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

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

“…Interestingly, HU210 had no effect on 2-DG uptake in adipose tissue in these experiments, indicating that adipose tissue CB1R plays a negligible role in mediating the acute changes of insulin sensitivity with CB1R agonism/antagonism. Altered glucose and lipid metabolism, and insulin sensitivity have been shown with chronic modulation of CB1R in peripheral tissues, including the liver [18,20]. Our study is complementary to the anticipated long-term effects of CB1R modulation on insulin sensitivity, in that we demonstrate an acute prominent effect on insulin action in muscle.…”

“…Whole-body Cb1r (also known as Cnr1) knockout (Cb1r −/− ) mice are resistant to dietinduced obesity, while wild-type littermates on the same diet with identical energy intake become obese [16]. In addition, there is direct experimental evidence that CB1R antagonism increases energy expenditure in peripheral tissues [14,17,18].…”

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

“…Unfortunately, the centrally mediated side effects, anxiety and depression being the most clinically relevant, preclude the clinical use of Rimonabant and other class-related compounds. However, the results of our study represent a further reason to develop CB1 receptor antagonists with a restricted access to the central nervous system, thus avoiding negative psychotropic actions, 49 and investigate their application in the setting of liver cirrhosis.…”

The Role of the Endocannabinoid System in the Pathogeny of Type 2 Diabetes

“…Nevertheless, emerging evidence supported the idea that interrupting endocannabinoid action selectively only in peripheral tissues may be an approach to treat the metabolic consequences of obesity and related diseases, including type 2 diabetes, without causing the undesirable CNS effects that occurred with rimonabant. The studies of Tam and colleagues brought back the attention to the ECS (Tam et al, 2010). Tam et al first developed a CB1 antagonist (AM6545) that retained binding activity but could not penetrate the brain due to its reduced lipid solubility (Tam et al, 2010).…”

“…The studies of Tam and colleagues brought back the attention to the ECS (Tam et al, 2010). Tam et al first developed a CB1 antagonist (AM6545) that retained binding activity but could not penetrate the brain due to its reduced lipid solubility (Tam et al, 2010). Therefore, it could not block the CB1 receptors in the CNS.…”