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The Endocannabinoid System in Energy Homeostasis and the Etiopathology of Metabolic Disorders
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.
... 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). ...
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). ...
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. ...
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. ...
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]. ...
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]. ...
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. ...
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. ...
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. ...
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). ...
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] . ...
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. ...
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]. ...
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]. ...
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]. ...
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). ...
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]. ...
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). ...
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). ...
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. ...
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. ...
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. ...
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). ...
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]. ...
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. ...
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]. ...
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]. ...
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. ...
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. ...
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. ...
Cannabis sativa L. subspecies sativa is a subspecies of the genus Cannabis (Cannabaceae), also known as industrial hemp. It is a herbaceous and double-jawed plant. Tetrahydrocannabinol (THC), a psychoactive compound found in cannabis plants, and the non-psychoactive cannabidiol (CBD) are essential compounds in industry and medicine. These compounds are very similar to endocannabinoids, which are found in the human body. As a result, both compounds have the potential to interact with the body's endocannabinoid system. They exhibit chemical activity in areas affected by oxidative stress, such as the cardiovascular system, muscle development, liver and lung function, reproductive function, metabolism, neurological activities, and cell aging. Since the human body's free radical and antioxidant levels are destabilized, antioxidants fail to neutralize free radicals, resulting in oxidative damage, i.e. a stress effect. This balance in the body can be influenced by compounds like THC and CBD acting on cellular receptors. Thus, the occurrence of various diseases is observed. This review examined the effect of the active substances in the cannabis plant on oxidative stress and the diseases that develop as a result of this stressful situation.
... 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). ...
Parkinson’s disease (PD) is a neurodegenerative disease usually caused by neuroinflammation, oxidative stress and other etiologies. Recent studies have found that the cannabinoid system present in the basal ganglia has a strong influence on the progression of PD. Altering the cannabinoid receptor activation status by modulating endogenous cannabinoid (eCB) levels can exert an anti-movement disorder effect. Therefore, the development of drugs that modulate the endocannabinoid system may be a novel strategy for the treatment of PD. However, eCB regulation is complex, with diverse cannabinoid receptor functions and the presence of dopaminergic, glutamatergic, and γ-aminobutyric signals interacting with cannabinoid signaling in the basal ganglia region. Therefore, the study of eCB is challenging. Here, we have described the function of the cannabinoid system in the basal ganglia and its association with PD in three parts (eCBs, cannabinoid receptors, and factors regulating the cannabinoid metabolism) and summarized the mechanisms of action related to the cannabinoid analogs currently aimed at treating PD. The shortcomings identified from previous studies and the directions that should be explored in the future will provide insights into new approaches and ideas for the future development of cannabinoid-based drugs and the treatment of PD.
... 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). ...
La prévention primaire et secondaire des pathologies inflammatoires chroniques telles que l’obésité et la maladie de Crohn (MC) reposent majoritairement sur des mesures hygiéno-diététiques incluant l’activité physique et la nutrition. Dans le cadre de ce travail de thèse, l’objectif principal était d’étudier l’influence de modalités d’exercice - exercice imposé de type intermittent de haute intensité (HIIT) ou activité de roue spontanée - associé à un apport en lin, riche en acides gras polyinsaturés (AGPI) n-3, sur les interrelations « composition corporelle – inflammation – microbiote intestinal » dans un contexte de pathologies inflammatoires chroniques (obésité, MC) sur modèles murins. Le deuxième objectif était d’étudier spécifiquement deux formes de lin, à travers la graine ou l’huile, afin de déterminer si la matrice de la graine de lin extrudée pouvait avoir des effets qui lui sont propres. Nos résultats indiquent qu’un programme de type HIIT est efficace pour prévenir la prise de poids et de masse grasse, et que le lin, indépendamment de sa forme, diminue l’inflammation. Nos travaux ont également montré un effet majeur du HIIT et de la graine de lin extrudée (TRADILIN, Valorex®) sur la modulation de la composition du microbiote intestinal associé à la muqueuse. Certaines de ces variations étaient corrélées aux modulations de la composition corporelle mais non à l’inflammation. Nos travaux ont montré spécifiquement un effet synergique du HIIT et de l’huile de lin sur l’abondance d’Oscillospira spp. et sur la conversion de l’acide α-linolénique en acide docosahexaénoïque. En conclusion, nos résultats montrent qu’un apport en lin, et particulièrement sous forme de graines extrudées, associé à une activité physique imposée et suffisamment intense, pourraient être efficace dans la prévention et/ou la prise en charge des pathologies inflammatoires chroniques telles que l’obésité et la MC. Les interrelations « composition corporelle – inflammation – microbiote intestinal », restent toutefois à approfondir et les mécanismes sous-jacents à explorer.
Retinol-binding protein 2 (RBP2, also known as cellular retinol-binding protein 2 (CRBP2)) is a member of the fatty acid-binding protein family and has been extensively studied for its role in facilitating dietary vitamin A (retinol) uptake and metabolism within enterocytes of the small intestine. RBP2 is present in highest concentrations in the proximal small intestine where it constitutes approximately 0.1–0.5% of soluble protein. Recent reports have established that RBP2 binds monoacylglycerols (MAGs) with high affinity, including the canonical endocannabinoid 2-arachidonoylglycerol (2-AG). Crystallographic studies reveal that retinol, 2-AG, or other long-chain MAGs alternatively can bind in the retinol-binding pocket of RBP2. It also has been demonstrated recently that Rbp2-deficient mice are more susceptible to developing obesity and associated metabolic phenotypes when exposed to a high fat diet, or as they age when fed a conventional chow diet. When subjected to an oral fat challenge, the Rbp2-deficient mice release into the circulation significantly more, compared to littermate controls, of the intestinal hormone glucose-dependent insulinotropic polypeptide (GIP). These new findings regarding RBP2 structure and actions within the intestine are the focus of this review.
