Cardiovascular disease (CVD) and type 2 diabetes are two major chronic diseases of increasing prevalence in the United States 1, 2. CVD is a leading cause of death in the United States contributing to 40% of disease-related deaths with a prevalence of approximately 64 million individuals in 2001 2. Type 2 diabetes has increased in prevalence from 8.9% during 1976–1980, to 12.3% during 1988–1994, in individuals 40–74 years of age 1. It has been observed that several cardiovascular risk factors, such as dyslipidaemia and hypertension, are associated with type 2 diabetes. Moreover, the early metabolic changes in pre-diabetes, such as hyperglycaemia and insulin resistance are associated with an increased risk of CVD 3. In addition to dyslipidaemia, hypertension, insulin resistance and hyperglycaemia, obesity is a major risk factor contributing to the progression of type 2 diabetes and CVD 4. Unfortunately, obesity, a condition describing excess body weight in the form of fat, has more than doubled in the US population since the early 1960s, from 13.4% to more than 30%, and is a major concern in the medical community 5. The development of insulin resistance, dyslipidaemia, hypertension, chronic inflammation and a hypercoagulable/prothrombotic state, have been associated with obesity; and the simultaneous presentation of these conditions in various combinations has been referred to as metabolic syndrome 6. Different mechanisms linking obesity to CVD have been proposed 4–7. In addition to body weight, accumulation of abdominal (or visceral) body fat represents an independent risk factor for CVD. Abdominal obesity is indeed the most frequent feature of metabolic syndrome and is causally linked to the metabolic dysfunctions characterizing the syndrome 4. The current pharmacotherapeutic approach is to target the individual risk factors or disease components of the metabolic syndrome. Thus, individuals with multiple cardiovascular or metabolic risk factors may require several drug therapies at the same time.
The identification and characterization of the endogenous cannabinoid system (ECS) has provided insights into the neuroendocrine regulation of eating behaviour, energy balance and metabolism. Recent evidence indicates that the ECS modulates several physiologic functions through central and peripheral mechanisms, and dysregulation of the ECS may be linked to abdominal obesity and other risk factors for CVD and type 2 diabetes. The purpose of this review is to outline the recent advances in our understanding of the ECS and to discuss the clinical relevance of this work with respect to obesity and associated metabolic risk factors.
Description of the endogenous cannabinoid system
Modern day attempts to understand the pharmacologic basis for the orexigenic as well as psychotropic effects of plant-derived cannabinoids 8, 9 led to the identification of Δ9-tetrahydrocannabinol (Δ9-THC) 10 and opened the door to the field of endocannabinoid biology. It has only been 17 years since the cloning of cannabinoid type 1 (CB1) receptor 11. Shortly thereafter, a second CB receptor, identified as cannabinoid type 2 (CB2), was described and cloned 12. The identification of CB receptors and the description of their endogenous ligands, the endocannabinoids, suggested the existence of the ECS. This system appeared in evolution before the development of vertebrates and has been very well preserved across species 13. In mammals, the ECS has been recently recognized to have a role in the modulation of several physiological processes, including neuroprotection 14, regulation of hormone secretion 15, locomotion 16 and energy homeostasis 17, 18, among others.
The CB1 and CB2 receptors are members of the G protein-coupled receptor superfamily 19. There is evidence that one or more additional CB receptors may exist, however, they remain to be further characterized. Activation of both CB1 and CB2 receptors plays a role in modulation of adenylate cyclase and extracellular signal-regulated kinases. In addition, the CB1 receptor is reported to affect both potassium and calcium channels. A more detailed description of the cellular pathways modulated by CB1 and CB2 receptors can be found in previously published reviews 19–21.
