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Endocannabinoids and Their Receptors as Targets for Obesity Therapy

Julie Gardener

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Endocannabinoids and Their Receptors as Targets for Obesity Therapy​
Annette D. de Kloet and Stephen C. Woods
Endocrinology June 1, 2009



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).

FIG. 1.
Events at a brain synapse where CB1s are expressed. In most instances an action potential in the presynaptic membrane (Stimulus 1) elicits the release of stored neurotransmitter (GABA), which crosses to the postsynaptic membrane and activates its receptor. An action then occurs in the postsynaptic cell. In some instances another stimulus (Stimulus 2) acts on the postsynaptic cell, causing synthetic enzymes for CBs to become active. CBs (anandamide and/or 2-AG) are formed from phospholipid components of the cell membrane and immediately released into the synapse. They activate CB1 on the presynaptic membrane, and this in turn leads to reduced neurotransmitter released when an action potential occurs. Therefore, activation of the CB1 acts as a brake, slowing the passage of information from the presynaptic to the postsynaptic cell.


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.

FIG. 2.
The ECS causes a net anabolic action in the brain as well as in the periphery. In the brain, increased CB1 activity in the hypothalamus as well as in limbic areas leads to increased food intake and facilitation of autonomic and endocrine pathways favoring energy storage. CB1s are also expressed in many tissues where they also elicit a net anabolic action, including the liver, skeletal muscle, GI tract, and adipose tissue.


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.


Disclosure Summary: The authors have nothing to disclose.
First Published Online April 16, 2009
Abbreviations: 2-AG, 2-Arachidonoylglycerol; CB, cannabinoid; CB1, cannabinoid receptor-1; ECS, endocannabinoid system; FAAH, fatty acid amide hydrolase; GABA, γ-aminobutyric acid; GI, gastrointestinal; Δ9-THC, Δ9-tetrahydrocannabinol.
Received January 13, 2009.
Accepted February 17, 2009.
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References

