ArticleLiterature Review

The Endocannabinoid System in Energy Homeostasis and the Etiopathology of Metabolic Disorders

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Abstract

Endocannabinoids and cannabinoid CB1 receptors are known to play a generalized role in energy homeostasis. However, clinical trials with the first generation of CB1 blockers, now discontinued due to psychiatric side effects, were originally designed to reduce food intake and body weight rather than the metabolic risk factors associated with obesity. In this review, we discuss how, in addition to promoting energy intake, endocannabinoids control lipid and glucose metabolism in several peripheral organs, particularly the liver and adipose tissue. Direct actions in skeletal muscle and pancreas are also emerging. This knowledge may help in the design of future therapies for the metabolic syndrome.

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... The ECS also regulates renal function, lung function, the differentiation of myocytes, bone formation, mitochondrial performance and multiple aspects involved in the differentiation and regulation of skin [7][8][9][10][11]. ...
... Dissociated Gβγ subunits also influence downstream signalling and play a dominant role in the activation the PI3K/AKT pathway (65)(66)(67). Section 2. CB1 and CB2 activation and the effect on ROS levels in the CNS and periphery 2.1 CB1 activation and the effect on ROS levels in the brain 9 Considerable in vivo and in vitro evidence suggests that CB1 activation suppresses ROS formation and lipid peroxidation in the brain (68,69), leading to reduced tissue damage and lower levels of neuroinflammation (70,71). Mechanistically, these beneficial effects appear to be mediated by the reduction or prevention of glutamate-mediated N-methyl D-aspartate (NMDA) excitotoxicity (70,(72)(73)(74). ...
... performance of the electron transport chain in the mitochondria and decreasing oxidative phosphorylation (9,77,78). Hepatic CB1 receptor upregulation also increases oxidative stress via the upregulation of ceramide production leading to the development of endoplasmic reticulum (ER) stress and cell dysfunction or death (79). CB1R upregulation in pancreatic islet β-cells also increases intracellular oxidative stress ultimately leading to the development of ER stress and cellular demise (80). ...
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The endocannabinoid system (ECS) appears to regulate metabolic, cardiovascular, immune, gastrointestinal, lung, and reproductive system functions, as well as the central nervous system. There is also evidence that neuropsychiatric disorders are associated with ECS abnormalities as well as oxidative and nitrosative stress pathways. The goal of this mechanistic review is to investigate the mechanisms underlying the ECS's regulation of redox signaling, as well as the mechanisms by which activated oxidative and nitrosative stress pathways may impair ECS-mediated signaling. Cannabinoid receptor (CB)1 activation and upregulation of brain CB2 receptors reduce oxidative stress in the brain, resulting in less tissue damage and less neuroinflammation. Chronically high levels of oxidative stress may impair CB1 and CB2 receptor activity. CB1 activation in peripheral cells increases nitrosative stress and inducible nitric oxide (iNOS) activity, reducing mitochondrial activity. Upregulation of CB2 in the peripheral and central nervous systems may reduce iNOS, nitrosative stress, and neuroinflammation. Nitrosative stress may have an impact on CB1 and CB2-mediated signaling. Peripheral immune activation, which frequently occurs in response to nitro-oxidative stress, may result in increased expression of CB2 receptors on T and B lymphocytes, dendritic cells, and macrophages, reducing the production of inflammatory products and limiting the duration and intensity of the immune and oxidative stress response. In conclusion, high levels of oxidative and nitrosative stress may compromise or even abolish ECS-mediated redox pathway regulation. Future research in neuropsychiatric disorders like mood disorders and deficit schizophrenia should explore abnormalities in these intertwined signaling pathways.
... In addition, the endocannabinoidome plays an intrinsic role on memory, stress processing, and reward pathways involved in addiction [84]. Alterations in the system are associated with a wide range of diseases: obesity, Parkinson's disease, Alzheimer's dementia, multiple sclerosis, Huntington's chorea, amyotrophic lateral sclerosis, schizophrenia, depression, atherosclerosis, cancer, inflammatory bowel disease, liver steatosis and fibrosis, and infertility [40,114,139,190,202,247,263]. Understanding these alterations in the endocannabinoidome system may allow for future disease modifying or palliative interventions. ...
... The IC50 for this to occur ranges between 22 and 25 umol/l which is a plasma concentration of 6-8 ng/ml [81,285]. Other proposed mechanisms include activation of PPARalpha which has an IC50 of 5 umol/l or a plasma concentration of 1.6 ng/ml [263,264]. CBD also increases palmitoylethanolamide (PEA) levels through competitive inhibition of FAAH. Palmitoylethanolamide (PEA) itself is a potent activator of PPAR-alpha [95,139]. ...
... It is generally composed of (1) a G-proteincoupled receptor, cannabinoid 1 (CB1R), which is highly concentrated in the CNS, but also abundant in the peripheral tissues; (2) two principal endogenous endocannabinoids (eCB) 2-arachidonoylglycerol (2-AG) and anandamide (AEA)); and (3) the serine hydrolases monoacylglycerol lipase (MAGL), and fatty acid amide hydrolase (FAAH) that metabolize 2-AG and AEA (Di Marzo and Matias, 2005;Matias and Di Marzo, 2007). eCBS helps to shape neuronal connectivity in the brain during development and into adulthood (Mato et al., 2003), however, it is also involved in numerous pathways controlling appetite, including the gut-microbiota-adipose-brain regulatory loop and other parameters directly-related to energy balance (Jo et al., 2005;Quarta et al., 2010;Silvestri and Di Marzo, 2013;Forte et al., 2020). ...
... Body weight effects could be attributed to CPF direct inhibition of FAAH and MAGL, leading to build up of AEA and 2-AG in the brain (Carr et al., 2020, over stimulation of the hypothalamus and nucleus accumbens resulting in increased hunger and motivation to eat (Di Marzo and Matias, 2005). Increased peripheral eCBs affecting a multitude of pathways, especially at low CPF doses, were likely associated with dysbiosis and inflammation, (Silvestri and Di Marzo, 2013) related to many diseases (e.g., T2D, metabolic syndrome, hypertension) (Borrelli and Izzo, 2009;Després et al., 2006). ...
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Marilyn Silva. Retired from a career in toxicology and risk assessment. Increased childhood and adult obesity are associated with chlorpyrifos (CPF), an organophosphate pesticide. Cannabis (Δ⁹Tetrahydrocannabinol: Δ⁹THC) use has increased globally with legalization. CPF applications on cannabis crops lacks federally regulated tolerances and may pose health risks through exposure during development and in adulthood. Both CPF and Δ⁹THC affect the endocannabinoid system (eCBS), a regulator of appetite, energy balance, and gut microbiota, which, if disrupted, increases risk for obesity and related diseases. CPF inhibits eCB metabolism and Δ⁹THC is a partial agonist/antagonist at the cannabinoid receptor (CB1R). Effects of each on obesogenic parameters were examined via literature search. Male rodents with CPF exposure showed increased body weights, dysbiosis, inflammation and oxidative stress, potentially associated with increased eCBs acting through the gut-microbiota-adipose-brain regulatory loop. Δ⁹THC generally decreased body weights via partial agonism at the CB1R, lowering levels of eCBs. Dysbiosis and/or oxidative stress associated inflammation occurred with CPF, but these parameters were not tested with Δ⁹THC. Database deficiencies included limited endpoints to compare between chemicals/age-groups, inter-study variables (dose ranges, dosing vehicle, rodent strain, treatment duration, etc.). CPF and Δ⁹THC were not tested together, but human co-chemical effects would depend on exposure ratio, subject age, exposure duration, and health status, among others. An overriding concern is that both chemicals are well-documented developmental neurotoxins in addition to their low dose effects on energy balance. A co-exposure risk assessment is warranted with increased use and lack of federal CPF regulation on cannabis.