In the central nervous system (CNS), the CB1 receptor is highly expressed in the forebrain, basal ganglia, cerebellum, hippocampus and cerebral cortex 22, 23. In fact, the CB1 receptor is among the most abundant G protein-coupled receptors present in the brain 24. Although not abundantly expressed in the hypothalamus, a key integrative area in the regulation of energy balance, activation of the hypothalamic CB1 receptor is highly efficient 24. The CB1 receptor is expressed on axons and nerve terminals of neurons and interneurons as well as on astrocytes 24. Activation of CB1 receptors, usually located pre-synaptically, modulates the release of several neurotransmitters, such as gamma-aminobutyric acid (GABA), dopamine, noradrenaline, glutamate and serotonin (5-HT) 25. CB1 receptors are also located on peripheral nerves, including those innervating the gastrointestinal tract 26, and on organs including liver 27, muscle 15, 28, adipose tissue 29, 30, pancreas 31 and many other tissues 32.
The CB2 receptor is primarily expressed in the immune system, such as in the spleen, thymus and circulating immune cells 32. However, CB2 receptors have also been recently identified in regions of the brain (cortex and cerebellum) and brainstem 33, 34. Brainstem-located CB2 receptors may play a role in the inhibition of emesis in conjunction with CB1 receptors 33. For the purposes of this review, we will mainly focus on CB1 receptors.
The discovery of CB receptors led to the identification of their ligands, endogenous lipid mediators named endocannabinoids that bind to CB receptors. Anandamide (the ethanolamide of arachidonic acid) was the first endocannabinoid identified 35 and is so called from the Sanskrit word ‘ananda’ that means ‘bliss.’ Soon thereafter, the second endocannabinoid was isolated and named 2-arachidonoyl glycerol (2-AG) 36. Three other endocannabinoids, less well characterized, have been identified so far: noladin ether 37, virhodamine 38, and N-arachidonoyl dopamine 39.
In the brain, endocannabinoids work at synaptic level as neuromodulators. They are synthesized from cell membrane phospholipids and are immediately released, usually from the postsynaptic side, but act in a retrograde manner by binding to pre-synaptic CB1 receptors (see reviews 20, 21, 40). Unlike classical neurotransmitters, endocannabinoids, owing to their lipophilic nature, are not stored in vesicles, but are rapidly produced and degraded. Neurons produce both anandamide and 2-AG following depolarization of the membrane and an increase of intracellular calcium. Anandamide is formed by hydrolysis of N-arachidonoyl phosphatidyl ethanolamine by a phospholipase D, whereas 2-AG is formed following hydrolysis of phosphatidylinositol by phospholipase C and diacylglycerol lipase. Following synthesis, anandamide and 2-AG are released into the extracellular space and bind CB1 receptors. Activation of pre-synaptic CB1 receptors leads to modulation of neurotransmitter release, thus affecting synaptic activity (see comprehensive reviews 20, 21, 40) (Figure 1). Endocannabinoids are rapidly metabolized. Inactivation of anandamide occurs by cellular re-uptake and subsequent hydrolysis by a fatty acid amide hydrolase (FAAH). 2-AG degradation in neurons is primarily due to hydrolysis by monoacylglycerol lipase. Both monoacylglycerol lipase and FAAH are largely expressed in the brain as well as in peripheral organs 41, 42 and their specific localization provides further evidence of the role of the ECS in those sites. For an in-depth description of endocannabinoids synthesis and degradation, the reader can refer to recently published reviews 20, 21, 40.
Anandamide and 2-AG have similar binding affinity for CB1 and CB2 receptors 19. 2-AG has been shown to have higher efficacy at the CB2 receptor 43 and acts as a full agonist at both the CB1 and CB2 receptors, whereas anandamide is only a partial agonist 44, 45. Therefore, 2-AG is considered by many as the true endocannabinoid ligand. 2-AG is the most abundant endocannabinoid in the rodent brain, occurring at a concentration 170 times greater than that of anandamide 46. Endocannabinoids are also present in peripheral organs, such as the gastrointestinal tract and liver 27, 47. Moreover, they can be found in the bloodstream, usually bound to albumin 48.
Synthetic cannabinoid receptor agonists and antagonists
Among the synthetic cannabinoid receptor agonists, CP 55,940, 49 WIN 55,212-2 50 and HU 210 51 are worth mentioning because they have been largely used to investigate the physiological functions of the ECS and, specifically, its role in energy balance. Among the synthetic antagonists, SR 141 716 52, AM 251 53 and AM 281 54 are specific for CB1 receptors. Several inhibitors of anandamide cellular re-uptake or transport and of anandamide hydrolysis have also been identified, presenting multiple pharmacologic opportunities to affect the ECS 55, 56.
