Obesity and the Endocannabinoid System: Is There Still a Future for CB1 Antagonists in Obesity?

Antonia Serrano 0 Francisco Javier Pavon 0 Juan Suarez 0 Miguel Romero-Cuevas 0 Elena Baixeras 0 Pilar Goya 0 Fernando Rodrguez de Fonseca 0 0 P. Goya Instituto de Qumica Mdica , Consejo Superior de Investigaciones Cientficas, Juan de la Cierva 3, 28006 Madrid, Spain 1 ) Instituto IBIMA , Laboratorio de Medicina Regenerativa, Hospital Regional Universitario Carlos Haya , Avenida Carlos Haya 82, Edificio de Gerencia, Mlaga 29010, Spain The current epidemic of obesity in western countries is being worsened by the lack of effective pharmacotherapies. The apparent success of a central nervous systemacting cannabinoid CB1 receptor antagonist-based treatment for obesity was hampered by the appearance of psychiatric side effects in certain patients. These adverse effects forced its withdrawal from the market. However, the discovery that the main beneficial metabolic effects of cannabinoid CB1 receptor antagonists were derived of its activity in peripheral tissues, including the adipose tissue, opened the possibility of rescuing this type of therapy. This goal might be achieved by differential medicinal chemistry approaches. The present review examines these options that include peripheral-restricted cannabinoid CB1 receptor antagonists, dual ligands and combinatorial therapies using sub-effective doses of CB1 receptor antagonists that might be devoid of side effects. - In the last few decades, the incidence of overweight and obesity has grown to epidemic proportions. Obesity is a complex metabolic disorder characterized by an imbalance in energy homeostasis, abnormal increase of adipose tissue, and dysregulation of hormones, cytokines and other important signaling systems. This multi-factorial disorder is associated with co-morbidities such as cardiovascular risk, hypertension, sleep apnea, diabetes mellitus, hepatic steatosis and certain types of cancer among others. Its impact on national health systems has led to substantial research efforts towards the discovery of novel anti-obesity therapies. Among the new targets for pharmaceutical development of anti-obesity drugs, the endogenous cannabinoid system (ECS) remains a focus of attention. This signaling system is widely distributed in the central nervous system and peripheral tissues, and is involved in physiological actions related to food intake and energy homeostasis, predominantly via the cannabinoid type 1 receptor (CB1). Animal studies and clinical trials have shown that blockade of CB1 receptor induces weight loss, improves cardiometabolic risk factors and insulin resistance, and causes metabolic benefits. Therefore, all these data have emphasized the potential of CB1 receptor blockade as a therapeutic strategy in obesity. Following this rationale, several cannabinoid receptors antagonists have been developed and some of them have reached clinical trials. One of them, rimonabant, eventually reached the market after approval by the European Medicines Agency. Nevertheless, the central actions of the prototypic CB1 receptor antagonist rimonabant have also been associated with the appearance, in clinical trials, of adverse psychiatric side effects, such as anxiety and depression, in patients treated for obesity. These adverse effects have motivated the withdrawal of rimonabant from the market. However, the question remains whether peripheral blockade of CB1 receptors is still an acceptable mechanism/strategy for the treatment of obesity. The aim of this review is twofold: to summarize the effects of CB1 receptor blockade in energy balance and to discuss the development of new approaches for obesity as effective therapies with reduced side effects. The Endogenous Cannabinoid System The ECS is a physiological signaling system which comprises cannabinoid receptors, endogenous ligands and enzymes responsible for the synthesis, transport and inactivation of these ligands [1 ]. The best characterized endogenous cannabinoids are N-arachidonoylethanolamine (also known as anandamide, AEA) and 2-arachidonoylglycerol (2-AG), both derived from arachidonic acid conjugated with ethanolamine or glycerol, respectively [24]. Although AEA and 2-AG were originally identified as synaptic neuromodulators in neuronal systems, endocannabinoids are implicated in the regulation of several physiological processes in other non-nervous tissues. Therefore, endocannabinoids are present in brain, plasma, and peripheral tissues exerting agonist activity at cannabinoid receptors. Two major types of cannabinoid receptors have been characterized and cloned: CB1 and CB2, both of which belong to the super-family of G protein-coupled receptors. While CB1 receptors are highly expressed in brain and are also found in peripheral tissues (e.g. muscle, gastrointestinal tract, pancreas, liver and adipose tissue) [58], CB2 receptors are mainly located in immune cells (T cells, B cells and monocytes) although there is evidence for their expression in both neurons and glial cells in the brain [9, 10]. In addition to classical cannabinoid receptors, other targets have been found to be modulated by endocannabinoids including the transient receptor potential vanilloid type 1 channel and orphan G protein-coupled receptors, such as GPR55 [11 ]. Endocannabinoids are not stored in cellular vesicles, but are produced on demand, and rapidly degraded by intracellular enzymes; thus, the importance of the enzymes involved in their synthesis and degradation. The major route for AEA production is from phospholipid precursors through the action of N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) [12], while 2-AG derives primarily from the hydrolytic metabolism of 1,2-diacylglycerol (DAG) mediated by two sn-1-selective DAG lipases, DAGL and DAGL [13]. Inactivation of the endocannabinoid signaling is mediated by cellular reuptake and subsequent intracellular hydrolysis. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been identified as enzymes primarily responsible for the degradation of AEA and 2-AG, respectively [14, 15]. Additional metabolic pathways have been described using specific molecular inhibitors and genetic models lacking particular enzymes [16]. The ECS in Obesity The widespread presence of the ECS indicates its physiological relevance in the regulation of a variety of biological processes (e.g. modulation of neural development, immune function, synaptic plasticity and learning, emotional state, pain). In recent years, there has been substantial interest in investigating the role of endocannabinoid signaling in the regulation of metabolism and energy homeostasis, mainly due to the abundance of CB1 receptor expression in brain regions and peripheral tissues involved in the control of feeding behavior and energy balance. CB1 receptors, as well as endocannabinoid producing machinery have been described in the gut [17], liver [18], muscle [19 ], endocrine pancreas [20] and white adipose tissue [21, 22]. In this reg (...truncated)