic and hedonic central regulation of food intake.
... eCBs regulate food metabolism in a central manner by modulating, via activation of CB1 receptors, the activity of hypothalamic neurons and the release of orexigenic and anorexigenic neuropeptides. In fact, obesity can be associated with the upregulation of the ECS involving an increase in eCB tone where CB1 receptors play one of the most important roles [26]. In this sense, monoacylglycerol lipase (MAGL) is involved in energy balance and plays an important role in energy homeostasis by regulating lipolysis, inflammation, incretin, and insulin signaling (reviewed in [27,28]). ...
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Abstract Purpose of review: This article provides a concise overview of how cannabinoids and the endocannabinoid system (ECS) have significant implications for the prevention and treatment of metabolic syndrome (MetS) and for the treatment of cardiovascular disorders, including cardiac fibrosis. Recent findings: Over the past few years, the ECS has emerged as a pivotal component of the homeostatic mechanisms for the regulation of many bodily functions, including inflammation, digestion, and energy metabolism. Therefore, the pharmacological modulation of the ECS by cannabinoids represents a novel strategy for the management of many diseases. Specifically, increasing evidence from preclinical research studies has opened new avenues for the development of cannabinoid-based therapies for the management and potential treatment of MetS and cardiovascular diseases. Current information indicates that modulation of the ECS can help maintain overall health and well-being due to its homeostatic function. From a therapeutic perspective, cannabinoids and the ECS have also been shown to play a key role in modulating pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic, and cardiovascular diseases, as well as cancer and pain. Thus, targeting and modulating the ECS with cannabinoids or cannabinoid derivatives may represent a major disease-modifying medical advancement to achieve successful treatment for MetS and certain cardiovascular diseases. Keywords: Cannabinoids; Cardiac fibrosis; Cardiovascular disease; Endocannabinoid system; Metabolic syndrome.
... Humans and other mammals, when given a choice, generally prefer food that contains fats, sugars, or a combination of both [1]. Homeostatic and hedonic feeding are controlled by diverse, albeit overlapping, neural and molecular signaling pathways throughout the brain, including those regulated by the endocannabinoid (eCB) system [2][3][4][5]. Recent studies, however, suggest important roles for the peripheral eCB system in energy homeostasis and intake of palatable food . ...
Article
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The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut-brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CB1Rs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CB1R antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CB1R-deficient mice (IntCB1-/-) to investigate if intestinal CB1Rs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB1-/- mice when compared to control mice for up to 6 h. Together, these data suggest that CB1Rs in the murine intestinal epithelium are required for acute WD preferences.
... Several groups have been investigating the endocannabinoid system (Capasso et al. 2018;Monteleone et al. 2017;Pucci et al. 2018bPucci et al. , 2019, because of its known interactions with other pathways involved in the hedonic aspect of food, including DA reward circuitry (D'Addario et al. 2014;Lau et al. 2017). For instance, CB1 receptor antagonists reduced binge eating in different rodent models (Dore et al. 2014;Parylak et al. 2012;Scherma et al. 2013). ...
Chapter
Preclinical models cannot explain all of the complex internal and external factors that influence eating behaviors in humans. Still, they represent an essential tool to investigate the underlying neuro- and psychobiology implicated in disorders that are associated with binge eating. Several environmental conditions induce aberrant feeding behavior on calorie-dense food in animal models of binge eating. Various kinds of stress (acute or chronic), the combination of repeated cycles of food restriction and refeeding plus stress, food deprivation, and limited access to palatable food have been used to elicit binge-like eating episodes to model human behaviors. Animal studies have revealed the involvement of different neurotransmitter pathways, especially dopamine, opioids, CRF, serotonin, orexin, and GABAergic systems in binge-like eating. They may aid in the ultimate goal of identifying novel, safe, and effective therapeutic targets.
... Similarly, the cholecystokinin analog CCK-8S (10 μg/kg) acutely decreased palatable food intake (Fig. 3A). Since only the anorectic action of gut-born signals was efficient in counteracting binge-like consumption, we also investigated the effect of endocannabinoids (eCBs) which are important mediators of nutrients-induced adaptive responses within the gutbrain axis [34,35]. We acutely inhibited the CB1R with the global acting antagonist/inverse agonist AM251 (3 mg/kg, i.p.) and observed a dramatic reduction of BE-like consumption (Fig. 3A). ...
