Characterization of AJ5012 as a Novel Peripheral Cannabinoid 1 Receptor Antagonist in Mouse Models of Obesity

Obesity-induced adipose tissue inflammation, in which the NLRP3 inflammasome is a pivotal mediator, is implicated in the development of insulin resistance. Cannabinoid 1 receptor (CB1R) antagonists have been shown to improve insulin resistance and the associated metabolic abnormalities, but their therapeutic development was discontinued due to neuropsychiatric side effects. Although growing evidence suggests the role of CB1Rs in proinflammatory signaling, their direct effects on adipose tissue inflammation have not yet been evaluated. Here we report that the peripherally restricted CB1R antagonist AJ5012, which exhibits beneficial metabolic effects comparable with its brain-penetrant parent compound rimonabant, suppresses macrophage infiltration into white adipose tissue, activation of the NLRP3 inflammasome, and production of proinflammatory cytokines in diet-induced obese mice. Moreover, we identified the downstream signaling pathways by which CB1R regulates proinflammatory gene expression. These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.