... Capsaicin can indeed play its role in a receptor-independent manner through the inactivation of nuclear factor κB (NF-κB) and activation of peroxisome proliferator-activated receptor γ (PPARγ) [29]. Another mechanism is represented by the regulation of the production of the endocannabinoids (eCBs), which are lipid mediators that act as major regulators of energy homeostasis [30][31][32] and, together with a plethora of eCB-related molecules, receptors and metabolic enzymes, constitute the endocannabinoidome (eCBome), a complex lipid-signaling system [33]. Some of these molecules, such as long-chain unsaturated mono-acyl-glycerols (MAGs) and, particularly, N-acyl-ethanolamines (NAEs), are wellestablished endogenous activators of TRPV1 channels [34,35]. ...
... In the present study, we assessed the effects of a 12 weeks dietary supplementation of CAE (equivalent to 4 mg capsaicinoids/day, of which 2.4 mg were capsaicin, 1.4 mg were dihydrocapsaicin and 0.2 mg were nordihydrocapsaicin) in reproductive-aged women with overweight and obesity undergoing a calorie-reduced diet (−500 kcal/day) on the gut microbiota and the expanded endocannabinoid system known as the eCBome. These are two major players that control energy homeostasis, independent from their effects on body weight and food intake, and that are disrupted in obesity and other metabolic disorders [32,37]. We report for the first time that CAE inhibited changes in circulating eCBome lipids induced by the caloric restriction in control participants and induced alterations in the gut microbiota in directions that may favor beneficial actions on the metabolic consequences of obesity. ...
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Capsaicinoids, the pungent principles of chili peppers and prototypical activators of the transient receptor potential of the vanilloid type-1 (TRPV1) channel, which is a member of the expanded endocannabinoid system known as the endocannabinoidome (eCBome), counteract food intake and obesity. In this exploratory study, we examined the blood and stools from a subset of the participants in a cohort of reproductive-aged women with overweight/obesity who underwent a 12-week caloric restriction of 500 kcal/day with the administration of capsaicinoids (two capsules containing 100 mg of a capsicum annuum extract (CAE) each for a daily dose of 4 mg of capsaicinoids) or a placebo. Samples were collected immediately before and after the intervention, and plasma eCBome mediator levels (from 23 participants in total, 13 placebo and 10 CAE) and fecal microbiota taxa (from 15 participants in total, 9 placebo and 6 CAE) were profiled using LC–MS/MS and 16S metagenomic sequencing, respectively. CAE prevented the reduced caloric-intake-induced decrease in beneficial eCBome mediators, i.e., the TRPV1, GPR119 and/or PPARα agonists, N-oleoyl-ethanolamine, N-linoleoyl-ethanolamine and 2-oleoyl-glycerol, as well as the anti-inflammatory N-acyl-ethanolamines N-docosapentaenyl-ethanolamine and N-docosahexaenoyl-ethanolamine. CAE produced few but important alterations in the fecal microbiota, such as an increased relative abundance of the genus Flavonifractor, which is known to be inversely associated with obesity. Correlations between eCBome mediators and other potentially beneficial taxa were also observed, thus reinforcing the hypothesis of the existence of a link between the eCBome and the gut microbiome in obesity.
... Therefore, the eCB is ubiquitous in the body, in cell membranes of the brain, organs, connective tissues, glands and immune system cells. Furthermore, eCB is also found at the intersections of several other systems, allowing for communication and coordination between different cells in the body [47][48][49]. ...
... Several physiological mechanisms occur in the body when cannabinoid receptors are stimulated, such as reduced pain and inflammation, increased appetite, thermoregulation, intraocular pressure, energy balance, metabolism, sleep improvement, stress reduction, motivation, disposition, memory, among others. Cannabinoid receptors' main components consist of: (i) the receptors per se found on the surface of cells, which transmit information to deeper cells about changes in conditions, initiating an appropriate cellular response; (ii) endocannabinoids, characterized by small cannabinoid receptor activating molecules; (iii) metabolic enzymes that work by breaking down endocannabinoids after their use, so that they are used only when necessary, never longer [47][48][49]. This is an interesting fact of the eCB system, which acts only on demand, that is, it activates only when necessary and works to repair or modulate the function of other mediators. ...
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Zebrafish is considered an unprecedented animal model in drug discovery. A review of the literature presents highlights and elucidates the biological effects of chemical components found in Cannabis sativa. Particular attention is paid to endocannabinoid system (eCB) and its main receptors (CB1 and CB2). The zebrafish model is a promising one for the study of cannabinoids because of the many similarities to the human system. Despite the recent advances on the eCB system, there is still the need to elucidate some of the interactions and, thus, the zebrafish model can be used for that purpose as it respects the 3Rs concept and reduced time and costs. In view of the relevance of cannabinoids in the treatment and prevention of diseases, as well as the importance of the zebrafish animal model in elucidating the biological effects of new drugs, the aim of this study was to bring to light information on the use of the zebrafish animal model in testing C. sativa- based medicines .
... The endocannabinoid (eCB) system is an endogenous signaling pathway formed by lipid-derived endogenous mediators (endocannabinoids), their receptors (cannabinoid type 1 and type 2 (CB 1 and CB 2 )), and the enzymes involved in their synthesis and degradation [3]. The endocannabinoid receptor CB 1 R in the brain is involved in the regulation of food intake and energy homeostasis. ...
... As has been mentioned above, the use of CB 1 R antagonists or inverse agonists, such as rimonabant, exert anti-obesity actions but have undesirable psychiatric side-effects. In recent years, it has become evident that the peripheral eCB system plays an important role in both food intake regulation [9] and glucose and lipid homeostasis, with major actions in the liver and adipose tissue [3,10], thereby representing an emerging target for the development of new pharmacologic tools to fight against metabolic diseases. In addition, DiPatrizio also highlights the potential of new CB 1 R antagonists with low brain penetrance, which may be effective and safe therapeutic options for the treatment of obesity and related conditions [4,11]. ...
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Obesity represents the most prevalent metabolic disease in the world at present, posing an important public health challenge [...]
... On the other hand, a first hydrolysis by phospholipase C-β (PLC-β) and a second reaction by diacylglycerol lipase (DAGL) are required for 2-AG formation [4][5][6]. Once synthetised, The ECS controls many biological events, such as synaptic plasticity, neuroprotection, immune response modulation, energy homeostasis [11][12][13], and over the past twenty years, a growing number of evidence has shown that its alteration correlates with the onset of various diseases including cancer [14,15]. ...
... respectively) ( Table 1). The ECS controls many biological events, such as synaptic plasticity, neuroprotection, immune response modulation, energy homeostasis [11][12][13], and over the past twenty years, a growing number of evidence has shown that its alteration correlates with the onset of various diseases including cancer [14,15]. ...
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The tumour microenvironment (TME) is now recognised as a hallmark of cancer, since tumour:stroma crosstalk supports the key steps of tumour growth and progression. The dynamic co-evolution of the tumour and stromal compartments may alter the surrounding microenvironment, including the composition in metabolites and signalling mediators. A growing number of evidence reports the involvement of the endocannabinoid system (ECS) in cancer. ECS is composed by a complex network of ligands, receptors, and enzymes, which act in synergy and contribute to several physiological but also pathological processes. Several in vitro and in vivo evidence show that ECS deregulation in cancer cells affects proliferation, migration, invasion, apoptosis, and metastatic potential. Although it is still an evolving research, recent experimental evidence also suggests that ECS can modulate the functional behaviour of several components of the TME, above all the immune cells, endothelial cells and stromal components. However, the role of ECS in the tumour:stroma interplay remains unclear and research in this area is particularly intriguing. This review aims to shed light on the latest relevant findings of the tumour response to ECS modulation, encouraging a more in-depth analysis in this field. Novel discoveries could be promising for novel anti-tumour approaches, targeting the microenvironmental components and the supportive tumour:stroma crosstalk, thereby hindering tumour development.
... The endocannabinoid system has pleiotropic functions in the body, and plays a key role in the development of obesity and its comorbidities being a mediator in the relationship between the gut microbiota and host metabolism [15]. Circulating endocannabinoids (ECs) and their congeners N-acylethanolamines (NAEs) are metabolically connected to diet and are tightly involved in the regulation of energy homeostasis, appetite cues, pain sensation, inflammation, immunity, obesity and dysmetabolism [16][17][18]. Indeed, plasma ECs and NAEs concentrations, as well as NAEs ratios, are considered biomarkers of white adipose tissue distribution reflecting blood cholesterol and insulin resistance in obesity [18,19] in addition to being involved in food liking and intake [20,21]. ...
