A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice

What is it about?

The endocannabinoid (EC) tone, owing to increased EC synthesis or cannabinoid 1 receptor (CB1R) expression or activity, is elevated in obesity and type 2 diabetes, and chronic blockade of CB1R with brain-penetrant CB1R antagonists such as rimonabant induces weight loss and improves metabolic abnormalities. However, their therapeutic development was discontinued due to undesirable neuropsychiatric side effects. There is an increasing body of evidence to indicate that the beneficial effects on metabolic parameters and feeding behavior are mediated by peripheral CB1R blockade, whereas the neuropsychiatric side effects are caused by the blockade of CB1R in the brain. To reduce their brain penetrance, we generated AJ5012 by modifying the structure of rimonabant and evaluated it as a novel peripherally restricted CB1R antagonist. AJ5012 had a higher degree of selectivity for CB1R over CB2R and markedly reduced brain penetrance without eliciting centrally mediated neurobehavioral effects. In mouse models with genetic or diet-induced obesity, AJ5012 exhibited comparable beneficial effects with rimonabant in terms of hyperglycemia, dyslipidemia, hepatic steatosis, energy expenditure, and insulin resistance. Moreover, the peripheral CB1R blockade by AJ5012 suppressed the activation of the NLRP3 inflammasome and the resultant adipose tissue inflammation in mouse models with obesity. In addition to macrophage, activation of CB1R in 3T3-L1 adipocyte induced the expression of proinflammatory genes, which was fully inhibited by AJ5012. Our results suggest that the blockade of peripheral CB1R may break the links between adipose tissue inflammation and obesity-induced insulin resistance by reversing NLRP3 inflammasome activity.

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