Article
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The regulation of food intake, a sine qua non requirement for survival, thoroughly shapes feeding and energy balance by integrating both homeostatic and hedonic values of food. Unfortunately, the widespread access to palatable food has led to the development of feeding habits that are independent from metabolic needs. Among these, binge eating (BE) is characterized by uncontrolled voracious eating. While reward deficit seems to be a major contributor of BE, the physiological and molecular underpinnings of BE establishment remain elusive. Here, we combined a physiologically relevant BE mouse model with multiscale in vivo approaches to explore the functional connection between the gut-brain axis and the reward and homeostatic brain structures. Our results show that BE elicits compensatory adaptations requiring the gut-to-brain axis which, through the vagus nerve, relies on the permissive actions of peripheral endocannabinoids (eCBs) signaling. Selective inhibition of peripheral CB1 receptors resulted in a vagus-dependent increased hypothalamic activity, modified metabolic efficiency, and dampened activity of mesolimbic dopamine circuit, altogether leading to the suppression of palatable eating. We provide compelling evidence for a yet unappreciated physiological integrative mechanism by which variations of peripheral eCBs control the activity of the vagus nerve, thereby in turn gating the additive responses of both homeostatic and hedonic brain circuits which govern homeostatic and reward-driven feeding. In conclusion, we reveal that vagus-mediated eCBs/CB1R functions represent an interesting and innovative target to modulate energy balance and counteract food-reward disorders.
Chapter
The endocannabinoid signaling system is a ubiquitous means of (sub) cellular information transduction. Investigation of the system’s molecular components and the biochemical processes they participate in was stimulated some 25 years ago by seminal evidence that Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the principal psychoactive component of Cannabis sp., exerts its psychotropic effects mainly through engaging and activating a class-A (rhodopsin-like) G protein-coupled receptor (GPCR), cannabinoid receptor 1 (CB1R), in the central nervous system. Subsequent investigations have explored the mechanisms of action of other phytocannabinoids (e.g., cannabidiol) and the principal endogenous cannabinoid lipid transmitters in humans and other mammals [the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], leading to the identification of an additional cannabinoid receptor [cannabinoid receptor 2 (CB2R)] and insight into the key physiological roles of the enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) in terminating, respectively, 2-AG and AEA signaling functions. The importance of the endocannabinoid system in regulating many biological processes has stimulated the design and synthesis of structurally diverse small molecules as candidate therapeutics targeted to CB1R, CB2R, MGL, or FAAH. Given the increasing prevalence of legalized social and medicinal cannabis use and the emergence of ultra-potent, synthetic cannabinoids as illicit “street drugs,” current medicinal chemistry efforts aim to address the public health problems presented by cannabis use disorders (CUDs), both acute (e.g., cannabis overdose) and chronic (i.e., addiction). Within this context, this review discusses various therapeutic modalities targeted to CB1R, CB2R, MGL, and FAAH and highlights their potential to yield CUD therapies. Intrinsic pharmacological properties of CB1R neutral antagonists and MGL and FAAH inhibitors are regarded as key to potentially safe and efficacious medications for treating acute cannabis toxicity and/or CUDs.
Article
Stimulation of cannabinoid CB1 receptors generally increases ingestion. However, the non-selective cannabinoid receptor agonist HU-210 exerts the opposite effect. The first objective of this study was to investigate the role of CB1 receptors in this “atypical” effect. Studies on the endocannabinoid system investigating the microstructure of licking for palatable solutions reported inconsistent results as for the role of CB1 receptors in “liking” and “wanting”. The second objective was to deal with these inconsistencies investigating the within-session time-course of licking-burst number. The microstructure of licking for a 10% sucrose solution in 30-min sessions was analysed in two experiments. In Experiment 1, the effect of the CB1 receptor antagonist-inverse agonist rimonabant (0.5, 1 mg/kg) on HU-210 effect (100 μg/kg) was investigated. A dose range of HU-210 (25, 50, 100 μg/kg) was examined in Experiment 2. In Experiment 1, both HU-210 and rimonabant reduced licking due to reduced burst number. Moreover, HU-210 reduced the intra-burst lick rate, an index of motor competence. HU-210 effects were antagonised by rimonabant, and vice versa. Rimonabant decreased burst number late in the session at 0.5 mg/kg, and since the beginning of the session at 1 mg/kg. In Experiment 2, HU-210 failed to affect overall ingestion. These results suggest that HU-210 effect – when present – depends on CB1 receptor stimulation, possibly leading to impairment of the motor competence necessary for licking. The reduction of burst number late in the session observed with rimonabant 0.5 mg/kg, which resembles the effect of reward devaluation, might suggest reduced “liking”.
Chapter
The brain plays a key role in the regulation of body weight and glucose metabolism. Peripheral signals including hormones, metabolites, and neural afferent signals are received and processed by the brain which in turn elicits proper behavioral and metabolic responses for maintaining energy and glucose homeostasis. The cAMP/protein kinase A (PKA) pathway acts downstream G-protein-coupled receptors (GPCR) to mediate the physiological effects of many hormones and neurotransmitters. Activated PKA phosphorylates various proteins including ion channels, enzymes, and transcription factors and regulates their activity. Recent studies have shown that neuronal cAMP/PKA activity in multiple brain regions are involved in the regulation of feeding, energy expenditure, and glucose homeostasis. In this chapter I summarize recent genetic and pharmacological studies concerning the regulation of body weight and glucose homeostasis by cAMP/PKA signaling in the brain.