Background:
Dementia is a common chronic condition, mainly affecting older adults, characterised by a progressive decline in cognitive and functional abilities. Medical treatments for dementia are limited. Cannabinoids are being investigated for the treatment of dementia.
Objectives:
To determine the efficacy and safety of cannabinoids for the treatment of dementia.
Search methods:
We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialised Register - on 8 July 2021, using the terms cannabis or cannabinoid or endocannabinoid or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The register contains records from all major healthcare databases (the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many clinical trials registries and grey literature sources.
Selection criteria:
We included all randomised controlled trials (RCTs) of cannabinoids for the treatment of dementia. We included participants of any age and of either sex with diagnosed dementia of any subtype, or with unspecified dementia of any severity, from any setting. We considered studies of cannabinoids administered by any route, at any dose, for any duration, compared with placebo, no treatment, or any active control intervention.
Data collection and analysis:
Two review authors independently screened and selected studies for inclusion, extracted data, and assessed the risk of bias in included studies. When necessary, other review authors were involved in reaching consensus decisions. We conducted meta-analyses using a generic inverse variance fixed-effect model to derive estimates of effect size. We used GRADE methods to assess our confidence in the effect estimates.
Main results:
We included four studies (126 participants) in this review. Most participants had Alzheimer's disease; a few had vascular dementia or mixed dementia. Three studies had low risk of bias across all domains; one study had unclear risk of bias for the majority of domains. The included studies tested natural delta-9-tetrahydrocannabinol (THC) (Namisol) and two types of synthetic THC analogue (dronabinol and nabilone). Three trials had a cross-over design. Interventions were applied over 3 to 14 weeks; one study reported adverse events over 70 weeks of follow-up. One trial was undertaken in the USA, one in Canada, and two in The Netherlands. Two studies reported non-commercial funding, and two studies were conducted with the support of both commercial and non-commercial funding. Primary outcomes in this review were changes in global and specific cognitive function, overall behavioural and psychological symptoms of dementia (BPSD), and adverse events. We found very low-certainty evidence suggesting there may be little or no clinically important effect of a synthetic THC analogue on cognition assessed with the standardised Mini-Mental State Examination (sMMSE) (mean difference (MD) 1.1 points, 95% confidence interval (CI) 0.1 to 2.1; 1 cross-over trial, 28 participants). We found low-certainty evidence suggesting there may be little or no clinically important effect of cannabinoids on overall behavioural and psychological symptoms of dementia assessed with the Neuropsychiatric Inventory (or its modified nursing home version) (MD -1.97, 95% CI -3.87 to -0.07; 1 parallel group and 2 cross-over studies, 110 participants). All included studies reported data on adverse events. However, the total number of adverse events, the total numbers of mild and moderate adverse events, and the total number of serious adverse events (SAEs) were not reported in a way that permitted meta-analysis. There were no clear differences between groups in numbers of adverse events, with the exception of sedation (including lethargy), which was more frequent among participants taking nabilone (N = 17) than placebo (N = 6) (odds ratio (OR) 2.83, 95% CI 1.07 to 7.48; 1 cross-over study, 38 participants). We judged the certainty of evidence for adverse event outcomes to be low or very low due to serious concerns regarding imprecision and indirectness.
Authors' conclusions:
Based on data from four small, short, and heterogeneous placebo-controlled trials, we cannot be certain whether cannabinoids have any beneficial or harmful effects on dementia. If there are benefits of cannabinoids for people with dementia, the effects may be too small to be clinically meaningful. Adequately powered, methodologically robust trials with longer follow-up are needed to properly assess the effects of cannabinoids in dementia.
Pregnenolone is a steroid with specific characteristics, being the first steroid synthesized from cholesterol at all sites of steroidogenesis, including the brain. For many years, pregnenolone was defined as an inactive precursor of all steroids, as no specific target had been discovered. But, over the last decade, it has become a steroid of interest since it has been recognized as being a biomarker for brain-related disorders through the development of metabolomic approaches and advanced analytical methods. In addition, physiological roles for pregnenolone emerged when specific targets were discovered.
In this review, we will highlight the discovery of the selective interaction of pregnenolone with the type-1 cannabinoid receptor (CB1R). After describing the specific characteristic of CB1Rs, we will discuss the newly discovered mechanisms of their regulation by pregnenolone. In particular, we will describe the action of pregnenolone as a negative allosteric modulator (NAM) and a specific signaling inhibitor of the CB1R. These particular characteristics of pregnenolone provide a great strategic opportunity for therapeutic development in CB1-related disorders. Finally, we will outline new perspectives using innovative genetic tools for the discovery of original regulatory mechanisms of pregnenolone on CB1-related functions.
