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Endocannabinoids And Their Receptors As Targets For Obesity Therapy

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Abstract

As the incidence of obesity continues to increase, the development of effective therapies is a high priority. The endocannabinoid system has emerged as an important influence on the regulation of energy homeostasis. The endocannabinoids anandamide and 2-arachidonoylglycerol act on cannabinoid receptor-1 (CB1) in the brain and many peripheral tissues causing a net anabolic action. This includes increasing food intake, and causing increased lipogenesis and fat storage in adipose tissue and liver. The endocannabinoid system is hyperactive in obese humans and animals, and treating them with CB1 antagonists causes weight loss and improved lipid and glucose profiles. Although clinical trials with CB1 antagonists have yielded beneficial metabolic effects, concerns about negative affect have limited the therapeutic potential of the first class of CB1 antagonists available.

Energy homeostasis is regulated by a complex calculus of interconnected peripheral and central mechanisms that function synergistically to maintain adequate levels of energy intake, storage, and utilization. Although this system is normally adequate to cope with a broad range of challenges, environmental factors associated with modern society have led to an apparent dysregulation and a concomitant elevated incidence of obesity and obesity related complications. Consequently, there is an urgent need to understand critical components of this control system to develop more effective therapies. The recent recognition of the endocannabinoid system (ECS) as a key modulator of many aspects of energy homeostasis has identified it as a promising target, and this review summarizes what is known of the actions of the ECS to influence metabolism by acting in the brain and throughout the body.

Several lines of evidence implicate the ECS in the etiology of obesity and related metabolic disorders. Its key elements are the cannabinoid (CB) receptors, endocannabinoids, and the enzymes that synthesize and inactivate the endocannabinoids. Administering cannabinoid receptor-1 (CB1) agonists causes a net anabolic response, including increased food intake and fat storage, whereas administering CB1 antagonists causes reduced food intake and weight loss. CB1 antagonists also improve glucose and lipid profiles in individuals with hyperlipidemia or type 2 diabetes (1, 2, 3). Obese humans and animals have elevated ECS activity, and clinical trials with CB1 antagonists have proven successful at ameliorating many obesity related symptoms (1, 2, 3, 4, 5).

History

It has been recognized for centuries that food intake increases in response to administration of Δ9-tetrahydrocannabinol (Δ9-THC), the active CB receptor agonist in marijuana, and CB receptor agonists have been prescribed to reverse weight loss since the 1980s. In the 1990s, CB receptors and their endogenous ligands were discovered and characterized, identifying the ECS as a potentially important target for the treatment of obesity (6, 7, 8, 9). Over the ensuing years, pharmacological agents that stimulate or antagonize CB receptors or interfere with the metabolism of endocannabinoids have been developed, and at the same time, mice with genetic manipulations of the various components of the ECS have been created. The availability of all of these tools has led to an explosion of research aimed at understanding the role of the ECS in the etiology of obesity and metabolic functioning. In addition, the results of several clinical trials using CB1 antagonists such as rimonabant (SR141716) and taranabant (MK0364) indicate that these compounds can be quite effective at reducing weight and alleviating many of the metabolic disturbances of obesity (1, 2, 3, 4). However, side effects related to central actions of these compounds have been a concern, and have precluded approval by the Food and Drug Administration and other organizations. Both rimonabant and taranabant antagonize CB1, and at higher levels also have inverse agonist properties.

CB Receptors

In 1990, the first CB receptor, CB1, was cloned (9), and the cloning of the second receptor, CB2, soon followed (8). Although both receptors are seven-transmembrane, G protein-coupled receptors, they differ structurally, in the tissues they populate and in their potential as targets for obesity therapy. CB1 is widely expressed in the periphery and is the most abundant G protein-coupled receptor in the brain, and CB1 activation is responsible for most CB-mediated influence over energy homeostasis. In the brain, most CB1s are located presynaptically on neurons where they function to suppress the release of neurotransmitters, including glutamate and γ-aminobutyric acid (GABA) (10, 11) (Fig. 1⇓). Specifically, increased CB1 activity modulates adenylate cyclase and ion channels in the presynaptic membrane, resulting in less calcium influx and, consequently, less transmitter release. Therefore, increased CB1 activity acts as a brake, reducing transmitter flux across synapses. In contrast, CB2s are predominantly found in peripheral tissues where they regulate immune function and proinflammatory cytokine action (12, 13). CB2s have not been thought to have a major role in energy homeostasis, and their therapeutic utility is not clear. Nonetheless, CB2s are expressed in microglia in the central nervous system and in pancreatic islet cells (12, 13, 14, 15).

