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

摘要

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.