Background and aims
The COVID-19 pandemic has prompted researchers to look for effective therapeutic targets. The effect of endocannabinoid system against infectious diseases is investigated for several years. In this study, we evaluated the expression level of CNR1 and CNR2 genes in patients with COVID-19 with and without diabetes to provide new insights regarding these receptors and their potential effect in COVID-19 disease.
Methods
In this study, peripheral blood monocytes cells (PBMCs) were isolated from eight different groups including COVID-19 patients, diabetic patients, and healthy individuals. RNA were extracted to evaluate the expression level of CNR1 and CNR2 genes using real-time PCR. The correlation between the expression levels of these genes in different groups were assessed.
Results
A total of 80 samples were divided into 8 groups, with each group consisting of ten samples. When comparing severe and moderate COVID-19 groups to healthy control group, the expression levels of the CNR1 and CNR2 genes were significantly higher in the severe and moderate COVID-19 groups. There were no significant differences between the mild COVID-19 group and the healthy control group. It was found that the expression levels of these genes in patients with diabetes who were infected with SARS-COV-2 did not differ across COVID-19 groups with varying severity, but they were significantly higher when compared to healthy controls.
Conclusion
Our study suggests the possible role of endocannabinoid system during SARS-COV-2 pathogenicity as the expression of CNR1 and CNR2 were elevated during the disease.
Monoacylglycerol lipase (MAGL) constitutes a serine hydrolase that orchestrates endocannabinoid homeostasis and exerts its function by catalyzing the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA). As such, selective inhibition of MAGL represents a potential therapeutic and diagnostic approach to various pathologies including neurodegenerative disorders, metabolic diseases and cancers. Based on a unique 4-piperidinyl azetidine diamide scaffold, we developed a reversible and peripheral-specific radiofluorinated MAGL PET ligand [18F]FEPAD. Pharmacokinetics and binding studies on [18F]FEPAD revealed its outstanding specificity and selectivity towards MAGL in brown adipose tissue (BAT) – a tissue that is known to be metabolically active. We employed [18F]FEPAD in PET studies to assess the abundancy of MAGL in BAT deposits of mice and found a remarkable degree of specific tracer binding in the BAT, which was confirmed by post-mortem tissue analysis. Given the negative regulation of endocannabinoids on the metabolic BAT activity, our study supports the concept that dysregulation of MAGL is likely linked to metabolic disorders. Further, we now provide a suitable imaging tool that allows non-invasive assessment of MAGL in BAT deposits, thereby paving the way for detailed mechanistic studies on the role of BAT in endocannabinoid system (ECS)-related pathologies.
Background: The current social and legal landscape is likely to foster the medicinal and recreational use of cannabis. Synthetic cannabinoid use is associated with acute kidney injury (AKI) in case reports; however, the association between natural cannabis use and AKI risk in patients with advanced chronic kidney disease (CKD) is unknown. Materials and Methods: From a nationally representative cohort of 102,477 U.S. veterans transitioning to dialysis between 2007 and 2015, we identified 2215 patients with advanced CKD who had undergone urine toxicology (UTOX) tests within a year before dialysis initiation and had inpatient serial serum creatinine levels measured within 7 days after their UTOX test. The exposure of interest was cannabis use compared with no use as ascertained by the UTOX test. We examined the association of this exposure with AKI using logistic regression and inverse probability of treatment weighting with extensive adjustment for potential confounders. Results: The mean age of the overall cohort was 61 years; 97% were males, 51% were African Americans, 97% had hypertension, 76% had hyperlipidemia, and 75% were diabetic. AKI occurred in 56% of the cohort, and in multivariable-adjusted analysis, cannabis use (when compared with no substance use) was not associated with significantly higher odds of AKI (odds ratio 0.85, 95% confidence interval 0.38-1.87; p=0.7). These results were robust to various sensitivity analyses. Conclusions: In this observational study examining patients with advanced CKD, cannabis use was not associated with AKI risk. Additional studies are needed to characterize the impact of cannabis use on risk of kidney disease and injury.
Background: Chronic hepatitis B virus (HBV) infection may evolve into cirrhosis and hepatocellular carcinoma, and this progression may be accelerated by specific risk factors, including overweight and obesity. Although evidence for a protective effect of cannabis use on elevated body weight has been found for other populations, no data are available for HBV-infected patients. Aims: We aimed to identify risk factors (including cannabis use) for overweight and obesity in patients with HBV chronic infection. Methods: Using baseline data from the French ANRS CO22 Hepather cohort, we performed two separate analyses, one using "central obesity" (based on waist circumference) and the other "overweight" and "obesity" (based on body mass index) as outcomes. Logistic and multinomial regressions were used to model central obesity and overweight/obesity, respectively. Results: Among the 3706 patients in the study population, 50.8% had central obesity, 34.7% overweight, and 14.4% obesity. After multivariable adjustment, current cannabis use was associated with a 59% lower risk of central obesity compared with no lifetime use (adjusted odds ratio [95% CI]: 0.41 [0.24 to 0.70]). It was also associated with a 54% and 84% lower risk of overweight (adjusted relative risk ratio [95% CI]: 0.46 [0.27 to 0.76]) and obesity (0.16 [0.04 to 0.67]), respectively. Conclusions: Cannabis use was associated with lower risks of overweight and obesity in patients with HBV chronic infection. Future studies should test whether these potential benefits of cannabis and cannabinoid use translate into reduced liver disease progression in this high-risk population.