... Circulating endocannabinoids (ECs) and their congeners N-acylethanolamines (NAEs) are metabolically connected to diet and are tightly involved in the regulation of energy homeostasis, appetite cues, pain sensation, inflammation, immunity, obesity and dysmetabolism [16][17][18]. Indeed, plasma ECs and NAEs concentrations, as well as NAEs ratios, are considered biomarkers of white adipose tissue distribution reflecting blood cholesterol and insulin resistance in obesity [18,19] in addition to being involved in food liking and intake [20,21]. We have recently observed several correlations between circulating NAEs, habitual diet and systemic inflammation in subjects with an ileostomy [22]. ...
... In addition, the endocannabinoidome plays an intrinsic role on memory, stress processing, and reward pathways involved in addiction [84]. Alterations in the system are associated with a wide range of diseases: obesity, Parkinson's disease, Alzheimer's dementia, multiple sclerosis, Huntington's chorea, amyotrophic lateral sclerosis, schizophrenia, depression, atherosclerosis, cancer, inflammatory bowel disease, liver steatosis and fibrosis, and infertility [40,114,139,190,202,247,263]. Understanding these alterations in the endocannabinoidome system may allow for future disease modifying or palliative interventions. ...
... The IC50 for this to occur ranges between 22 and 25 umol/l which is a plasma concentration of 6-8 ng/ml [81,285]. Other proposed mechanisms include activation of PPARalpha which has an IC50 of 5 umol/l or a plasma concentration of 1.6 ng/ml [263,264]. CBD also increases palmitoylethanolamide (PEA) levels through competitive inhibition of FAAH. Palmitoylethanolamide (PEA) itself is a potent activator of PPAR-alpha [95,139]. ...
... The endocannabinoid system (ECS) plays a crucial role in activation of key processes for AT metabolic function including lipogenesis and adipogenesis as well as inhibition of lipolytic activity [9]. The ECS is a central regulator of whole body metabolism and energy homeostasis by reducing the duration and intensity of negative energy balance in mammals [10]. However, its role in ruminant physiology is only recently emerging [9,11,12]. ...
... The enzymes that synthesize and degrade the ECS ligands, the endocannabinoids (eCBs), were also detected in AT [15,16]. The activation of CB1 receptor in adipocytes triggers de novo biosynthesis of fatty acids, accumulation of triglycerides, and minimizes lipolysis [10]. We have demonstrated that dairy cows calving in summer that exhibited a high degree of AT lipolysis postpartum (PP) had 2-fold elevated levels of the main eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) compared to prepartum levels. ...
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Environmental heat load (HL) adversely affects the performance of dairy cows. The endocannabinoid system (ECS) regulates metabolism and the stress response, thus we hypothesized that HL may affect the ECS of dairy cows. Our objective was to determine the levels of endocannabinoids (eCBs) and gene and protein expressions of the ECS components in adipose tissue (AT) and plasma of early postpartum (PP) and late-lactation cows. In addition, we examined eCBs in milk, and studied the interaction of eCBs with bovine cannabinoids receptors CB1 and CB2. In the first experiment, plasma and AT were sampled from cows calving during summer (S, n = 9) or winter (W, n = 9). Dry matter intake (DMI) and energy balance (EB) were lower in S vs. W, and relative gene expressions of transient-receptor-potential-cation-channel-subfamily-V-member-1 (TRPV1), the cannabinoid receptors CNR1 (CB1) and CNR2 (CB2), and monoglyceride lipase (MGLL) were decreased in AT of S compared to W. Protein abundance of peroxisome proliferator-activated-receptor-alpha (PPAR-α) was decreased, while tumor-necrosis factor-α (TNF-α) was increased in AT of S vs. W. Other components of the ECS were not different between S and W calving cows. To study whether the degree of HL may affect the ECS, we performed a second experiment with 24 late-lactation cows that were either cooled (CL) or not cooled (heat-stressed; HS) during summer. DMI was lower in HS vs. CL, AT protein abundance of PPAR-α was lower, and TRPV1 tended to be lower in HS vs. CL, but other components of the ECS were not different between groups. Milk levels of 2-arachidonoylglycerol (2-AG) tended to increase in HS vs. CL. Additionally, modeling of the bovine cannabinoid receptors demonstrated their binding to anandamide and 2-AG. Environmental HL, possibly via lower intake, is associated with limited alterations in ECS components in AT of dairy cows.
... The endocannabinoid system (ECS) comprises the cannabinoid receptors of type 1 (CB1R) and of type 2 (CB2R), the two endocannabinoids (ECs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes involved in their synthesis and degradation [193]. The ECS plays an important role in multiple aspects of neural functions [194,195] and is involved in the control of both glucose and lipid metabolism in the liver and adipose tissue [196][197][198]. In non-metabolic organs, the EC receptors are expressed at low levels, but may undergo up/down-regulation in pathological conditions. ...
... Literature reviews have focused on the effect of physical activity on the endocannabinoid system and its impact on the pathology of neurological and neurodegenerative diseases, such as depression, anxiety, multiple sclerosis, epilepsy, Parkinson's, and Alzheimer's disease, in animal and human models [9,16,17]. They also addressed the benefits of exercise-induced endocannabinoid changes on brain function (cognition, mood, appetite, reward system), the musculoskeletal and adipose tissue (glucose regulation, insulin sensitivity, lipogenesis), and stress [18][19][20]. Moreover, Hillard [11] compiled information on circulating endocannabinoid levels and metabolic regulation, sleep, inflammation, and exercise. ...
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Background Increased circulating endocannabinoids levels are typically associated with aerobic exercise. This phenomenon is associated with a “runner’s high,” a state of euphoria and well-being experienced after a long exercise. We will provide in this review a transparent and standardized methodology following the PRISMA-P and Cochrane Handbook for Systematic Reviews of Interventions for conducting a systematic review and meta-analysis for synthesizing the available evidence about the effects of physical activity on the circulating levels of AEA and 2-AG endocannabinoids in healthy subjects. Methods A multi-disciplinary team with basic and clinical expertise in exercise science developed this protocol. PubMed, EMBASE, Web of Science, CINAHL, SPORTDiscus, and Scopus will be the databases. A health sciences librarian was consulted in the development of the research. Search strategies will combine MeSH terms and free text words, including “exercise,” “exercise, physical,” “exercise training,” “physical activity,” “endocannabinoids,” “2-arachidonoyl-glycerol,” “glyceryl 2-arachidonate,” “2-AG,” “anandamide,” “AEA,” “n-arachidonoylethanolamide,” “adult,” “young adult,” and “middle-aged.” We will select experimental or quasi-experimental studies published through December 2021. The selection of studies, data extraction, assessment of the risk of bias, and the quality of evidence will be carried out in a paired and independent manner, and the consistency will be assessed using the statistics of Cohen Kappa. Methodological quality will be assessed using the Revised Cochrane risk of bias tool for randomized trials (RoB 2) and the Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) risk tool. We will use the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence, χ ² and I ² tests for heterogeneity, funnel plots, and the Egger test for publication bias. A meta-analysis for each data comparison will be performed whenever possible to determine the effect of physical activity on endocannabinoids’ circulating levels. Discussion This systematic review and meta-analysis will provide an overview of the evidence about physical activity over AEA and 2-AG endocannabinoids, including comparability of variables between studies, critical interpretation of results, and use of accurate statistical techniques. The endocannabinoid is molecules by which muscles communicate with other tissues and organs, mediating the beneficial effects of exercise on health and performance, including increased glucose uptake, improved insulin action, and mitochondrial biogenesis. They are essential to exercise. Thus, this study will review the acute effect of physical exercise on circulating levels of endocannabinoids in healthy individuals. The results of this study will potentially be transferred to doctors, health professionals, and legislators to guide their decision making, as well as will improve future research. Systematic review registration PROSPERO CRD42020202886 .
