Endocannabinoids and Their Receptors as Targets for Obesity Therapy

M I N I R E V I E W Minireview: Endocannabinoids and Their Receptors as Targets for Obesity Therapy Annette D. de Kloet and Stephen C. Woods Program in Neuroscience (A.D.d.K., S.C.W.) and Department of Psychiatry (S.C.W.), University of Cincinnati, Cincinnati, Ohio 45237 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. (Endocrinology 150: 2531–2536, 2009) E nergy 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 (1–3). Obese humans and animals have elevated ECS ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/en.2009-0046 Received January 13, 2009. Accepted February 17, 2009. First Published Online April 16, 2009 activity, and clinical trials with CB1 antagonists have proven successful at ameliorating many obesity related symptoms (1–5). History It has been recognized for centuries that food intake increases in response to administration of ⌬9-tetrahydrocannabinol (⌬9-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 –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– 4). However, side effects related to cenAbbreviations: 2-AG, 2-Arachidonoylglycerol; CB, cannabinoid; CB1, cannabinoid receptor-1; ECS, endocannabinoid system; FAAH, fatty acid amide hydrolase; GABA, ␥-aminobutyric acid; GI, gastrointestinal; ⌬9-THC, ⌬9-tetrahydrocannabinol. Endocrinology, June 2009, 150(6):2531–2536 endo.endojournals.org 2531 2532 De Kloet and Woods Minireview tral 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 proteincoupled 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 ␥-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 (12–15). Endocrinology, June 2009, 150(6):2531–2536 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 ⌬9-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 monoglycer (...truncated)