Obesity and nonalcoholic fatty liver disease (NAFLD) constitute global and growing epidemics that result in therapeutic dead ends. There is an urgent need for new and accessible treatments to improve and widen both preventive and curative approaches against NAFLD. The endocannabinoid system (ECS) is recognized as a complex signaling apparatus closely related to metabolic disorders and is a key target for treating NAFLD. Despite a lack of conclusive clinical trials, observational and pre-clinical studies highlight putative benefits of phytocannabinoids on liver steatosis through multiple pathways. Owing to both its safety profile and its diversity of active compounds acting primarily (although not exclusively) on the ECS-and its expanded version, the endocannabinoidome, the Cannabis plant should be considered a major prospect in the treatment of NAFLD. However, seizing this opportunity, and intensifying clinical research in this direction, will require overcoming both scientific and nonscientific barriers.
inner ear immunology in vestibular migraine and meniere disease, difrential proinflammatory profile
Neurodegenerative diseases are an increasing cause of global morbidity and mortality. They occur in the central nervous system (CNS) and lead to functional and mental impairment due to loss of neurons. Recent evidence highlights the link between neurodegenerative and inflammatory diseases of the CNS. These are typically associated with several neurological disorders. These diseases have fundamental differences regarding their underlying physiology and clinical manifestations, although there are aspects that overlap. The endocannabinoid system (ECS) is comprised of receptors (type-1 (CB1R) and type-2 (CB2R) cannabinoid-receptors, as well as transient receptor potential vanilloid 1 (TRPV1)), endogenous ligands and enzymes that synthesize and degrade endocannabinoids (ECBs). Recent studies revealed the involvement of the ECS in different pathological aspects of these neurodegenerative disorders. The present review will explore the roles of cannabinoid receptors (CBRs) and pharmacological agents that modulate CBRs or ECS activity with reference to Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and multiple sclerosis (MS).
We hypothesized that cannabis use is associated with cardiovascular disease (CVD) risk factors. This could explain the reported link between cannabis and cardiovascular events including stroke and myocardial infarction. This analysis included 7,159 participants (age 37.8 ± 12.4 years, 48.6% men, and 61.5% Caucasian) from the National Health and Nutrition Examination Survey years 2011 to 2018. Cannabis use was defined by self-report. Participants with a history of stroke or myocardial infarction were excluded. Composite CVD risk was assessed using the American College of Cardiology/American Heart Association 10-year atherosclerotic cardiovascular risk (ASCVD) score. Participants were classified based on their ASCVD risk levels as low (<5.0%), borderline (5.0% to 7.4%), intermediate (7.5% to 19.9%), and high (≥20.0%). Multinomial logistic regression was used to examine the association between cannabis use and ASCVD risk category using low-risk ASCVD category as the reference level. About 63.9% (n = 4,573) of participants had ever used cannabis. Ever cannabis use was associated with 60% increased odds of high-risk ASCVD score (odds ratio [OR] 95% confidence interval [CI] 1.60 [1.04 to 2.45], p = 0.03). We also observed a dose-response relation between increased use of cannabis and a higher risk of ASCVD. Those reporting ≥2 uses per month had 79% increased odds of high-risk ASCVD score (OR [95% CI] 1.79 [1.10 to 2.92], p = 0.02) and those reporting ≥1 use per day had 87% increased odds of high-risk ASCVD score (OR [95% CI] 1.87 [1.16 to 3.01], p <0.001]. In conclusion, cannabis use is associated with elevated CVD risk. Individuals using cannabis should be screened for CVD risk, and appropriate risk reduction strategies should be implemented.
Fibrates and omega‐3 polyunsaturated acids are used for the treatment of hypertriglyceridemia but have not demonstrated consistent effects on cardiovascular (CV) risk. In this study, we investigate how these two pharmacological agents influence plasma levels of bioactive lipid mediators, aiming to explore their efficacy beyond that of lipid‐lowering agents. Plasma from overweight patients with non‐alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia, participating in a randomized placebo‐controlled study investigating the effects of 12 weeks treatment with fenofibrate or omega‐3 free carboxylic acids (OM‐3CA) (200 mg or 4 g per day, respectively), were analyzed for eicosanoids and related PUFA species, N‐acylethanolamines (NAE) and ceramides. OM‐3CA reduced plasma concentrations of proinflammatory PGE2, as well as PGE1, PGD1 and thromboxane B2 but increased prostacyclin, and eicosapentaenoic acid‐ and docosahexaenoic acid‐derived lipids of lipoxygenase and cytochrome P450 monooxygenase (CYP) (e.g., 17‐HDHA, 18‐HEPE, 19,20‐DiHDPA). Fenofibrate reduced plasma concentrations of vasoactive CYP‐derived eicosanoids (DHETs). Although OM‐3CA increased plasma levels of the NAE docosahexaenoyl ethanolamine and docosapentaenoyl ethanolamine, and fenofibrate increased palmitoleoyl ethanolamine, the effect of both treatments may have been masked by the placebo (olive oil). Fenofibrate was more efficacious than OM‐3CA in significantly reducing plasma ceramides, pro‐inflammatory lipids associated with CV disease risk. Neither treatment affected putative lipid species associated with NAFLD. Our results show that OM‐3CA and fenofibrate differentially modulate the plasma mediator lipidome, with OM‐3CA promoting the formation of lipid mediators with potential effects on chronic inflammation, while fenofibrate mainly reducing ceramides. These findings suggest that both treatments could ameliorate chronic inflammation with possible impact on disease outcomes, independent of triglyceride reduction.