... 37 Some of these functions have been described also for PPARα, whose decreased expression (possibly explained by decreased levels of its endogenous ligands) has been associated with sarcopenia. 38 An increase in NAE (AEA, OEA, and PEA), but not 2-AG, levels was found here in the SWAT of aged rats (although plasma 2-AG levels positively correlated with fat mass, in agreement with previous studies 39 ). This finding could be explained by the concomitant decrease in the expression of Faah and increase in the expression of Ptnp22, which may have caused decreased degradation and, possibly, increased biosynthesis of NAEs, and by the simultaneous increase in the expression of both biosynthetic and catabolic enzymes for 2-AG in this tissue. ...
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Background: Activation of the endocannabinoid system (ECS) is associated with the development of obesity and insulin resistance, and with perturbed skeletal muscle development. Age-related sarcopenia is a progressive and generalized skeletal muscle disorder involving an accelerated loss of muscle mass and function, with changes in skeletal muscle protein homeostasis due to lipid accumulation and anabolic resistance. Hence, both obesity and sarcopenia share a common set of pathophysiological alterations leading to skeletal muscle impairment. The aim of this study was to characterize how sarcopenia impacts the ECS and if these modifications were related to the loss of muscle mass and function associated with aging in rats. Methods: Six-month-old and 24-month-old male rats were used to measure the contractile properties of the plantarflexors (isometric torque-frequency relationship & concentric power-velocity relationship) and to evaluate locomotor activity, motor coordination, and voluntary gait by open field, rotarod, and catwalk tests, respectively. Levels of endocannabinoids (AEA & 2-AG) and endocannabinoid-like molecules (OEA & PEA) were measured by LCF-MS/MS in plasma, skeletal muscle, and adipose tissue, while the expression of genes coding for the ECS were investigated by quantitative reverse transcription PCR (RT-qPCR). Results: Sarcopenia in old rats was exemplified by a 49% decrease in hindlimb muscle mass (P < 0.01), which was associated with severe impairment of isometric torque, power, voluntary locomotor activity, motor coordination, and gait quality. Sarcopenia was associated with (1) increased 2-AG (+32%, P = 0.07) and reduced PEA and OEA levels in the plasma (-25% and -40%, respectively, P < 0.01); (2) an increased content of AEA, PEA, and OEA in subcutaneous adipose tissue (P < 0.01); and (3) a four-fold increase of 2-AG content in the soleus (P < 0.01) and a reduced OEA content in EDL (-80%, P < 0.01). These alterations were associated with profound modifications in the expression of the ECS genes in the adipose tissue and skeletal muscle. Conclusions: Taken together, these findings demonstrate that circulating and peripheral tissue endocannabinoid tone are altered in sarcopenia. They also demonstrate that OEA plasma levels are associated with skeletal muscle function and loss of locomotor activity in rats, suggesting OEA could be used as a circulating biomarker for sarcopenia.
... Gut dysbiosis, lowgrade inflammation and gut permeability are indeed leading causes for obesity development (Levy et al., 2017;Sun et al., 2018). In obesity, the systemic elevation of the eCB tone (brain included) as well as the upregulation of the CB 1 receptor in adipose tissue, liver and muscle have been extensively demonstrated (Matias and Di Marzo, 2006;Starowicz et al., 2008;Silvestri and Di Marzo, 2013). Accordingly, blockade of CB 1 receptors may revert both systemic inflammation and dysbiosis induced in obese mice by chronic high-fat diet (HFD) regimen (Mehrpouya-Bahrami et al., 2017). ...
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The latest years have witnessed a growing interest towards the relationship between neuropsychiatric disease in children with autism spectrum disorders (ASD) and severe alterations in gut microbiota composition. In parallel, an increasing literature has focused the attention towards the association between derangement of the endocannabinoids machinery and some mechanisms and symptoms identified in ASD pathophysiology, such as alteration of neural development, immune system dysfunction, defective social interaction and stereotypic behavior. In this narrative review, we put together the vast ground of endocannabinoids and their partnership with gut microbiota, pursuing the hypothesis that the crosstalk between these two complex homeostatic systems (bioactive lipid mediators, receptors, biosynthetic and hydrolytic enzymes and the entire bacterial gut ecosystem, signaling molecules, metabolites and short chain fatty acids) may disclose new ideas and functional connections for the development of synergic treatments combining “gut-therapy,” nutritional intervention and pharmacological approaches. The two separate domains of the literature have been examined looking for all the plausible (and so far known) overlapping points, describing the mutual changes induced by acting either on the endocannabinoid system or on gut bacteria population and their relevance for the understanding of ASD pathophysiology. Both human pathology and symptoms relief in ASD subjects, as well as multiple ASD-like animal models, have been taken into consideration in order to provide evidence of the relevance of the endocannabinoids-microbiota crosstalk in this major neurodevelopmental disorder.
... In addition, eCBs also play a role in glial cells and in intracellular organelles [5][6][7][8][9] . In the brain, eCBs participate in short-term and long-term synaptic plasticity of glutamatergic and γ-aminobutyric acid (GABA)ergic synapses in a variety of regions, including the cerebral cortex, hippocampus, striatum, ventral tegmental area, amygdala and cerebellum 4,10 , playing important roles in a wide range of physiological processes such as development, emotional state, pain, the sleep-wake cycle, energy metabolism, reward and learning and memory [11][12][13][14][15] . Given the broad distribution and variety of functions of eCBs, dysregulation of the eCB system has been associated with a plethora of disorders, including neuropsychiatric and neurodegenerative diseases, epilepsy, cancer and others [16][17][18] . ...
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Endocannabinoids (eCBs) are retrograde neuromodulators with important functions in a wide range of physiological processes, but their in vivo dynamics remain largely uncharacterized. Here we developed a genetically encoded eCB sensor called GRABeCB2.0. GRABeCB2.0 consists of a circular-permutated EGFP and the human CB1 cannabinoid receptor, providing cell membrane trafficking, second-resolution kinetics with high specificity for eCBs, and shows a robust fluorescence response at physiological eCB concentrations. Using GRABeCB2.0, we monitored evoked and spontaneous changes in eCB dynamics in cultured neurons and acute brain slices. We observed spontaneous compartmentalized eCB transients in cultured neurons and eCB transients from single axonal boutons in acute brain slices, suggesting constrained, localized eCB signaling. When GRABeCB2.0 was expressed in the mouse brain, we observed foot shock-elicited and running-triggered eCB signaling in the basolateral amygdala and hippocampus, respectively. In a mouse model of epilepsy, we observed a spreading wave of eCB release that followed a Ca²⁺ wave through the hippocampus. GRABeCB2.0 is a robust probe for eCB release in vivo.
... Taken together, these studies underscore the involvement of TAS2Rs in regulation of energy intake. As the endocannabinoid system (ECS) also participates in controlling feeding behaviour and body composition homeostasis [179], it possibly interact with TAS2Rs. This interpretation is supported by the association between sensitivity to 6-PTU and plasma levels of two endocannabinoids, 2-arachidonylglycerol and arachidonylethanolamide, in normal-weight individuals. ...
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Bitter taste-sensing type 2 receptors (TAS2Rs or T2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), are of crucial importance in the perception of bitterness. Although in the first instance, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, numerous studies have detected these sensory receptor proteins in several extra-oral tissues, such as in pancreatic or ovarian tissues, as well as in their corresponding malignancies. Critical points of extra-oral TAS2Rs biology, such as their structure, roles, signaling transduction pathways, extensive mutational polymorphism, and molecular evolution, have been currently broadly studied. The TAS2R cascade, for instance, has been recently considered to be a pivotal modulator of a number of (patho)physiological processes, including adipogenesis or carcinogenesis. The latest advances in taste receptor biology further raise the possibility of utilizing TAS2Rs as a therapeutic target or as an informative index to predict treatment responses in various disorders. Thus, the focus of this review is to provide an update on the expression and molecular basis of TAS2Rs functions in distinct extra-oral tissues in health and disease. We shall also discuss the therapeutic potential of novel TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles.