↵ Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF 2006 Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368:1660—1672 CrossRefMedline
↵ Scheen AJ, Van Gaal LF 2007 Rimonabant as an adjunct therapy in overweight/obese patients with type 2 diabetes. Eur Heart J 28:1401—1402; author reply 1402 FREE Full Text
↵ Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S 2005 Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389—1397 CrossRefMedline
↵ Addy C, Li S, Agrawal N, Stone J, Majumdar A, Zhong L, Li H, Yuan J, Maes A, Rothenberg P, Cote J, Rosko K, Cummings C, Warrington S, Boyce M, Gottesdiener K, Stoch A, Wagner J 2008 Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers. J Clin Pharmacol 48:418—427 Abstract/FREE Full Text
↵ Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Bátkai S, Pacher P, Schön MR, Jordan J, Stumvoll M 2006 Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55:3053—3060 Abstract/FREE Full Text
↵ Devane WA, Axelrod J 1994 Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes. Proc Natl Acad Sci USA 91:6698—6701 Abstract/FREE Full Text
↵ Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R 1992 Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946—1949 Abstract/FREE Full Text
↵ Munro S, Thomas KL, Abu-Shaar M 1993 Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61—65 CrossRefMedline
↵ Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI 1990 Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561—564 CrossRefMedline
↵ Huang CC, Lo SW, Hsu KS 2001 Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J Physiol 532:731—748 Abstract/FREE Full Text
↵ Schlicker E, Kathmann M 2001 Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565—572 CrossRefMedline
↵ Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P 2007 CB2-receptor stimulation attenuates TNF-α-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol 293:H2210—H2218
↵ Klein TW 2005 Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400—411 CrossRefMedline
↵ Bermudez-Silva FJ, Sanchez-Vera I, Suárez J, Serrano A, Fuentes E, Juan-Pico P, Nadal A, Rodríguez de Fonseca F 2007 Role of cannabinoid CB2 receptors in glucose homeostasis in rats. Eur J Pharmacol 565:207—211 CrossRefMedline
↵ Bermúdez-Silva FJ, Suárez J, Baixeras E, Cobo N, Bautista D, Cuesta-Muñoz AL, Fuentes E, Juan-Pico P, Castro MJ, Milman G, Mechoulam R, Nadal A, Rodríguez de Fonseca F 2008 Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia 51:476—487 CrossRefMedline
↵ Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB 1996 Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83—87 CrossRefMedline
↵ Di Marzo V, Bisogno T, Sugiura T, Melck D, De Petrocellis L 1998 The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal- and basophil-like cells: connections with anandamide. Biochem J 331(Pt 1):15—19
↵ Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, Piomelli D 1994 Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686—691 CrossRefMedline
↵ Soria-Gómez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S, Navarro L, Di Marzo V, Prospéro-García O 2007 Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c-Fos expression in the hypothalamus. Br J Pharmacol 151:1109—1116 CrossRefMedline
↵ Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thöne-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U 2003 The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423—431 CrossRefMedline
↵ DiPatrizio NV, Simansky KJ 2008 Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J Neurosci 28:9702—9709 Abstract/FREE Full Text
↵ Di Marzo V, Matias I 2005 Endocannabinoid control of food intake and energy balance. Nat Neurosci 8:585—589 CrossRefMedline
↵ Kirkham TC, Williams CM, Fezza F, Di Marzo V 2002 Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 136:550—557 CrossRefMedline
↵ Artmann A, Petersen G, Hellgren LI, Boberg J, Skonberg C, Nellemann C, Hansen SH, Hansen HS 2008 Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta 1781:200—212 Medline
↵ Williams CM, Kirkham TC 1999 Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 143:315—317 CrossRefMedline
↵ Jamshidi N, Taylor DA 2001 Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 134:1151—1154 CrossRefMedline
↵ Verty AN, McGregor IS, Mallet PE 2005 Paraventricular hypothalamic CB(1) cannabinoid receptors are involved in the feeding stimulatory effects of δ(9)-tetrahydrocannabinol. Neuropharmacology 49:1101—1109 CrossRefMedline
↵ Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G 2001 Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822—825 CrossRefMedline
↵ Higgs S, Williams CM, Kirkham TC 2003 Cannabinoid influences on palatability: microstructural analysis of sucrose drinking after δ(9)-tetrahydrocannabinol, anandamide, 2-arachidonoyl glycerol and SR141716. Psychopharmacology (Berl) 165:370—377 Medline
↵ Melis T, Succu S, Sanna F, Boi A, Argiolas A, Melis MR 2007 The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food. Neurosci Lett 419:231—235 CrossRefMedline
↵ Dipatrizio NV, Simansky KJ 2008 Inhibiting parabrachial fatty acid amide hydrolase activity selectively increases the intake of palatable food via cannabinoid CB1 receptors. Am J Physiol Regul Integr Comp Physiol 295:R1409—R1414
↵ Thanos PK, Ramalhete RC, Michaelides M, Piyis YK, Wang GJ, Volkow ND 2008 Leptin receptor deficiency is associated with upregulation of cannabinoid 1 receptors in limbic brain regions. Synapse 62:637—642 CrossRefMedline
↵ Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, Harvey-White J, Liposits Z, Kunos G, Grossman AB, Fekete C, Korbonits M 2008 The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS ONE 3:e1797
↵ Tucci SA, Rogers EK, Korbonits M, Kirkham TC 2004 The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol 143:520—523 CrossRefMedline
↵ Huang H, Acuna-Goycolea C, Li Y, Cheng HM, Obrietan K, van den Pol AN 2007 Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin/orexin neurons: implications for cannabinoid actions on food intake and cognitive arousal. J Neurosci 27:4870—4881 Abstract/FREE Full Text
↵ Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA 2003 Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology (Berl) 167:103—111 Medline
↵ Di Marzo V, Côté M, Matias I, Lemieux I, Arsenault BJ, Cartier A, Piscitelli F, Petrosino S, Alméras N, Després JP 2009 Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia 52:213—217 CrossRefMedline
↵ Juan-Picó P, Fuentes E, Bermúdez-Silva FJ, Javier Díaz-Molina F, Ripoll C, Rodríguez de Fonseca F, Nadal A 2006 Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic β-cell. Cell Calcium 39:155—162 CrossRefMedline
↵ Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G 2005 Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115:1298—1305 CrossRefMedline
↵ Di Marzo V, Capasso R, Matias I, Aviello G, Petrosino S, Borrelli F, Romano B, Orlando P, Capasso F, Izzo AA 2008 The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet. Br J Pharmacol 153:1272—1280 CrossRefMedline
↵ Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C 1997 cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem 272:27218—27223 Abstract/FREE Full Text
↵ Pagano C, Pilon C, Calcagno A, Urbanet R, Rossato M, Milan G, Bianchi K, Rizzuto R, Bernante P, Federspil G, Vettor R 2007 The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. J Clin Endocrinol Metab 92:4810—4819 Abstract/FREE Full Text
↵ Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V 2006 Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 91:3171—3180 Abstract/FREE Full Text
↵ Starowicz KM, Cristino L, Matias I, Capasso R, Racioppi A, Izzo AA, Di Marzo V 2008 Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet. Obesity (Silver Spring) 16:553—565 CrossRefMedline
↵ Gasperi V, Fezza F, Pasquariello N, Bari M, Oddi S, Agrò AF, Maccarrone M 2007 Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol Life Sci 64:219—229 CrossRefMedline
↵ Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Bátkai S, Marsicano G, Lutz B, Buettner C, Kunos G 2008 Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 118:3160—3169 CrossRefMedline
↵ Burdyga G, Lal S, Varro A, Dimaline R, Thompson DG, Dockray GJ 2004 Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci 24:2708—2715 Abstract/FREE Full Text
↵ Liu YL, Connoley IP, Wilson CA, Stock MJ 2005 Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes (Lond) 29:183—187 CrossRefMedline
↵ Després JP, Golay A, Sjöström L 2005 Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121—2134 CrossRefMedline
↵ Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J 2006 Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295:761—775 Abstract/FREE Full Text
↵ Food and Drug Administration FDA Briefing document. NDA 21—888. Zimulti (rimonabant) Tablets, 20 mg. Sanofi Aventis. Advisory Committee–June 13, 2007. Available at http://www.fda.gov/ohrms/dockets/AC/07/briefing/2007—4306b1-fda-backgrounder.pdf (accessed August 9, 2007)
↵ Isoldi KK, Aronne LJ 2008 The challenge of treating obesity: the endocannabinoid system as a potential target. J Am Diet Assoc 108:823—31 CrossRefMedline

Source: Endocannabinoids and Their Receptors as Targets for Obesity Therapy
 
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