Role of the endocannabinoid system in the central regulation of energy balance
It is now well established that both CB1 receptor agonists and antagonists affect feeding behaviour in several experimental paradigms. Oral administration of Δ9-THC caused hyperphagia and increased the preference for palatable food in rats 57–59. In the same fashion, subcutaneous or intraperitoneal (IP) administration of anandamide increased food intake in pre-satiated rats or in food-restricted mice, respectively 60, 61. These effects were CB1 receptor-mediated, since pre-treatment with the CB1 receptor antagonist SR 141 716 inhibited the hyperphagia 59, 60. In fact, CB1 antagonism reduces eating of both bland and palatable food in different animal models 60, 62–64.
Mice lacking the CB1 receptor (CB1−/−) are slightly hypophagic and also exhibit a lean phenotype accompanied by reduced body weight and reduced fat mass 29. This animal model has been used to further confirm that the CB1 receptor is involved in feeding behaviour and that CB1 antagonism causes transient anorexia. In fact, the CB1 receptor antagonist SR 141 716 has no effect on the eating behaviour of CB1−/− mice 65. Moreover, CB2 receptor antagonists do not affect eating behaviour 66. In wild-type CB1+/+ mice made hyperphagic by brief food deprivation, treatment with SR 141 716 causes a reduction in food intake to a level similar to the food intake observed in CB1−/− mice 65. Thus, these studies with the CB1−/− mouse model highlight the potentially important role played by the ECS in the regulation of feeding.
The hypothalamus and the brainstem integrate information about homeostatic processes regulating eating behaviour and energy balance 67–69. Studies in which CB1 receptor antagonists and endocannabinoids have been administered intrahypothalamically provide direct evidence for a role of the ECS in the hypothalamic circuits regulating food intake. For instance, administration of anandamide into the ventromedial nucleus of the hypothalamus stimulated eating in pre-satiated rats, and pre-treatment with the CB1 receptor antagonist SR 141 716 blocked anandamide-induced overeating 70.
The effects of the ECS on eating behaviour are not limited to the hypothalamus, but are also mediated through the circuitry of reward, a network of synaptically interconnected neurons originating from different brain structures, such as the ventral tegmental area, medial forebrain bundle, nucleus accumbens, ventral pallidum, prefrontal cortex, and the amygdala 71, 72. Endocannabinoid levels (specifically 2-AG) are modulated by the body's energy status in both the hypothalamus and limbic forebrain, increasing after acute food deprivation and decreasing during feeding 73. Moreover, oral administration of Δ9-THC has been shown to increase the preference for palatable food and sucrose intake 57; and IP administration of Δ9-THC has been associated with increased intake of high fat diets compared to standard rat chow 74. Oral administration of both, Δ9-THC and anandamide, has not only been able to stimulate feeding behaviour but also increase the duration and number of bouts, suggesting an effect on the motivational aspects of the behaviour 75. Further evidence of the ECS involvement in the reward processes that modulate appetite comes from the observation that administration of 2-AG within the nucleus accumbens increases food intake in a CB1 receptor-dependent manner 73. Conversely, a conditioned-place preference for food and a selective preference for sucrose are blocked by SR 141 716 76, 77. Moreover, human subjects treated with SR 141 716 (Rimonabant, 20 mg/day) have reduced pre-meal motivation to eat 78, and show less desire for sweets and high-fat foods 79, however, reducing their food intake independently of food type and preference 78.
Besides, the ECS interacts with known neurotransmitters, neuropeptides and hormones involved in the regulation of food intake (Table 1). The characteristics of the ECS interactions with the serotoninergic, dopaminergic and opioidergic pathways have been discussed at length elsewhere 71, 72, 80.