... In the context of metabolic disorders, several studies demonstrated the existence of an association between altered levels or activation of eCB signaling at CB 1 receptors and the development of different pathological conditions such as obesity and type 2 diabetes [11][12][13][14][15][16], hepatic disorders (i.e., steatosis) [17,18], and intestinal/adipose tissue inflammation [19,20]. Conversely, several pieces of evidence suggest that activation of other eCBome receptors, such as CB 2 , PPARα and γ, GPR110 and GPR119 promotes important anti-inflammatory and/or incretin-like effects [21,22], which can be exploited to improve insulin sensitivity and energy expenditure, thus providing a means for countering obesity-linked metabolic dysfunctions and ameliorating the metabolic status [3,23]. ...
Article
Background Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes. Results The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice. Conclusions The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterize obesity and diabetes, possibly in relation with gut microbiome alterations.
... ble for the psychotropic and behavioral effects after the use of cannabinoids. The CB2 receptor is expressed in metabolically active peripheral organs such as the liver, adipose tissue, and pancreas [90,91] and functions as a key modulator of innate immunity and fuel metabolism, amongst other roles [91,92]. ...
Article
Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.
... Pathological alterations to the ECS have been described in nearly all chronic disorders and, in particular, addiction, neurodegenerative diseases, mood disorders, and obesity [65]. Obesity has been linked to an overactive ECS, as evidenced extensively in the literature, for example [81,[86][87][88]. Plasma endocannabinoids correlate positively with markers of obesity and metabolic disorders [89,90], and alterations to the genes encoding CB1, CB2, and FAAH have been associated, respectively, with metabolic syndrome and overweight and obesity [85,91]. ...
Article
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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.
... In addition to fibrosis, numerous studies have documented that an overactive endocannabinoid/CB 1 R system contributes to visceral obesity and its complications (37), including type-2 diabetes (21), and also play a role in the pathology of alcoholic liver disease (38) and viral hepatitis (39). Conversely, CB 1 R blockade has beneficial effects in preclinical models of these conditions as well as in overweight individuals with metabolic syndrome (40). ...
Article
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Scleroderma, or systemic sclerosis, is a multi-organ connective tissue disease resulting in fibrosis of the skin, heart, and lungs with no effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) and increased activity of inducible NO synthase (iNOS) promote tissue fibrosis including skin fibrosis, and joint targeting of these pathways may improve therapeutic efficacy. Recently, we showed that in mouse models of liver, lung and kidney fibrosis, treatment with a peripherally restricted hybrid CB1R/iNOS inhibitor (MRI-1867) yields greater anti-fibrotic efficacy than inhibiting either target alone. Here, we evaluated the therapeutic efficacy of MRI-1867 in bleomycin-induced skin fibrosis. Skin fibrosis was induced in C57BL/6J (B6) and Mdr1a/b-Bcrp triple knock-out (KO) mice by daily subcutaneous injections of bleomycin (2 IU/100 µL) for 28 days. Starting on day 15, mice were treated for 2 weeks with daily oral gavage of vehicle or MRI-1867. Skin levels of MRI-1867 and endocannabinoids were measured by mass spectrometry to assess target exposure and engagement by MRI-1867. Fibrosis was characterized histologically by dermal thickening and biochemically by hydroxyproline content. We also evaluated the potential increase of drug-efflux associated ABC transporters by bleomycin in skin fibrosis, which could affect target exposure to test compounds, as reported in bleomycin-induced lung fibrosis. Bleomycin-induced skin fibrosis was comparable in B6 and Mdr1a/b-Bcrp KO mice. However, the skin level of MRI-1867, an MDR1 substrate, was dramatically lower in B6 mice (0.023 µM) than in Mdr1a/b-Bcrp KO mice (8.8 µM) due to a bleomycin-induced increase in efflux activity of MDR1 in fibrotic skin. Furthermore, the endocannabinoids anandamide and 2-arachidonylglycerol were elevated 2-4-fold in the fibrotic vs. control skin in both mouse strains. MRI-1867 treatment attenuated bleomycin-induced established skin fibrosis and the associated increase in endocannabinoids in Mdr1a/b-Bcrp KO mice but not in B6 mice. We conclude that combined inhibition of CB1R and iNOS is an effective anti-fibrotic strategy for scleroderma. As bleomycin induces an artifact in testing antifibrotic drug candidates that are substrates of drug-efflux transporters, using Mdr1a/b-Bcrp KO mice for preclinical testing of such compounds avoids this pitfall.
... Moreover, continuous administration of THC causes CB1 receptor internalization and desensitization [121]. Thus, decreased CB1 expression can be associated with obesity, metabolism disorders leading to dysbiosis, and induced inflammation in the gut [122]. The addition of prebiotics, probiotics, and antibiotics into ob/ob mice models resulted in the modulation of CB1 receptors expression [119]. ...
Article
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Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
... AEA acts not only as a partial agonist at CB1 and CB2 (Devane et al., 1992) but also on selective cation channels TRPV1, a key element on inflammatory conditions and pain (Oliveira et al., 2019). AEA has a notable role in several physiological and neurobehavioural processes, namely, pain perception (Piscitelli & Di Marzo, 2013), emotional behaviour (Micale et al., 2013) and energy metabolism (Silvestri & Di Marzo, 2013). 2AG is the most abundant endocannabinoid in the brain and is considered a full agonist of CB1 and CB2 (Sugiura et al., 1995). ...
Article
The onset of frank psychosis is usually preceded by a prodromal phase characterized by attenuated psychotic symptoms. Currently, research on schizophrenia prodromal phase (ultra-high risk for psychosis - UHR) has focused on the risk of developing psychosis, on the transition to full blown psychosis, and on its prediction. Neurobiological differences between UHR individuals who fully recover (remitters) versus those who show persistent/progressive prodromal symptoms (non-remitters) have been little explored. The endocannabinoid system constitutes a neuromodulatory system that plays a major role in brain development, synaptic plasticity, emotional behaviors and cognition. It comprises two cannabinoid receptors (CB1/CB2), two endocannabinoid ligands, arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2AG) along with their inactivation enzymes. Despite much evidence that the endocannabinoid system is imbalanced during psychosis, very little is known about it in UHR. Therefore, we aimed to quantify the plasma endocannabinoid levels in UHR and healthy controls (HC) and verify if these metabolites could differentiate between remitters and non-remitters. Circulating concentrations of AEA (p=0.003) and 2AG (p<0.001) were lower in UHR when compared to HC, with no difference between remitters and non-remitters. Regarding clinical evolution, it was observed that out of 91 UHRs initially considered, 16 had psychiatric complaints (3 years follow-up). Considering those subjects, there were weak correlations between clinical parameters and plasma concentrations of endocannabinoids. Our results suggest that the endocannabinoids are imbalanced before frank psychosis and that changes can be seen in plasma of UHR individuals. These molecules proved to be potential biomarkers to identify individuals in the prodromal phase of psychosis.
... The endocannabinoid system (ECS) is a system of biological lipids, that essentially modulates the functions of the immune, endocrine, and nervous systems (Lu and Mackie, 2016;Zou and Kumar, 2018). In the brain, ECS is involved in various neurophysiological processes including neurogenesis, synaptic plasticity, as well as memory, and emotions (Bisogno and Di Marzo, 2008;Silvestri and Di Marzo, 2013). ...
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As human life expectancy increases, cognitive decline and memory impairment threaten independence and quality of life. Therefore, finding prevention and treatment strategies for memory impairment is an important health concern. Moreover, a better understanding of the mechanisms involved underlying memory preservation will enable the development of appropriate pharmaceuticals drugs for those who are activity limited. Exercise training as a non-pharmacological tool, has been known to increase the mean lifespan by maintaining general body health and improving the cardiovascular and nervous systems function. Among different exercise training protocols, aerobic exercise has been reported to prevent the progression of memory decline, provided adequate exertion level, duration, and frequency. Mechanisms underlying exercise training effects on memory performance have not been understood yet. Convergent evidence suggest several direct and indirect mechanisms at molecular and supramolecular levels. The supramolecular level includes improvement in blood circulation, synaptic plasticity and neurogenesis which are under controls of complex molecular signaling of neurotransmitters, neurotrophic factors, exerkines, and epigenetics factors. Among these various factors, irisin/BDNF signaling seems to be one of the important mediators of crosstalk between contracted skeletal muscles and the brain during exercise training. This review provides an affordable and effective method to improve cognitive function in old ages, particularly those who are most vulnerable to neurodegenerative disorders.