Endocannabinoid lipids are known to exert orexigenic effects via central cannabinoid CB1 and CB2 receptors, which have also been identified in islet endocrine cells. However, there is no consensus on whether the receptors are expressed by β-cells, nor what effect CB1 and CB2 receptor agonists have on insulin secretion. In the current study we have therefore used the mouse MIN6 β-cell line rather than primary islets, which are heterogeneous clusters of endocrine cells. Cannabinoid receptor and diacylglycerol lipase isoform mRNAs were detected in MIN6 cells by RT-PCR and immunocytochemistry was used to identify cannabinoid receptor expression by MIN6 cells. Changes in cyclic AMP and intracellular calcium were measured by immunoassay and microfluorimetry, respectively, and insulin secretion from perifused MIN6 pseudoislets was determined by radioimmunoassay. MIN6 β-cells express the cannabinoid synthesising enzyme diacylglycerol lipase and CB1 and CB2 receptors, which are coupled to inhibition of β-cell cyclic AMP generation and stimulation of intracellular calcium levels. Cannabinoid receptor activation with pharmacological agonists resulted in reversible elevations in insulin secretion at both 2 mM and 20 mM glucose. Synthesis of endocannabinoids by β-cells may provide an additional mechanism for stimulation of insulin secretion through activation of β-cell CB1 and/or CB2 cannabinoid receptors.
The function of small intestinal monoacylglycerol lipase (MGL) is unknown. Its expression in this tissue is surprising because one of the primary functions of the small intestine is to convert diet-derived MGs to triacylglycerol (TG), and not to degrade them. To elucidate the function of intestinal MGL, we generated transgenic mice that over-express MGL specifically in small intestine (iMGL mice). After only 3 weeks of high fat feeding, iMGL mice showed an obese phenotype; body weight gain and body fat mass were markedly higher in iMGL mice, along with increased hepatic and plasma TG levels compared to wild type littermates. The iMGL mice were hyperphagic and displayed reduced energy expenditure despite unchanged lean body mass, suggesting that the increased adiposity was due to both increased caloric intake and systemic effects resulting in a hypometabolic rate. The presence of the transgene resulted in lower levels of most MG species in intestinal mucosa, including the endocannabinoid 2-arachidonoyl glycerol (2-AG). The results therefore suggest a role for intestinal MGL, and intestinal 2-AG and perhaps other MG species, in whole body energy balance via regulation of food intake as well as metabolic rate.
Insulin controls fatty acid (FA) release from white adipose tissue (WAT) through direct effects on adipocytes and indirectly through hypothalamic signaling by reducing sympathetic nervous system outflow to WAT. Uncontrolled FA release from WAT promotes lipotoxicity, which is characterized by inflammation and insulin resistance that leads to and worsens type 2 diabetes. Here we tested whether early diet-induced insulin resistance impairs the ability of hypothalamic insulin to regulate WAT lipolysis and thus contributes to adipose tissue dysfunction. To this end we fed male Sprague-Dawley rats a 10% lard diet (high fat diet (HFD)) for 3 consecutive days, which is known to induce systemic insulin resistance. Rats were studied by euglycemic pancreatic clamps and concomitant infusion of either insulin or vehicle into the mediobasal hypothalamus. Short term HFD feeding led to a 37% increase in caloric intake and elevated base-line free FAs and insulin levels compared with rats fed regular chow. Overfeeding did not impair insulin signaling in WAT, but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux. HFD feeding also increased hypothalamic levels of the endocannabinoid 2-arachidonoylglycerol after only 3 days. In summary, overfeeding impairs hypothalamic insulin action, which may contribute to unrestrained lipolysis seen in human obesity and type 2 diabetes.
Cannabinoid type 1 (CB(1)) receptor activation is generally considered a powerful orexigenic signal and inhibition of the endocannabinoid system is beneficial for the treatment of obesity and related metabolic diseases. The hypothalamus plays a critical role in regulating energy balance by modulating both food intake and energy expenditure. Although CB(1) receptor signaling has been implicated in the modulation of both these mechanisms, a complete understanding of its role in the hypothalamus is still lacking. Here we combined a genetic approach with the use of adeno-associated viral vectors to delete the CB(1) receptor gene in the adult mouse hypothalamus and assessed the impact of such manipulation on the regulation of energy balance. Viral-mediated deletion of the CB(1) receptor gene in the hypothalamus led to the generation of Hyp-CB(1)-KO mice, which displayed an approximately 60% decrease in hypothalamic CB(1) receptor mRNA levels. Hyp-CB(1)-KO mice maintained on a normocaloric, standard diet showed decreased body weight gain over time, which was associated with increased energy expenditure and elevated β(3)-adrenergic receptor and uncoupling protein-1 mRNA levels in the brown adipose tissue but, surprisingly, not to changes in food intake. Additionally, Hyp-CB(1)-KO mice were insensitive to the anorectic action of the hormone leptin (5 mg/kg) and displayed a time-dependent hypophagic response to the CB(1) inverse agonist rimonabant (3 mg/kg). Altogether these findings suggest that hypothalamic CB(1) receptor signaling is a key determinant of energy expenditure under basal conditions and reveal its specific role in conveying the effects of leptin and pharmacological CB1 receptor antagonism on food intake.