Table 1. Known interactions between the ECS and hormones, neuropeptides and neurotransmitters involved in the regulation of energy balance
CB1 signalling prevents the anorexic action of the melanocortin system 87
CB1 signalling mediates the glucocorticoid inhibition of CRH release 86
Nucleus accumbens, ventral tegmental area
ECS modulates dopamine release 71; CB1 and dopamine receptors are co-localized 88
Nucleus accumbens, caudate putamen, striatum
CB1 and serotonin receptors are co-localized 88; additive interaction between serotonin and ECS in the modulation of food intake 89
Hypothalamus, nucleus accumbens, ventral tegmental area
Neuroanatomical interaction between the opioid system and the ECS 72; functional relationship between opioid and ECS in regulating feeding behaviour 72
Role of the endocannabinoid system in peripheral metabolism
Importantly, a role for the ECS in regulating appetite and metabolism is not restricted to the CNS, but appears to extend to several peripheral organs and tissues involved in energy intake, storage, or utilization. In this regard, CB1 receptors have been identified in a number of organs and tissues involved in the regulation of metabolism, including gut, adipose tissue, liver, muscle and pancreas. CB1 receptors innervating the gastrointestinal tract affect gastric emptying, gut motility and peristalsis and play a role in satiety signalling 90. Similar to what happens in the brain, anandamide levels increase in the small intestine after starvation and return to control levels with refeeding 47. In partially satiated rats, IP administration of anandamide and CB1 receptor agonist WIN 55,212-2 was able to stimulate hyperphagia, whereas intracerebroventricular (ICV) administration had no effect on eating behaviour 47. In the same way, IP administration of the CB1 receptor antagonist SR 141 716 reduced food consumption in partially satiated rats, while ICV administration of SR 141 716 had no effect 47. Sensory deafferentiation induced by the neurotoxin capsaicin prevented hyperphagia and hypophagia induced by peripheral administration of CB1 receptor agonists and antagonists, respectively, thus implying the existence of a peripheral mode of action for these compounds 47. CB1 receptors are also expressed in vagus efferent neurons that express cholecystokinin-1 receptors and the activity of peripheral ECS might be modulated by gut-derived signals of satiety. In fact, the satiety hormone cholecystokinin (CCK) mediates the down-regulation of CB1 receptor expression in vagus afferent neurons in response to feeding 91.
Evidence that peripheral ECS-mediated mechanisms affect both body weight and metabolism has been obtained using genetically modified obese rodent models and animals exposed to high-fat diets. In mice with diet-induced obesity (DIO), chronic (5-week period) oral administration of SR 141 716 caused a transient reduction of food intake, but weight loss persisted even after food intake returned to the levels of untreated animals 92. Interestingly, the magnitude of the effect from CB1 receptor blockade is weight-related; in fa/fa obese rats (characterized by a defect in the leptin receptor gene), treatment with a CB1 receptor antagonist had a greater effect on reducing food intake and body weight than in lean controls 93. The deletion of the CB1 receptor gene produces effects that are consistent with the results obtained from pharmacologically antagonizing the receptor. CB1−/− mice have a lower body weight despite the fact that their relative energy intake is similar to that of wild-type mice when expressed as a percentage of body weight 94. In addition, CB1−/− mice have approximately half the body fat (expressed as a percentage of body weight) of wild-type controls 94.
The leanness and reduced body fat observed in CB1−/− mice is attributed to changes in both central control of appetite and peripheral control of lipogenesis 29. CB1 receptor mRNA is expressed in the epididymal fat pads of wild-type mice, but is absent in CB1−/− mice 29. Stimulation of adipocyte differentiation and lipoprotein lipase activity by the CB1 receptor agonist WIN 55,212-2 are both blocked by SR 141 716 29. Moreover, the expression of CB1 receptor in adipose tissue seems to be related to the adiposity level. Adipose tissue of obese rats, such as fa/fa, has a 3-fold higher CB1 receptor mRNA expression than that of lean rats 30. Also, further reductions in adiposity and changes in adipocyte size following CB1 receptor antagonist treatment have been associated with altered expression of genes in adipose tissue that directly or indirectly regulate metabolic pathways involved in energy expenditure and storage 95.