... For instance, the "retrograde endocannabinoid signalling (ko04723)" pathway was significantly enriched in the comparisons of CY vs. C (with 39 DALs) and Y vs. C (with 37 DALs) (Fig. 5, Table S5-S7), although it was not enriched in the comparison of CY vs. Y (with 5 DALs). Retrograde endocannabinoid signalling is considered to be related to the maintenance of energy homeostasis (Silvestri and DiMarzo, 2013). Therefore, the difference between cattle-yak/yak and cattle is likely caused by their adaptation/stress to high altitudes. ...
Article
The quantitative comparisons of longissimus thoracis lipidomes among cattle-yak, yak, and cattle were carried out, and differentially abundant lipids (DALs) related to post-mortem physiology and meat quality were examined and discussed. Multivariate statistical analyses showed that the muscle lipidomes of cattle-yak, yak, and cattle were significantly different. Quantitative analysis results showed that there were 108 (cattle-yak vs. cattle), 106 (cattle-yak vs. yak), and 77 (yak vs. cattle) DALs between different muscles. Phospholipids containing long-chain polyunsaturated fatty acids were more abundant in the muscles of plateau cattle (cattle-yak and yak) than plain cattle (cattle), which is a bonus for the nutritional value of plateau cattle meat. Long-chain acylcarnitines accumulated in yak muscle, suggesting different levels of fatty acid β-oxidation and a potential influence on the post-mortem physiology of yak meat. The results show that the muscle lipid profiles of cattle-yak, yak, and cattle were significantly different, and could clearly distinguish by the OPLS-DA analysis. DALs reveal the difference in energy metabolism and lipid nutrition quality between plateau cattle (cattle-yak and yak) muscles and cattle muscle.
... The endocannabinoid system (ECS) comprises the cannabinoid receptors of type 1 (CB1R) and of type 2 (CB2R), the two endocannabinoids (ECs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes involved in their synthesis and degradation [193]. The ECS plays an important role in multiple aspects of neural functions [194,195] and is involved in the control of both glucose and lipid metabolism in the liver and adipose tissue [196][197][198]. In non-metabolic organs, the EC receptors are expressed at low levels, but may undergo up/down-regulation in pathological conditions. ...
Article
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Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.
... The eCB system participates in a plethora of physiological functions, including stress coping, anxiety, fear responses, social behavior, and energy storage (Silvestri and Di Marzo, 2013;Lutz et al., 2015;Wei et al., 2017;Ruiz de Azua and Lutz, 2019). Notably, the eCB system has been found to be altered in several pathological conditions such as anxiety disorders, post-traumatic stress disorder (PTSD), depression, autism, eating disorders, and irritable bowel syndrome (IBS) along with others. ...
Article
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The endocannabinoid system, with its receptors and ligands, is present in the gut epithelium and enteroendocrine cells, and is able to modulate brain functions, both indirectly through circulating gut-derived factors and directly through the vagus nerve, finally acting on the brain’s mechanisms regarding metabolism and behavior. The gut endocannabinoid system also regulates gut motility, permeability, and inflammatory responses. Furthermore, microbiota composition has been shown to influence the activity of the endocannabinoid system. This review examines the interaction between microbiota, intestinal endocannabinoid system, metabolism, and stress responses. We hypothesize that the crosstalk between microbiota and intestinal endocannabinoid system has a prominent role in stress-induced changes in the gut-brain axis affecting metabolic and mental health. Inter-individual differences are commonly observed in stress responses, but mechanisms underlying resilience and vulnerability to stress are far from understood. Both gut microbiota and the endocannabinoid system have been implicated in stress resilience. We also discuss interventions targeting the microbiota and the endocannabinoid system to mitigate metabolic and stress-related disorders.
... The discovery and study of the functions of CB1 receptor is undoubtedly one of the most fascinating chapters in the physiology of multicellular organisms . While the highest levels of expression are observed in the brain, CB1 receptors are widely distributed in the body and are present in a large number of organs, including muscles (Heyman et al., 2012;Mendizabal-Zubiaga et al., 2016a), the gastrointestinal tract (Izzo et al., 2015), the liver (Kunos and Osei-Hyiaman, 2008), the pancreas (Linari et al., 2009;Silvestri and Di Marzo, 2013), the adipose tissue (Cota et al., 2003) and others. CB2 receptor expression has been mostly described in peripheral immune cells (Maccarrone et al., 2015) and microglia (Tanaka et al., 2020), although it was eventually also detected in neurons (Jordan and Xi, 2019). ...
Thesis
The endocannabinoid system (ECS) is a crucial modulatory system involved in the regulation of diverse brain functions and behavior. The ECS is the target of the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), which exerts many of its psychotomimetic effects by binding to brain cannabinoid type-1 (CB1) receptors. Cannabis is currently the most widely used psychoactive substance worldwide, with the highest consumption rate observed among adolescents and young adults. Adolescence comprises a sensitive developmental period, during which cannabinoid drugs can easily disrupt the normative trajectory of brain maturation, giving rise to long-term consequences. Indeed, the association between adolescent cannabis use and persistent negative outcomes has long been the focus of neuroscience research, with numerous studies associating these outcomes with a range of neuropsychiatric disorders—psychotic disorders being some the most prominent. However, the mechanisms linking cannabinoid exposure to long-term behavioral effects are complex, and results in the field remain inconclusive. Animal models exposed to THC during developmental periods (e.g, adolescence) are therefore critical to assess the impact of cannabis use. By using a model of adolescent THC in mice, the first aim of this study was to characterize the specific adult behavioral profile of male and female mice. To this end, a set of psychotic-like behavioral processes related to motor, social and cognitive functions were evaluated in adulthood. Moreover, in order to assess possible alterations in mental sensory representations, which more accurately represent the distinctive features of the core psychotic symptoms (i.e. hallucinations and delusions), we investigated the effect of adolescent THC in a representation-mediated learning protocol. Resembling cannabis-induced psychotic states in humans, impairments in this protocol have been described after acute administration of THC, however the effect of adolescent THC has never been investigated. Altogether, our findings reveal sex-dependent effects, with adolescent THC mainly disrupting motor, social, and short-term memory functions in male mice, and associative learning and memory in female mice. The second aim of this study was to explore potential neurobiological mechanisms underlying the effects of adolescent THC. Therefore, we performed analysis of the CB1 receptor status and signaling targets (such as the ERK and CREB proteins), observing sex- and region-dependent changes. Our recent findings have shown that mitochondrial Complex I (CI) instability through the specific de-phosphorylation of its NDUFS4 subunit in astrocytes is the mechanism leading to persistent THC-induced social deficits. Here, we demonstrated that NDUFS4 phosphorylation is specifically decreased by adolescent THC in male, but not in female mice, suggesting that the phosphorylation status of this CI subunit might be responsible for the sex-specific behavioral effects. Notably, astroglial expression of a phosphomimetic mutant form of NDUFS4 was able to prevent the adolescent THC-induced behavioral effects on locomotion and social interaction in adult male mice. These results strongly support the idea that mitochondrial alterations in astrocytes are causally involved in the enduring behavioral effects of adolescent THC, highlighting the emerging role of cellular bioenergetics in the regulation of behavior.
... Strong evidence from animal models demonstrates that cannabinoids alleviate pain and reduce inflammation via the lipid-signaling endocannabinoid system. Multiple cannabinoid receptor types are found on immune cells and nerves known to be involved in pain and pain processing ( Fig. 1) [7,[36][37][38][39][40][41][42]. ...