Chapter
Since the early animal lesional and electric brain stimulation experiments of Hetherington and Ranson, it has been appreciated that lesions in certain parts of the hypothalamus can induce profound phenotypes of morbid obesity or dramatic wasting. These and other findings led to the postulation of hypothalamic “satiety” and “feeding” centers. Subsequent clinical observations in humans including characterization of children with morbid obesity associated with entities such as the Prader-Willi and Frohlich syndromes as well as Simmonds’ cachexia demonstrated that similar hypothalamic dysfunction phenotypes existed in human hypothalamic disease. The discovery of leptin and the subsequent better characterization of the hypothalamic basis for modulation of satiety, hunger, and energy balance as well as the discovery of various adipo- and enterocytokines with central hypothalamic modulatory effects crystallized hypothalamic obesity and wasting as distinct and important clinical entities. This manuscript seeks to provide a comprehensive overview of the causes, presentation, and basic pathophysiology of these two disparate but functionally related clinical syndromes.
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Ingestion of food activates a cascade of endocrine responses (thereby reflecting a contemporaneous feeding status) that include the release of hormones from the gastrointestinal (GI) tract, such as cholecystokinin (CCK), glucagonlike peptide YY (PYY), peptide PP, and oleoylethanolamide, as well as suppression of ghrelin secretion. The pancreas and adipose tissue, on the other hand, release hormones that serve as a measure of the current metabolic state or the long-term energy stores, that is, insulin, leptin, and adiponectin. It is well known and intuitively understandable that these hormones target either directly (by crossing the blood-brain barrier) or indirectly (e.g., via vagal input) the "homeostatic" brainstem-hypothalamic pathways involved in the regulation of appetite. The current article focuses on yet another target of the metabolic and GI hormones that is critical in inducing changes in food intake, namely, the reward system. We discuss the physiological basis of this functional interaction, its importance in the control of appetite, and the impact that disruption of this crosstalk has on energy intake in select physiological and pathophysiological states. We conclude that metabolic and GI hormones have a capacity to strengthen or weaken a response of the reward system to a given food, and thus, they are fundamental in ensuring that feeding reward is plastic and dependent on the energy status of the organism. © 2021 American Physiological Society. Compr Physiol 11:1425-1447, 2021.
Article
Despite the success of antiretroviral therapy in suppressing viral load, nearly half of the 37 million people infected with HIV experience cognitive and motor impairments, collectively classified as HIV-associated neurocognitive disorders (HAND). In the CNS, HIV-infected microglia release neurotoxic agents that act indirectly to elicit excitotoxic synaptic injury. HIV trans-activator of transcription (Tat) protein is one such neurotoxin that is thought to play a major role in the neuropathogenesis of HAND. The endocannabinoid (eCB) system provides on-demand neuroprotection against excitotoxicity, and exogenous cannabinoids attenuate neurotoxicity in animal models of HAND. Whether this neuroprotective system is altered in the presence of HIV is unknown. Here, we examined the effects of Tat on the eCB system in rat primary hippocampal cultures. Using whole-cell patch-clamp electrophysiology, we measured changes in retrograde eCB signaling following exposure to Tat. Treatment with Tat significantly reduced the magnitude of depolarization-induced suppression of excitation (DSE) in a graded manner over the course of 48 h. Interestingly, Tat did not alter this form of short-term synaptic plasticity at inhibitory terminals. The Tat-induced decrease in eCB signaling resulted from impaired CB1 receptor (CB1R)-mediated presynaptic inhibition of glutamate release. This novel loss-of-function was particularly dramatic for low-efficacy agonists such as the eCB 2-arachidonoylglycerol (2-AG) and Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in marijuana. Our observation that HIV Tat decreases CB1R function in vitro suggests that eCB-mediated neuroprotection may be reduced in vivo; this effect of Tat may contribute to synaptodendritic injury in HAND.
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Calorie restriction (CR) remains the most robust intervention to extend life span and improve health span. Using a global mass spectrometry–based metabolomics approach, we identified metabolites that were significantly differentially expressed in the plasma of C57BL/6 mice, fed graded levels of calorie restriction (10% CR, 20% CR, 30% CR, and 40% CR) compared with mice fed ad libitum for 12 hours a day. The differential expression of metabolites increased with the severity of CR. Pathway analysis revealed that graded CR had an impact on vitamin E and vitamin B levels, branched chain amino acids, aromatic amino acids, and fatty acid pathways. The majority of amino acids correlated positively with fat-free mass and visceral fat mass, indicating a strong relationship with body composition and vitamin E metabolites correlated with stomach and colon size, which may allude to the beneficial effects of investing in gastrointestinal organs with CR. In addition, metabolites that showed a graded effect, such as the sphinganines, carnitines, and bile acids, match our previous study on liver, which suggests not only that CR remodels the metabolome in a way that promotes energy efficiency, but also that some changes are conserved across tissues.
