Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Abstract

Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB 1 R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB 1 R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB 1 R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB 1 R in peripheral tissues, including the liver, as verified through the use of CB 1 R-deficient mice with or without transgenic expression of CB 1 R in the liver. These results suggest that targeting peripheral CB 1 R has therapeutic potential for alleviating cardiometabolic risk in obese patients. IntroductionEndocannabinoids are endogenous lipid mediators that interact with the same G protein-coupled receptors - CB 1 R and CB 2 R - that recognize plant-derived cannabinoids, and they regulate a broad range of physiological functions. CB 1 Rs are expressed at very high levels in the brain but are also present at much lower yet functionally relevant concentrations in various peripheral tissues, whereas the expression of CB 2 Rs is largely limited to cells of the immune and hematopoietic systems. Activation of CB 1 R results in increased appetite, insulin resistance, and increased hepatic lipogenesis, which suggests the involvement of the endocannabinoid/ CB 1 R system in obesity and its metabolic consequences (1). Indeed, obesity and its metabolic complications are characterized by an overactive endocannabinoid system (2-5), and chronic treatment with CB 1 R antagonists leads to weight loss and improved cardiometabolic risk profile in obese rodents (6, 7) and humans (8-11). However, concern over neuropsychiatric side effects, including anxiety, depression, and suicidal ideation (12), prevented approval of the first-in-class CB 1 R antagonist rimonabant in the United States and led to its withdrawal from the European market as well as the withdrawal of related compounds from preclinical development (13). Although the exact role of the endocannabinoid system in the control of mood and anxiety-like behaviors is not clear, CB 1 R in the prefrontal cortex, amygdala, and the mesolimbic dopaminergic reward pathway have been linked to the control of these behaviors (14). On the other hand, CB 1 Rs are also present in peripheral tissues including the liver (15-17), skeletal muscle (18,19), endocrine

Is fat taste ready for primetime?

“…We confirmed that rats strongly prefer emulsions containing 18:2 FA (5% + 20% vol/vol mineral oil) to those containing only mineral oil (25% vol/vol) in the 30 min sham two-bottle choice test [46]. We then pretreated separate groups of sham feeding rats with the peripherally restricted CB 1 R antagonists, AM6545 [85–87], or URB447 [38, 88], and presented 18:2 FA and mineral oil emulsions in the sham two-bottle choice test. Blocking peripheral CB 1 Rs inhibited the robust preferences displayed for 18:2 FA versus mineral oil alone.…”

Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

“…The association of increased feeding with cannabis use resulted in the development of CB 1 receptor antagonists/inverse agonists for weight loss and the approval (later retracted because of the potential for psychiatric side effects) of the ligand rimonabant (65). Despite this, the contribution of CB 1 receptors to energy balance and fat storage in the periphery has suggested that peripherally restricted CB 1 receptor antagonists/inverse agonists might well have clinical potency without the central nervous system liabilities (65)(66)(67). Peripherally restricted CB 1 agonists have also been promoted as potential therapeutic agents in both inflammatory and neuropathic pain (55).…”

A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans

“…In fact, because of the adverse side effects found in the clinical use of Rimonabant (a CB1 antagonist/inverse agonist capable of crossing the blood-brain barrier) for the management of obesity complications, peripheral-restricted CB1 antagonists are becoming a hottopic in the search for new drugs against obesity-related diseases (Bermudez-Silva et al 2010). Indeed, some of these new kinds of drugs have recently shown promising results in animal studies (Tam et al 2010). Interestingly, Rimonabant and AM251 (another CB1 antagonist/inverse agonist capable of crossing the blood-brain barrier) have been reported to activate GPR55, suggesting that some of the effects elicited by these drugs could be mediated by this receptor (Kapur et al 2009, Henstridge et al 2010.…”