Endocannabinoids

The best-known endocannabinoids are N-arachidonyl ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG). Both are long-chain polyunsaturated fatty acid by-products formed from phospholipid constituents of cell membranes when their synthetic enzymes are activated; both are agonists at CB1 and CB2, and both elicit many of the metabolic actions of Δ9-THC (Fig. 1⇑) (6, 7). Within the nervous system, they are immediately released into the synaptic cleft and thought to act mainly in a paracrine fashion, stimulating CB receptors on nearby cells. They are inactivated by a reuptake mechanism and, subsequently, hydrolyzed by fatty acid amide hydrolase (FAAH) (mainly for anandamide) or monoglyceride lipase (for 2-AG) (16, 17, 18). Although anandamide and 2-AG have differential potency in many tissues, and although their relative concentrations differ in the brain and blood, they generally elicit comparable actions.

Central ECS

Endogenous CBs and their receptors are present throughout much of the brain. Pertinent to this review, the ECS has a major role in brain areas involved in the regulation of both the homeostatic and hedonic aspects of food intake (19, 20, 21, 22, 23). Nonetheless, the lipophilic nature of endocannabinoids as well of synthetic ligands for CB receptors dictates that attempts to target specific functions or brain areas for therapeutic purposes are likely to fail because multiple, often undesirable, control systems are also likely to be impacted.

Consistent with a physiological role of the ECS in the control of energy homeostasis, and unlike what occurs in most brain areas, the levels of endocannabinoids in the hypothalamus, where homeostatic circuits are found, and in the limbic forebrain, where hedonic and motivational aspects of food intake are controlled, vary with nutritional status (23, 24) (Fig. 2⇓). In these areas, 2-AG levels are increased during fasting and reduced after refeeding (23). Administration of CB1 agonists systemically or directly into these brain regions elicits a short-term, stimulatory effect on feeding, and systemic or local brain administration of CB1 antagonists causes a dose-dependent hypophagia (23, 25, 26, 27, 28). Mice genetically engineered such that they lack CB1 (CB1−/− mice) consume significantly less food than wild-type controls after an 18-h fast, implying that endogenous CBs acting at CB1 normally facilitate the hyperphagic response that occurs after a fast (28). Consistent with this, administration of rimonabant reduces food intake in fasted animals that have their food returned.

Because of anecdotal reports that exogenous CBs (especially Δ9-THC) stimulate the intake of palatable foods as opposed to bland foods by humans, several reports have looked at this issue experimentally. Although the issue is controversial, rimonabant has selectively decreased consumption of palatable substances such as sucrose solution or pellets in rats (29). Rimonabant was recently reported to reduce the increase of dopamine elicited by consumption of palatable food in mesolimbic reward areas of the brain, suggesting a possible mechanism (30). A recent report by DiPatrizio and Simansky (21) implicated CB1 in the parabrachial nuclei in endocannabinoid-induced stimulation of palatable food intake. Parabrachial infusions of 2-AG stimulated acute intake of a high-fat/high-sucrose diet and of pure fat or sucrose but not of standard rodent chow, and this effect was blocked by CB1 antagonism. Finally, inhibiting FAAH, the enzyme that breaks down anandamide, stimulates the intake of palatable foods by rats (31).