The goal of this study was to determine whether administration of the CB(1) cannabinoid receptor antagonist rimonabant would alter fatty acid flux in nonhuman primates. Five adult baboons (Papio Sp) aged 12.1 ± 4.7 yr (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty acid and TG flux before and after 7 wk of treatment with rimonabant (15 mg/day). Animals were fed ad libitum diets, and stable isotopes were administered via diet (d(31)-tripalmitin) and intravenously ((13)C(4)-palmitate, (13)C(1)-acetate). Plasma was collected in the fed and fasted states, and blood lipids were analyzed by GC-MS. DEXA was used to assess body composition and a hyperinsulinemic euglycemic clamp used to assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, body weight, plasma, and tissue endocannabinoid concentrations or the quantity of liver-TG fatty acids originating from de novo lipogenesis (19 ± 6 vs. 16 ± 5%, for pre- and posttreatment, respectively, P = 0.39). However, waist circumference was significantly reduced 4% in the treated animals (P < 0.04), glucose disposal increased 30% (P = 0.03), and FFA turnover increased 37% (P = 0.02). The faster FFA flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3 vs. 23 ± 4%, P = 0.02) and a twofold increase in TRL-TG turnover (1.5 ± 0.9 vs. 3.1 ± 1.4 μmol·kg(-1)·h(-1), P = 0.03). These data support the potential for a strong effect of CB(1) receptor antagonism at the level of adipose tissue, resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose storage, and significant improvements in glucose homeostasis.
n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides.
In a 'prevention study', C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ∼35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine.
Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT.
Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. In this condition, the subject eats also when not in a state of short-term energy depletion, and food is consumed uniquely because of its gustatory rewarding properties. The physiological mechanisms underlying this eating behavior are not deeply understood, but endogenous rewarding mediators like ghrelin and endocannabinoids are likely involved.
To explore the role of these substances in hedonic eating, we measured changes in their plasma levels in eight satiated healthy subjects after ad libitum consumption of highly palatable food as compared with the consumption of nonpalatable food in isoenergetic amounts with the same nutrient composition of the palatable food.
The consumption of food for pleasure was characterized by increased peripheral levels of both the peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol. Levels of the other endocannabinoid anandamide and of anandamide-related mediators oleoylethanolamide and palmitoylethanolamide, instead, progressively decreased after the ingestion of both highly pleasurable and isoenergetic nonpleasurable food. A positive correlation was found between plasma 2-arachidonoyl glycerol and ghrelin during hedonic but not nonhedonic, eating.
The present preliminary findings suggest that when motivation to eat is generated by the availability of highly palatable food and not by food deprivation, a peripheral activation of two endogenous rewarding chemical signals is observed. Future research should confirm and extend our results to better understand the phenomenon of hedonic eating, which influences food intake and, ultimately, body mass.
Background/aims:
Antagonism of the endocannabinoid receptor-1 (CB1R) directly improves whole-body metabolic parameters of insulin resistance. The present investigation determined the effects of chronic CB1R antagonism on whole-body and skeletal-muscle insulin action in insulin-sensitive lean and insulin-resistant obese Zucker rats.
Methods:
Animals were either fed ad libitum or in pairs, or treated with SR141716 (10 mg/kg i.p. for 14 days).
Results:
Food intake was significantly reduced (p < 0.05) after initial SR141716 treatment and remained decreased in both lean and obese animals until day 13. Fasting plasma glucose decreased (24%) and insulin increased (43%) in lean SR141716-treated (24%) rats compared to lean ad libitum-fed controls, but not in the corresponding obese groups. Fasting plasma free fatty acids were reduced by CB1R antagonism in lean (21%) and obese (42%) animals. Whole-body insulin sensitivity was increased (36%) in obese SR141716-treated rats compared to obese ad libitum-fed controls, which was associated with reduced insulin secretion during an oral glucose tolerance test. Insulin-stimulated glucose transport activity in the soleus was greatest in the respective SR141716-treated lean and obese groups compared to the corresponding ad libitum- and pair-fed controls. Chronic SR141716 treatment did not induce alterations in signaling factors associated with the regulation of glucose transport [protein kinase B (Akt), glycogen synthase kinase-3β, 5'-AMP-dependent protein kinase, or p38 mitogen-activated protein kinase] in the soleus.
Conclusions:
These results indicate that, while the chronic treatment with CB1R antagonism markedly diminished food intake in lean and obese Zucker rats, there are also significant metabolic improvements in whole-body and skeletal-muscle insulin action mediated by CB1R antagonism through mechanisms independent of reduced caloric intake.