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Purpose of Review Changing attitudes about marijuana have led to an increase in use of medicinal marijuana, especially for painful chronic conditions. Patients ask rheumatologists for guidance on this topic. This review provides up-to-date information on the safety and efficacy of medicinal cannabis for rheumatic disease pain. Recent Findings The number of publications related to rheumatic disease and cannabis has increased, but recent literature skews heavily toward reviews vs primary research. Data supporting a role for cannabinoids in rheumatic disease continue to grow. Observational and survey studies show increased use of medicinal cannabis, both by people with rheumatic disease and the general population, and suggest that patients find these treatments beneficial. Prospective studies, however, including randomized controlled clinical trials, are rare and sorely needed. Summary As medicinal cannabis use for rheumatic diseases rises, despite lack of evidence, we review the sparse data available and provide tips for conversations about medicinal cannabis for rheumatologists.
... The endocannabinoid is involved in both cerebral and distal energy metabolism [46]. Endocannabinoids act as retrograde synaptic plasticity neuromodulators of appetite and food intake, lipogenesis, and cravings [47,48]. Local endocannabinoids prevent fat accumulation. ...
Article
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Obesity, type 2 diabetes, and cardiovascular illnesses have known risk factors in the pathophysiology of an unhealthy diet. Obesity now affects almost a third of the world’s population and is widely seen as a side effect of the Industrial Revolution. The current study aimed to determine natural phytoconstituents that have a significant role in the management of obesity. In this view, we have selected the plant Boerhavia diffusa which has different pharmacological actions and is traditionally used to treat sickness caused by lifestyle modification. The methanolic extract of the plant material was prepared and then further fractionated by means of solvents (n-hexane, chloroform, n-butanol, and water). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis was done by taking the active constituent of the plant (Punarnavine, Boeravinone B, and Eupalitin). The molecular docking analysis of these compounds is also performed by targeting the cannabinoid receptor (CR). Structural analysis of the best complex was done using the Discovery Studio visualizer tool. High-performance thin-layer chromatography (HPTLC) analysis was done by using a solvent system (chloroform and methanol in a ratio of 8:2). The in vivo study was done on the Sprague–Dawley (SD) rats treated with a high-fat diet to induce obesity and different parameters such as body weight, behavioral activity, organ fat pad weight, lipid profile, and liver biomarkers (AST, ALT, BUN, and creatinine) were estimated. The result of the study suggested that the phytoconstituents of B. diffusa upon molecular docking revealed the possible binding mechanisms with the CR and thus show potent anti-obesity action.
... These receptors are widely expressed in peripheral tissues and in the central nervous system. The endocannabinoid system is known to play a crucial role in energy metabolism by influencing food intake and reward at the level of the hypothalamus and nucleus accumbens, respectively, as well as by modulating energy expenditure in peripheral tissues in experimental models and humans [51]. Moreover, it has been recently shown that the endocannabinoid system influences dietary fat sensitivity in both the oral cavity and intestine via CB1 receptors [52]; endocannabinoids also enhance hedonic eating [53]. ...
Article
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Obesity is a well-recognized global health problem, and bariatric surgery (BS)-induced weight reduction has been demonstrated to improve survival and obesity-related conditions. Sleeve gastrectomy (SG) is actually one of the most performed bariatric procedures. The underlying mechanisms of weight loss and its maintenance after SG are not yet fully understood. However, changes to the taste function could be a contributing factor. Data on the extent of the phenomenon are limited. The primary objective was to assess, through validated questionnaires, the percentage of patients who report an altered perception of post-SG taste and compare the frequency of intake of the different food classes before SG and after 1 year follow-up. The secondary objective was to evaluate the total body weight change. Materials and methods: We prospectively investigated the changes in food choice and gustatory sensitivity of 52 patients (55.8% females) 12 months after SG. The mean initial weight and body mass index (BMI) were 130.9 ± 24.7 kg and 47.4 ± 7.1 kg/m2, respectively. The frequency of food intake was assessed by food-frequency questionnaire, while changes in taste perception were assessed using the taste desire and enjoyment change questionnaire. The change in total body weight was also assessed. Results: A significant decrease in the intake frequency of bread and crackers (p < 0.001), dairy products and fats (p < 0.001), sweets and snacks (p < 0.001) and soft drinks (p < 0.001), and a significant increase in the frequency of vegetable and fruit consumption (p < 0.001) were observed at 12 months after SG in both genders. On the contrary, we found no significant changes in the frequency of meat and fish intake in females (p = 0.204), whereas a significant change was found in males (p = 0.028). Changes in perceived taste intensity of fatty foods (p = 0.021) and tart foods (p = 0.006) for females and taste of bitter foods for females and males (p = 0.002; p = 0.017) were found. Regarding the change in food desire for both genders, there was a decrease in the desire for sweet, fatty, and salty foods, whereas there was an increasing trend in the desire for tart foods, especially for females. Significant reduction in total body weight and BMI was observed in both genders at the time of follow-up. Conclusions: Based on our findings, we are able to support the evidence that changes in taste, desire, and enjoyment of taste are very common after SG, with a reduced preference for food with high sugar and fat content and an increased postoperative preference for low-sugar and -fat foods. However, further investigation is needed to clarify this issue. The molecular, hormonal, and central mechanisms underlying these changes in taste perception need to be further elucidated, as they could identify new targets able to modify obesogenic eating behavior, opening up a novel personalized therapeutic approach to obesity.
... Considering the widespread distribution of CBR in the human body, the endocannabinoid system is largely involved in various aspects associated with pathological conditions such as pain [79][80][81][82], metabolic [83], neurodegenerative [46,84], stress-related disorders [45], neuroprotection, cardio protection, cellular migration, addiction, inflammation and antiviral effect [85]. ...
Article
The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established, however, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, and indirect mechanisms of inflammatory / autoimmune origin. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potential promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review we address the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a decrease in viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.
... 2-AG is an endogenous cannabinoid, which has the functions of regulating glucose and lipid metabolism [25]. Diabetes can cause myocardial lipid and carbohydrate metabolism disorders. ...
Article
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Purpose Diabetic cardiomyopathy (DM) is the cause of late cardiac dysfunction in diabetic patients. Myocardial fibrosis is the main pathological mechanism, and it is associated with transforming growth factor-β1(TGF-β1) expression up-regulation. 2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid that can effectively improve myocardial cell energy metabolism and cardiac function. Here, we evaluated the protective effect of 2-AG on diabetic cardiomyopathy. Methods Male C57BL/6 mice were injected with 2-AG intraperitoneally for 4 weeks (10 micro g/kg/day) after 12 weeks of diabetic modeling. After 4 weeks, heart function was evaluated by echocardiography. Heart structure was assessed by hematoxylin and eosin staining. Cardiac fibrosis was analyzed using immunohistochemistry, Sirius red stain, and western blot. Results After modeling in diabetic mice, cardiac ultrasonography showed decreased cardiac function and pathological findings showed myocardial fibrosis. 2-AG could effectively inhibit the up-regulation of TGF-β1 and Smad2/3, reduce myocardial fibrosis, and ultimately improve cardiac function in diabetic mice. Conclusion 2-AG reduces cardiac fibrosis via the TGF-β1/Smad2/3 pathway and is a potential pathway for the treatment of cardiac dysfunction in diabetic mice.
... Dementsprechend konnten auch in der vorliegenden Studie Zusammenhänge zwischen Craving und CART Expression und Proteinmenge nachgewiesen werden, die sogar die statistische Qualität eines Vorhersagemodells aufweisen. Andererseits ist CART ein wichtiger Botenstoff, der die Nahrungsaufnahme reguliert(Lau, et al., 2018), sowie Cannabis über die Aktivierung des Endocannabinoidsystems(Silvestri & Di Marzo, 2013). Möglicherweise erklärt dieser Zusammenhang die Ergebnisse der vorliegenden Studie, da Suchtdruck bzw. ...