The CB1 receptor is also expressed on hepatocytes, pancreas, and skeletal muscle 15, 27, 31. In liver, increases in CB1 receptor mRNA and anandamide levels were reported in wild-type mice on a high-fat diet 27; and diet-induced obesity was associated with increased hepatic CB1-mediated fatty acid synthesis 27.
In rat and mouse pancreas, CB1 and CB2 receptors have been identified in the islet of Langerhans, with CB1 receptors localized in alpha cells, and CB2 receptors localized in both alpha and beta cells 31, 96. Moreover, 2-AG and anandamide both appear to cause a reduction in glucose-induced insulin secretion, and the effects of 2-AG are blocked by a CB2 receptor antagonist 31. In addition, rat insulinoma β-cells express both CB1 and CB2 receptors, and produce endocannabinoids 97. In this cell model, endocannabinoids are under the negative control of insulin. However, high glucose exposure transforms insulin down-regulation of endocannabinoids into up-regulation; and stimulation of insulin release during high glucose seems to be CB1-dependent 97.
In skeletal muscle, CB1 receptors have also been recently reported with the levels being higher in the muscle of DIO mice compared with that of lean mice 15. In ob/ob mice, administration of CB1 receptor antagonist, increased basal oxygen consumption and glucose uptake by skeletal muscle, possibly suggest that CB1 antagonism can increase energy expenditure and help preserve insulin sensitivity in muscle 28.
The role of the endocannabinoid system in human obesity
Experimental evidence shows that alteration of the ECS in several tissue types or anatomical locations (such as the hypothalamus, limbic system, adipose tissue, liver and muscle) is associated with increased body weight, adiposity and changes in metabolism. Observational human studies also indicate that dysregulation of the ECS contributes to obesity. Engeli et al. found that plasma anandamide and 2-AG levels were significantly elevated in obese women compared with lean women 98. The following reports have shown that visceral fat of obese subjects contains significantly higher 2-AG levels than subcutaneous fat 97 and that patients (both men and women) characterized by abdominal obesity have higher circulating 2-AG levels 99, 100. In fact, a significant correlation exists between circulating 2-AG levels and visceral fat mass 99. Moreover, both lean and obese subjects have higher CB1 and FAAH mRNA expression in the visceral than in the subcutaneous fat depot. However, mRNA levels are overall decreased in adipose tissue of obese compared with lean subjects 98, 99.
Increased 2-AG levels also correlate with fasting insulin levels 99, 100, and with greater glycemic response during an oral glucose test 100. Conversely, they are negatively associated to glucose infusion rate during clamp 99. Interestingly, subjects with type 2 diabetes and uncorrected hyperglycemia have increased circulating levels of endocannabinoids 97.
Dysregulation of the ECS is also associated with eating disorders. Patients diagnosed with restricting anorexia nervosa or binge eating disorder exhibit elevated plasma levels of anandamide 101. With restricting anorexia nervosa, the elevated plasma levels of anandamide may be secondary to decreased plasma leptin levels. In binge eating disorder there are increased plasma leptin levels because of the higher fat stores, but deficiencies in leptin signalling may account for the higher levels of anandamide 101. Therefore, elevated levels of endocannabinoids and dysfunction of the ECS may significantly contribute to the pathophysiology of human obesity.
Hypotheses for endocannabinoid system dysregulation
A number of environmental factors may contribute to dysregulation of the ECS, including stress and diet. Stress may impact the ECS as suggested by evidence linking glucocorticoids and the ECS in the hypothalamus 86. Though the direct link has yet to be determined, preliminary evidence indicates that diets high in long-chain polyunsaturated fatty acids, 20 : 4n26 and 22 : 6n23, known biological precursors of N-acylethanolamines (NAEs; anandamide and 2-AG), are associated with increased levels of NAEs in the brain 102. Moreover, alteration in the function or in the circulating levels of hormones involved in the regulation of energy balance (i.e. leptin, CCK, ghrelin) might be causally linked to dysregulation of the ECS 65, 82, 91.