Although it is somewhat of a generalization, the ECS can be considered to exert an overall anabolic tone in the nervous system. As discussed previously, increasing ECS activity locally in the brain promotes energy intake and storage, and administering CB1 antagonists either systemically or locally in the brain decreases food intake and causes weight loss in animals (23, 25, 26, 27, 28). Furthermore, the ECS interacts with other hormones, neurotransmitters, and neuropeptides involved in energy balance in predictable ways. For example, hypothalamic levels of endocannabinoids are decreased after leptin administration, and defective leptin signaling is associated with elevated hypothalamic endocannabinoid levels as well as obesity (28, 32). Consistent with this, leptin receptor-deficient mice have up-regulated CB1 expression in limbic brain regions influencing hedonic aspects of meals (32). Administering ghrelin into the hypothalamic paraventricular nucleus increases food intake, and this is blocked by systemic rimonabant (33, 34). Endogenous CBs also stimulate activity of hypothalamic melanin-concentrating hormone and inhibit hypocretin/orexin neurons, both consistent with increased anabolic tone (35).

Collectively, these findings indicate that the ECS plays a role in promoting food intake, and is a key player in the neural circuitry associated with homeostatic and hedonically driven feeding behavior. Furthermore, there is evidence that hyperactivity of the central ECS likely contributes to obesity and associated symptoms of type 2 diabetes and cardiovascular disease. Nonetheless, the overall impact of endocannabinoids on metabolism is unlikely to be due to a central action alone. One reason is that when CB1 antagonists are administered chronically, food intake is only transiently reduced, lasting at most 1—2 wk, whereas the decline of body weight and improvement of lipid and glucose parameters continue as long as the treatment continues and far longer than the behavioral effect (28, 36). The implication is that the ECS has other actions throughout the body that contribute to its anabolic tone.

Peripheral ECS

Obese animals and humans have elevated plasma and adipose tissue levels of anandamide and 2-AG, and these levels become lower after weight loss (5, 37). Indeed, CB1s have been identified in several peripheral tissues involved in the maintenance of energy homeostasis, including adipose tissue, liver, skeletal muscle, the gastrointestinal (GI) tract, and the endocrine pancreas (Fig. 2⇑), and CB1 expression in these tissues varies with nutritional status and obesity (5, 15, 38, 39, 40). Furthermore, CB1−/− mice are resistant to diet-induced obesity despite comparable food intake as wild-type controls (20).

Adipose Tissue

Adipose tissue contains all of the elements of the ECS, including anandamide and 2-AG, CB1, and the enzymes that hydrolyze anandamide and 2-AG (20, 41, 42). In adipocytes, CB1 stimulation increases formation and storage of triglycerides, decreases the expression of adiponectin, and facilitates the uptake of glucose (20, 42, 43). Stimulation of primary epididymal adipocytes with a CB1 agonist dose dependently increases lipoprotein lipase activity, an effect blocked by the administration of rimonabant (20). Increased lipoprotein lipase enhances the sequestering of fatty acids by adipocytes.

All of these ECS components are dysregulated in obesity, with elevated levels of endocannabinoids in the epididymal fat of diet-induced obese mice and in the visceral adipose tissue of obese humans (20, 43, 44). Furthermore, adipose tissue has increased expression of all of the ECS elements during times of adipocyte differentiation (45). The exact role of the ECS in adipose tissue is likely to be complex because levels of CBs themselves are elevated, yet levels of CB1 and FAAH are both down-regulated in obese humans and rodents (5). CB1 is differentially expressed in different fat depots, with a higher level being found in visceral relative to sc fat in humans.

Liver

Hepatocytes express CB1, and similarly to adipose tissue, the ECS is up-regulated in the liver in obesity (39, 46). Hepatic levels of endocannabinoids are elevated in obese animals fed a high-fat diet compared with lean controls, and this has been attributed to a decrease in FAAH activity. Within the liver, endocannabinoids stimulate the activity of several lipogenic factors, leading to increased fatty acid synthesis and, as a result, contribute to the development of fatty liver (39, 46). CB1 agonists increase fatty acid synthesis in isolated hepatocytes by inducing the expression of the lipogenic transcription factor, sterol regulatory element binding protein-1c, and its target enzymes acetyl- coenzyme A carboxylase 1 and fatty acid synthase (39). In addition, sterol regulatory element binding protein-1c is reduced in the liver and adipose tissue of CB1−/− mice, and CB1−/− mice are resistant to diet-induced obesity and do not develop a fatty liver when maintained on a high-fat diet. Finally, liver-specific CB1 knockout mice have less steatosis, hyperglycemia, and insulin and leptin resistance than wild-type mice when fed a diet high in fat (46).