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The endocannabinoid system (ECS) regulates brain development and function, energy metabolism and stress in a sex-, age- and tissue-dependent manner. The ECS comprises mainly the bioactive lipid ligands anandamide (AEA) and 2-aracdonoylglycerol (2-AG), cannabinoid receptors 1 and 2 (CB1 and CB2), and several metabolizing enzymes. The endocannabinoid tonus is increased in obesity, stimulating food intake and a preference for fat, reward, and lipid accumulation in peripheral tissues, as well as favoring a positive energy balance. Energy balance and stress responses share adaptive mechanisms regulated by the ECS that seem to underlie the complex relationship between feeding and emotional behavior. The ECS is also a key regulator of development. Environmental insults (diet, toxicants, and stress) in critical periods of developmental plasticity, such as gestation, lactation and adolescence, alter the ECS and may predispose individuals to the development of chronic diseases and behavioral changes in the long term. This review is focused on the ECS and the developmental origins of health and disease (DOHaD).
Chapter
Obesity is a growing global health problem and is well-recognized to be a major contributing factor for increased risk of several non-communicable diseases including cardiovascular disease, diabetes and cancer in both the developed and developing world. This development is multi-factorial, but an increasingly sedentary lifestyle coupled with unhealthy dietary practices are key risk factors. Effective interventions for weight management would therefore not only be seen to reduce the epidemic of obesity, but also to lessen the risk for obesity-related morbidities. This article will briefly describe some factors that can cause obesity. Since men and women are different in their fat mass and distribution profile, and that ethnic groups are disproportionately affected by obesity, it is conceivable that disparities also exist in the occurrence of obesity and the consequential development of non-communicable diseases. Although the major adverse health outcomes due to obesity are mentioned, the influence and the role of sex, specifically women’s health, and ethnicity in the increased risk as well as development of obesity-induced health complications will also be discussed.
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Exchange protein directly activated by cAMP (Epac) is a direct effector for the ubiquitous second messenger cAMP. Epac activates the phospholipase Cε (PLCε) pathway. PLCβ has been linked to the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we report that Epac facilitates endocannabinoid-mediated retrograde synaptic depression through activation of PLCε. Intracellular loading of a selective Epac agonist 8-CPT-2Me-cAMP into ventral tegmental area (VTA) dopamine neurons enabled previously ineffective stimuli to induce depolarization-induced suppression of inhibition (DSI) and long-term depression of IPSCs (I-LTD) in the VTA. DSI and I-LTD are mediated by 2-AG since they were blocked by a diacylglycerol lipase inhibitor. The effects of 8-CPT-2Me-cAMP on DSI and I-LTD were absent in Epac2 and PLCε knock-out mice, but remained intact in Epac1 knock-out mice. These results identify a novel mechanism for on-demand synthesis of retrograde signaling 2-AG by the Epac2-PLCε pathway. We investigated the functional significance of Epac2-PLCε-2-AG signaling in regulating inhibitory synaptic plasticity in VTA dopamine neurons induced by in vivo cocaine exposure. We showed that cocaine place conditioning led to a decrease in the frequency and amplitude of spontaneous IPSCs and an increase in action potential firing in wild-type mice, but not in Epac2 or PLCε knock-out mice. Together, these results indicate that the Epac2-PLCε-2-AG signaling cascade contributes to cocaine-induced disinhibition of VTA dopamine neurons.
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Circuit-specific signaling of ventral tegmental area (VTA) dopamine neurons drives different aspects of motivated behavior, but the neuromodulatory control of these circuits is unclear. We tested the actions of co-expressed lateral hypothalamic peptides, orexin A (oxA) and dynorphin (dyn), on projection-target-defined dopamine neurons in mice. We determined that VTA dopamine neurons that project to the nucleus accumbens lateral shell (lAcbSh), medial shell (mAcbSh), and basolateral amygdala (BLA) are largely non-overlapping cell populations with different electrophysiological properties. Moreover, the neuromodulatory effects of oxA and dyn on these three projections differed. OxA selectively increased firing in lAcbSh- and mAcbSh-projecting dopamine neurons. Dyn decreased firing in the majority of mAcbSh- and BLA-projecting dopamine neurons but reduced firing only in a small fraction of those that project to the lAcbSh. In conclusion, the oxA-dyn input to the VTA may drive reward-seeking behavior by tuning dopaminergic output in a projection-target-dependent manner.
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