Impaired aerobic exercise capacity and skeletal muscle dysfunction are associated with cardiometabolic diseases. Acute administration of capsaicin enhances exercise endurance in rodents, but the long-term effect of dietary capsaicin is unknown. The capsaicin receptor, the transient receptor potential vanilloid 1 (TRPV1) cation channel has been detected in skeletal muscle, the role of which remains unclear. Here we report the function of TRPV1 in cultured C2C12 myocytes and the effect of TRPV1 activation by dietary capsaicin on energy metabolism and exercise endurance of skeletal muscles in mice. In vitro, capsaicin increased cytosolic free calcium and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in C2C12 myotubes through activating TRPV1. In vivo, PGC-1α in skeletal muscle was upregulated by capsaicin-induced TRPV1 activation or genetic overexpression of TRPV1 in mice. TRPV1 activation increased the expression of genes involved in fatty acid oxidation and mitochondrial respiration, promoted mitochondrial biogenesis, increased oxidative fibers, enhanced exercise endurance and prevented high-fat diet-induced metabolic disorders. Importantly, these effects of capsaicin were absent in TRPV1-deficient mice. We conclude that TRPV1 activation by dietary capsaicin improves energy metabolism and exercise endurance by upregulating PGC-1α in skeletal muscles. The present results indicate a novel therapeutic strategy for managing metabolic diseases and improving exercise endurance.
The elucidation of the role of endocannabinoids in physiological and pathological conditions and the transferability of the importance of these mediators from basic evidence into clinical practice is still hampered by the indefiniteness of their circulating reference intervals. In this work, we developed and validated a two-dimensional LC/MS/MS method for the simultaneous measurement of plasma endocannabinoids and related compounds such as arachidonoyl-ethanolamide, palmitoyl-ethanolamide, and oleoyl-ethanolamide, belonging to the N-acyl-ethanolamide (NAE) family, and 2-arachidonoyl-glycerol and its inactive isomer 1-arachidonoyl-glycerol from the monoacyl-glycerol (MAG) family. We found that several pitfalls in the endocannabinoid measurement may occur, from blood withdrawal to plasma processing. Plasma extraction with toluene followed by on-line purification was chosen, allowing high-throughput and reliability. We estimated gender-specific reference intervals on 121 healthy normal weight subjects fulfilling rigorous anthropometric and hematic criteria. We observed no gender differences for NAEs, whereas significantly higher MAG levels were found in males compared with females. MAGs also significantly correlated with triglycerides. NAEs increased with age in females, and arachidonoyl-ethanolamide correlated with adiposity and metabolic parameters in females. This work paves the way to the establishment of definitive reference intervals for circulating endocannabinoids to help physicians move from the speculative research field into the clinical field.
Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gene for the secreted glycoprotein lipocalin 2 (lcn2), which has been implicated in obesity and insulin resistance, was among those most responsive to alterations in CB1 signaling. The expression pattern of IDFP mice segregated from DMSO mice in hierarchal cluster analysis and AM251 pre-administration reduced (>50%) the majority (303 of 533) of the IDFP induced alterations. Pathway analysis revealed that IDFP altered expression of genes involved in lipid, fatty acid and steroid metabolism, the acute phase response, and amino acid metabolism in a CB1-dependent manner. PCR confirmed array results of key target genes in multiple independent experiments. Overall, we show that acute IDFP treatment induces hepatic TG accumulation and insulin resistance, at least in part through the CB1 receptor, and identify novel cannabinoid responsive genes.
Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA(2). These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.
We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function.
Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.
Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake.
Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.
The endocannabinoid system (ECS) is a ubiquitously expressed signalling system, with involvement in lipid metabolism and obesity. There are reported changes in obesity of blood concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonoylglcyerol (2-AG), and of adipose tissue expression levels of the two key catabolic enzymes of the ECS, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Surprisingly, however, the activities of these enzymes have not been assayed in conditions of increasing adiposity. The aim of the current study was to investigate whether FAAH and MGL activities in human subcutaneous adipocytes are affected by body mass index (BMI), or other markers of adiposity and metabolism.
Subcutaneous abdominal mature adipocytes, fasting blood samples and anthropometric measurements were obtained from 28 metabolically healthy subjects representing a range of BMIs. FAAH and MGL activities were assayed in mature adipocytes using radiolabelled substrates. Serum glucose, insulin and adipokines were determined using ELISAs.
MGL activity showed no relationship with BMI or other adiposity indices, metabolic markers (fasting serum insulin or glucose) or serum adipokine levels (adiponectin, leptin or resistin). In contrast, FAAH activity in subcutaneous adipocytes correlated positively with BMI and waist circumference, but not with skinfold thickness, metabolic markers or serum adipokine levels.
In this study, novel evidence is provided that FAAH activity in subcutaneous mature adipocytes increases with BMI, whereas MGL activity does not. These findings support the hypothesis that some components of the ECS are upregulated with increasing adiposity in humans, and that AEA and 2-AG may be regulated differently.
Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions.
Omega-3 polyunsaturated fatty acids (ω-3-PUFA) are known to ameliorate several metabolic risk factors for cardiovascular disease, and an association between elevated peripheral levels of endogenous ligands of cannabinoid receptors (endocannabinoids) and the metabolic syndrome has been reported. We investigated the dose-dependent effects of dietary ω-3-PUFA supplementation, given as krill oil (KO), on metabolic parameters in high fat diet (HFD)-fed mice and, in parallel, on the levels, in inguinal and epididymal adipose tissue (AT), liver, gastrocnemius muscle, kidneys and heart, of: 1) the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), 2) two anandamide congeners which activate PPARα but not cannabinoid receptors, N-oleoylethanolamine and N-palmitoylethanolamine, and 3) the direct biosynthetic precursors of these compounds.