Specific gene polymorphisms affecting the regulation of the ECS activity might also contribute to the development of obesity. For instance, a specific gene missense polymorphism, FAAH 385 A/A, has been found to occur at a higher frequency among individuals with a higher body mass index (BMI) 103. Individuals with the FAAH 385 A/A polymorphism have approximately half of the FAAH protein level and enzymatic activity compared with those that express the wild-type protein 104. In addition, polymorphisms in the CNR1 gene, which encodes for the CB1 receptor in humans, have been identified in individuals with anorexia nervosa 105. Although the relationship between genes and environmental factors that leads to dysregulation of the ECS remains to be delineated, targeting the ECS activity appears to be an important approach for improving metabolic control. Recently, CB1 antagonism (with rimonabant 20 mg/day) has been proven to be effective at reducing body weight and abdominal obesity in overweight and obese individuals (BMI ≥ 27 kg/m2) 79, 106–108.
Targeting the endocannabinoid system with CB1 receptor antagonists
The role of the ECS in the regulation of eating behaviour and energy balance has been illustrated in part through the identification of CB1 receptors and endocannabinoids in the CNS and in peripheral organs, as well as through the ability of CB1 receptor antagonists in obese and non-obese animal models to modify eating behaviour and lipid and glucose metabolism. Dysregulation of the ECS may contribute to common human obesity (Figure 2). This hypothesis has important implications, given the clear epidemiological evidence linking abdominal obesity to increased risks of developing the various cardiometabolic risk factors which in turn increase the risk of CVD and type 2 diabetes 4, 109. CB1 receptor antagonists, targeting the ECS, positively impact obesity, dyslipidaemia and insulin resistance.
CB1 receptor antagonists and weight loss
In DIO mice, CB1 receptor antagonist treatment was associated with significant weight reduction, similar to the weight reduction observed in rats switched from high fat to standard rat chow 110. Moreover, DIO mice treated with CB1 receptor antagonists SR 141 716 or AM 251 were characterized by a persistent loss in body weight even after their food intake returned to control levels 92, 111. Clinical trials conducted on overweight and obese patients with BMI ≥ 27 kg/m2 who were on a hypocaloric diet, have shown that oral CB1 receptor antagonist (rimonabant 20 mg/day) administration for 1 year resulted in weight loss of upto 8.6 kg compared with1.4–2.3 kg in placebo-treated individuals 79, 106, 108. The reduction in body weight occurred during the first 36–40 weeks of the study period. Long-term treatment (2 years) with CB1 receptor antagonist was able to stabilize body weight and prevent weight regain 107.
CB1 receptor antagonists and regional adiposity
In DIO mice, administration of SR 141 716 or AM 251 resulted in site-specific reductions in inguinal subcutaneous, retroperitoneal, and mesenteric adipose tissue mass 95, 111. Taking into account that the ECS results particularly activated in subjects with visceral obesity 99, 100, it is noteworthy mentioning that in obese patients with BMI ≥ 27 kg/m2 on a hypocaloric diet, CB1 receptor antagonist (rimonabant 20 mg/day) administration resulted in a decrease in waist circumference (an indirect measure of abdominal obesity) of up to 9.1 cm as compared with a 1.9–3.4 cm decrease observed in placebo-treated individuals, thus suggesting a significant decrease in abdominal obesity 79, 106, 108. A clinical trial evaluating the effect of rimonabant on visceral fat reduction in abdominally obese subjects is currently under way (VICTORIA trial, www.clinicaltrials.gov).
CB1 receptor antagonists and dyslipidaemia
Reductions in total cholesterol and low-density lipoprotein cholesterol (LDL) levels were associated with CB1 receptor antagonist treatment in obese mice on a high-fat diet 110. CB1 receptor antagonist (rimonabant 20 mg/day) treatment in overweight and obese individuals also improved lipid profiles by increasing high-density lipoprotein cholesterol (HDL) and decreasing triglycerides 79, 106, 108. Levels of HDL increased continuously throughout 2-year treatment with a CB1 receptor antagonist, whereas body weight stabilized 107. Significantly, only a portion (approximately 50%) of the effect associated with CB1 receptor antagonist treatment on HDL was attributed to weight loss 79, 108. The additional improvement in lipid profile appears to involve a CB1 receptor-mediated effect that is independent of weight loss. A clinical trial is currently ongoing to evaluate the effect of rimonabant on HDL and triglycerides in abdominally obese subjects with atherogenic dyslipidaemia (low HDL and/or high triglycerides) (ADAGIO trial, www.clinicaltrials.gov).