Other Tissues

CB1 and CB2 are both expressed in the endocrine pancreas, CB1 in glucagon-containing α-cells and CB2 within both β- and α-cells (38), and rat insulinoma cells produce endocannabinoids that are under the negative control of insulin (43). CB2 activation decreases insulin secretion, and there is evidence that hyperactivity of the ECS during periods of hyperglycemia may contribute to the hyperinsulinemia characteristic of obesity (38). CB1s are also expressed in the GI system as well as on vagal nerves conveying satiation signals from the GI tract to the brain (40, 47). Increased CB activity has been found to reduce satiation elicited by cholecystokinin (47) and to enhance the ability of ghrelin to stimulate more food intake (34). Skeletal muscle expresses CB1, and Liu et al. (48) observed that the rate of glucose uptake by isolated soleus muscle is increased in mice treated with rimonabant for 7 d.

The key point is that the ECS is present in many organs important in energy homeostasis, and that the obese state is characterized by ECS hyperactivity. CB1 activity in the brain facilitates overeating and fat storage, and these signals presumably act synergistically with direct CB actions in multiple other tissues to exacerbate glucose and lipid dynamics, as well as fat storage.

Clinical Trials Considering CB1 Antagonism

Several large multicenter, double-blind randomized clinical trials have been reported in which a selective CB1 antagonist or placebo was administered chronically to obese humans with or without type 2 diabetes or hyperlipidemia, and determined the effect on body weight and indicators of glucose and lipid control (1, 2, 3, 4, 49, 50). Although details of individual studies can be found in the various references, there were very consistent findings across trials. Most of the reports administered rimonabant (SR141716; 20 mg/d), and the findings appear comparable for taranabant (MK0364, 6 mg/d).

Although there were slight differences among some subpopulations, as a rule and relative to placebo, subjects receiving the CB1 antagonist/inverse agonist lost body weight (an average of 4—6 kg over 1 yr), had increased high-density lipoprotein cholesterol and adiponectin, and had reduced waist circumference, plasma triglycerides, glycosylated hemoglobin, and fasting insulin. They also had improved glucose tolerance. Importantly, many of the metabolic improvements were greater than what would have been expected from the weight loss alone, consistent with a reduction of CB1 tone on many organ systems.

There was an approximate 2-fold increase in the risk of psychiatric adverse events in subjects receiving the CB1 antagonist relative to placebo, including anxiety, depressed mood, and sleep disturbances. Importantly, individuals with a history of severe depression or other psychiatric disorders, or who had recently used antidepressant medications, were excluded from the studies. The Food and Drug Administration recently ruled against approval of rimonabant due to a lack of safety data in people with depression (51). Although rimonabant was approved by the European Medicines Agency in June 2006 (http://www.emea.europa.eu/humandocs/PDFs/EPAR/acomplia/32982607en.pdf), the European Medicines Agency recently recommended that rimonabant is contraindicated in patients with ongoing major depression and in patients being treated with antidepressants (Ref. 52 ; and see http://www.emea.europa.eu/humandocs/PDFs/ EPAR/acomplia/32982607en.pdf).

Conclusion

Over the past quarter of a century, the prevalence of obesity and comorbidities has skyrocketed. This may be attributed to the surplus in the availability of calorically dense foods. As the incidence of obesity continues to increase, the development of an effective obesity therapy is becoming more essential, and manipulation of the ECS is a promising candidate for such treatments. Reducing ECS activity by CB1 antagonists leads to a shift in the system from positive to negative energy balance, making the ECS an excellent potential target for the development of new obesity therapies. Current formulations of CB1 antagonists are fat soluble and readily cross the blood-brain barrier, such that their oral or systemic administration, in addition to having peripheral actions, influences many neural circuits, only some of which are directly related to metabolism. Undesired central side effects of CB1 antagonism, such as a tendency to become depressed in some patients, pose enough risk to preclude approval of current formulations at present. Therefore, developing formulations of CB1 antagonists that do not enter the brain, or that target only certain organs or neural circuits and not others, would be an important direction for research.

Source, Graphs and Figures: Endocannabinoids and Their Receptors as Targets for Obesity Therapy
 
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