Thesis
1.1.1 Backgounds and Objectives Cannabis is the most popular drug worldwide and while 149-271 million people aged 15-64 years use an illicit drug at least once a year, the due of cannabis users is about 125-203 million (World Drug Report 2020). In high-income countries such as United States or Europe, cannabis use typically begins in late teenage years and peaks in the middle 20s as it decreases when young people marry and/or enter worklife (Brodbeck, et al., 2013). However, 10% of people who ever used cannabis, become daily and about 25% weekly users (Hall & Lynskey, 2020). Δ9-tetrahydrocannabinol (THC) is said to be responsible for the psychoactive effects of cannabis. The activation of the endocannabinoid system via CB1 and CB2 also intervenes with the mesolimbic dopaminergic system. This is assumed to be the cause of dependency on drugs while affecting the drug-dependent reward system (Koob & Volkow, 2016). Cannabis dependency is the most common type of drug dependence following alcohol and tobacco with a prevalence of 1-2% of adults per year (Degenhardt, et al., 2019). Cannabis can cause withdrawal symptoms including anxiety, insomnia and depression. Chronic cannabis abuse is said to be a high risk-factor for developing a psychiatric illness like schizophrenia-like psychosis and psychotic symptoms, thereby linking cannabis to the dopaminergic system (Murray, et al., 2017; Di Forti, et al., 2019; Gobbi, et al., 2019; Hasan, et al., 2020; Swapnali & Borah, 2020). The cocaine- and amphetamine- regulated Transcript is said to have a pivotal role in the drug-associated reward system (Hubert, et al., 2008; Kimmel, et al., 2000; Yu, et al., 2017). The role of CART in addiction is underlined by studies showing an upregulation of central CART by chronic misuse of cocaine and other psychostimulants as well as nicotine and alcohol (Chengpeng, et al., 2017; Fagergren & Hurd, 2007; Cho, et al., 2015; O Koylu, et al., 2006; Kaya, et al., 2016; Liu, et al., 2018; Walker, et al., 2021). CART-Gene alterations have also linked this system to Addiction in general (Lohoff, et al., 2008). However, little is known about the effects of Downers like Opioids and Cannabis on CART expression levels (Bakhtazad, et al., 2016; Malboosi, et al., 2020) and so far, nothing has been published on the effects of CART-level in connection with Cannabis. Further, nothing is known about the effects of these drugs on peripheral CART-mRNA and CART-peptides-level alterations in humans. Therefore, the aim of this study was to determine whether there is an effect on these peptides in the peripheral blood of chronic cannabis users, compared to smokers and non-smokers. 1.1.2 Methods and Material The present study was approved by the Ethics Committee of the University of Erlangen-Nuremberg. As 36 subjects suffered from THC dependence, 20 age- and sex-matched cigarette smokers and 21 non-smokers were recruited for this pilot study, in total 77 people. The 36 THC dependent subjects had an established diagnosis of THC dependence according to DSM-V and ICD-10. As assessed with the Symptom Check List SCL-90 (Derogatis, et al., 1976) and a brief physical examination, all of the participants were otherwise physically and mentally healthy. Beyond that, several clinical scales were surveyed: The SWLS was employed to measure satisfaction with life (Diener, et al., 1985). Craving was assessed with a visual analogue scale. The WHO-Assist V3.0 was performed for the assessment of the involvement with alcohol, nicotine and illegal substances such as Cannabis. With the Fagerström Test (FTNA) (Heatherton, et al., 1991) the severity of nicotine dependence was assessed. We took one blood sample after acute consumption of Cannabis and Tobacco and measured Serum CART protein levels using a commercially available enzyme immunoassay (ELISA) kit as well as a polymerase chain reaction kit for the quantitative analysis of CART-mRNA extracted from peripheral white blood cells. Those results were then investigated statistically. 1.1.3 Results and Observations There was a highly significant connection between CART-peptide levels in peripheral serum and CART-mRNA-level in peripheral white blood cells and there were significant differences in these levels regarding the independant groups (Cannabis / Smokers / non-smokers). The level of CART-mRNA and CART-Protein were at highest in non-smokers and lowest in cannabis dependency. Furthermore, the analysis of logistic multiregression could show a prediction model for Craving with respect to CART-mRNA and CART-peptid levels. There was no significant connection between body weight and CART-levels in this population, although a tendency towards a statistical connection could be shown. 1.1.4 Conclusion Our results indicate a direct relationship between CART-mRNA and the CART-protein, consistent for smokers, non-smokers and THC group. Furthermore, these findings suggest an inhibitory effect on CART-mRNA and therefore CART-protein levels in connection to Cannabis exposure. Experimental results supporting CART modulation by chronic drug abuse, raised the hypothesis that CART could play a pivotal role in the molecular vulnerability to substance dependency. As shown for alcohol abuse, the activation of hypothalamic CART neuropeptide, with increased hypothalamic CART levels after ethanol exposure, may be a common mechanism underlying drug-seeking behavior (Dayas et al. 2008). CART has also been linked to the system of energy homeostasis (Lau, et al., 2018). Dysfunction of this circuit with the alteration of central hypothalamic CART has been linked to obesity and eating disorders (Hunter, et al., 2004). Thus, the findings of this study underpin the suspicion of CART having a crucial role in addiction itself and maybe there is a way that peripheral fluctuations of those neuropeptides mirror the effects of central processes connected to addiction. In this context, CART might be a thrilling target for further researches in this area, maybe even as a target for therapy of Addiction and food related health issues.
... It also increases skeletal muscle breakdown, which activates defective oxidative metabolism at the mitochondrial level via oxidative phosphorylation. [75][76][77] As a result, ECS is defined as "part of a specialized phenotype selected to make the most of periods of excess and to manage with food scarcity". [78] According to research, the CB2 receptor is found in cells of the human pancreas. ...
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... Degradation of eCBs is very rapid (Di Marzo et al., 1994;Maccarrone et al., 1998;Castillo et al., 2012) and is generally divided into two pathways-hydrolysis and oxidation (Castillo et al., 2012). The main hydrolytic enzymes of the first pathway are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are responsible for hydrolyzing AEA and 2-AG, respectively, and produce hydrolysis products such as ethanolamine or glycerol (Silvestri and Di Marzo, 2013). The main degrading enzyme of 2-AG is MAGL, a presynaptic localization enzyme that hydrolyzes 2-AG to AA and glycerol (Dinh et al., 2002;Tanimura et al., 2012). ...
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... Enfin, les AGPI n-3 impactent le système endocannabinoïde, qui régule la prise alimentaire, la balance énergétique, le métabolisme des lipides et des glucides ainsi que l'inflammation. Cependant, il est encore trop peu étudié à ce jour (Silvestri & Di Marzo, 2013). ...
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Activated cannabinoid 1 receptor (CB1R) signaling has been implicated in the development of phenotypes associated with fatty liver, insulin resistance, and impaired suppression of hepatic glucose output. Endoplasmic reticulum stress-associated liver-specific transcription factor CREBH is emerging as a critical player in various hepatic metabolic pathways and regulates hepatic gluconeogenesis in diet-induced obese settings. In this study, we elucidated the critical role of CREBH in mediating CB1R signaling to regulate glucose homeostasis in primary rat and human hepatocytes. mRNA and protein levels and glucose production were analyzed in primary rat and human hepatocytes. ChIP assays were performed together with various transcriptional analyses using standard techniques. CB1R activation by 2-arachidonoylglycerol (2-AG) specifically induced CREBH gene expression via phosphorylation of the JNK signaling pathway and c-Jun binding to the AP-1 binding site in the CREBH gene promoter. 2-AG treatment significantly induced hepatic gluconeogenic gene expression and glucose production in primary hepatocytes, and we demonstrated that the CREBH binding site mutant significantly attenuated 2-AG-mediated activation of the gluconeogenic gene promoter. Endogenous knockdown of CREBH led to ablation of 2-AG-induced gluconeogenic gene expression and glucose production, and the CB1R antagonist AM251 or insulin exhibited repression of CREBH gene induction and subsequently inhibited gluconeogenesis in both rat and human primary hepatocytes. These results demonstrate a novel mechanism of action of activated CB1R signaling to induce hepatic gluconeogenesis via direct activation of CREBH, thereby contributing to a better understanding of the endocannabinoid signaling mechanism involved in regulating the hepatic glucose metabolism.
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International Journal of Obesity is a monthly, multi-disciplinary forum for papers describing basic, clinical and applied studies in biochemistry, genetics and nutrition, together with molecular, metabolic, psychological and epidemiological aspects of obesity and related disorders