CB1 receptor antagonists and glucose homeostasis
CB1−/− mice exhibit lower plasma insulin levels compared with wild-type controls when exposed to a high-fat diet 94. Elevated serum insulin levels 92, 110 and glucose levels 110 in DIO mice are reduced with CB1 receptor antagonist treatment. Likewise, fasting glucose and fasting insulin in overweight and obese individuals are decreased following CB1 receptor antagonist therapy 108. In obese subjects with type 2 diabetes, inadequately controlled by metformin or sulphonylurea, CB1 receptor antagonist treatment (rimonabant 20 mg/day) not only reduced body weight and waist circumference, but also HbA levels 79. The placebo-corrected reduction in HbA1C levels seen with CB1 antagonist was clinically relevant 79. Moreover, 57% of placebo-subtracted effects of 20 mg/day rimonabant on HbA levels was independent of weight loss 79.
A direct effect of CB1 receptor antagonists on peripheral metabolism, specifically glucose homeostasis, has been supported by the presence and activity of the ECS in peripheral organs (see previous section on peripheral ECS). A possible explanation that has been given for the improved glucose metabolism resides in the increased mRNA and plasma levels of adiponectin observed after treatment with CB1 receptor antagonists 30, 106, 110. Adiponectin, an adipocyte-derived cytokine, appears to have at least some role in the modulation of obesity-related insulin resistance through its involvement in the regulation of glucose homeostasis and fatty acid oxidation 112. In this regard, decreased levels of adiponectin are associated with obesity and insulin resistance; whereas, increased adiponectin levels ameliorate insulin resistance and glucose intolerance 113. In particular, plasma adiponectin levels are negatively correlated to visceral obesity 114, a condition in which the ECS results more activated 97. Interestingly, Côté et al. have found a negative correlation between adiponectin and 2-AG levels in abdominally obese subjects 100, although, other studies have not 99. The ECS may thus help modulate adiponectin levels, since treatment with SR 141 716 increased adiponectin levels in adipose tissue of fa/fa obese rats but not in lean controls 30. Furthermore, DIO mice treated with SR 141 716 were characterized by increased adiponectin levels as compared with untreated mice 110. In adipose tissue from CB1−/− mice, adiponectin levels remained unchanged after SR 141 716 treatment, but increased in wild-type mice, demonstrating a CB1-mediated effect 30. Finally, it is worth mentioning that in addition to adiponectin's positive impact on insulin sensitivity, this adipokine has been shown to exhibit anti-inflammatory properties 115.
Amelioration of inflammatory indices
Obesity is known to be associated with a subclinical inflammatory state 116. C-reactive protein is an acute-phase protein that is considered a marker of inflammation and a predictive indicator of CVD 117. Plasma C-reactive protein levels are positively correlated and adiponectin levels are negatively correlated with increasing body weight and fat mass 118, 119. In DIO mice, chronic treatment with SR 141 716 down-regulates the gene expression of pro-inflammatory proteins in adipose tissue 95. In overweight and obese individuals, the oral administration of CB1 receptor antagonist for 1 year resulted in increased plasma adiponectin levels 106 and decreased plasma C-reactive protein levels 79, 106.
The ECS, through central and peripheral mechanisms, regulates various aspects of energy balance regulation. CB1 receptors expressed in the CNS and in peripheral tissues are involved in the regulation of energy balance. Dysregulation of the ECS has been associated with the development of obesity; and CB1 receptor antagonism reverses obesity and improves lipid and glucose metabolism (risk factors critical to the development of CVD and type 2 diabetes). Thus, therapeutics targeting the ECS, such as CB1 receptor antagonists, may prove effective at significantly reducing the development of cardiovascular disease, type 2 diabetes and obesity.
Funding for editorial support was provided by SANOFI-AVENTIS US.
Conflict of interest
D.C. has received consulting fees from SANOFI-AVENTIS US.