Lipids were identified and quantified using liquid chromatography coupled to atmospheric pressure chemical ionization single quadrupole mass spectrometry (LC-APCI-MS) or high resolution ion trap-time of flight mass spectrometry (LC-IT-ToF-MS).
Eight-week HFD increased endocannabinoid levels in all tissues except the liver and epididymal AT, and KO reduced anandamide and/or 2-AG levels in all tissues but not in the liver, usually in a dose-dependent manner. Levels of endocannabinoid precursors were also generally down-regulated, indicating that KO affects levels of endocannabinoids in part by reducing the availability of their biosynthetic precursors. Usually smaller effects were found of KO on OEA and PEA levels.
Our data suggest that KO may promote therapeutic benefit by reducing endocannabinoid precursor availability and hence endocannabinoid biosynthesis.
Oral sensory signals drive dietary fat intake, but the neural mechanisms underlying this process are largely unknown. The endocannabinoid system has gained recent attention for its central and peripheral roles in regulating food intake, energy balance, and reward. Here, we used a sham-feeding paradigm, which isolates orosensory from postingestive influences of foods, to examine whether endocannabinoid signaling participates in the positive feedback control of fat intake. Sham feeding a lipid-based meal stimulated endocannabinoid mobilization in the rat proximal small intestine by altering enzymatic activities that control endocannabinoid metabolism. This effect was abolished by surgical transection of the vagus nerve and was not observed in other peripheral organs or in brain regions that control feeding. Sham feeding of a nutritionally complete liquid meal produced a similar response to that of fat, whereas protein or carbohydrate alone had no such effect. Local infusion of the CB(1)-cannabinoid receptor antagonist, rimonabant, into the duodenum markedly reduced fat sham feeding. Similarly to rimonabant, systemic administration of the peripherally restricted CB(1)-receptor antagonist, URB 447, attenuated sham feeding of lipid. Collectively, the results suggest that the endocannabinoid system in the gut exerts a powerful regulatory control over fat intake and might be a target for antiobesity drugs.
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.
Since the first reports of endocannabinoid-mediated retrograde signaling in 2001, great advances have been made toward understanding the molecular basis and functions of the endocannabinoid system. Electrophysiological studies have revealed that the endocannabinoid system is functional at various types of synapses throughout the brain. Basic mechanisms have been clarified as to how endocannabinoids are produced and released from postsynaptic neurons and regulate neurotransmitter release through activating presynaptic cannabinoid CB(1) receptors, although there remain unsolved questions and some discrepancies. In addition to this major function, recent studies suggest diverse functions of endocannabinoids, including control of other endocannabinoid-independent forms of synaptic plasticity, regulation of neuronal excitability, stimulation of glia-neuron interaction, and induction of CB(1)R-independent plasticity. Using recently developed pharmacological and genetic tools, behavioral studies have elucidated the roles of the endocannabinoid system in various aspects of neural functions. In this review, we make a brief overview of molecular mechanisms underlying the endocannabinoid-mediated synaptic modulation and also summarize recent findings, which shed new light on a diversity of functional roles of endocannabinoids.
Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols (MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades 2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated by hormone-sensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly, however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR.
The endocannabinoid (EC) system has been implicated as an important regulator of energy homeostasis. In obesity and type 2 diabetes, EC tone is elevated in peripheral tissues including liver, muscle, fat, and also centrally, particularly in the hypothalamus. Cannabinoid receptor type 1 (CB₁) blockade with the centrally and peripherally acting rimonabant induces weight loss and improves glucose homeostasis while also causing psychiatric adverse effects. The relative contributions of peripheral versus central EC signaling on glucose homeostasis remain to be elucidated. The aim of this study was to test whether the central EC system regulates systemic glucose fluxes.
We determined glucose and lipid fluxes in male Sprague-Dawley rats during intracerebroventricular infusions of either WIN55,212-2 (WIN) or arachidonoyl-2'-chloroethylamide (ACEA) while controlling circulating insulin and glucose levels through hyperinsulinemic, euglycemic clamp studies. Conversely, we fed rats a high-fat diet for 3 days and then blocked central EC signaling with an intracerebroventricular infusion of rimonabant while assessing glucose fluxes during a clamp.
Central CB₁ activation is sufficient to impair glucose homeostasis. Either WIN or ACEA infusions acutely impaired insulin action in both liver and adipose tissue. Conversely, in a model of overfeeding-induced insulin resistance, CB₁ antagonism restored hepatic insulin sensitivity.
Thus central EC tone plays an important role in regulating hepatic and adipose tissue insulin action. These results indicate that peripherally restricted CB₁ antagonists, which may lack psychiatric side effects, are also likely to be less effective than brain-permeable CB₁ antagonists in ameliorating insulin resistance.
Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action.
We measured EC production in isolated human and mouse islets and β-cell line in response to glucose and KCl. We evaluated human and mouse islets, several β-cell lines, and CB1R-null (CB1R(-/-)) mice for the presence of a fully functioning EC system. We investigated if ECs influence β-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice.
ECs are generated within β-cells, which also express CB1Rs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CB1R results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in β-cells and leads to increased β-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased β-cell proliferation and mass, coupled with enhanced IR signaling in β-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on β-cells in a Gα(i)-dependent manner.
These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes.
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