A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice
Han, J. H., Shin, H., Park, J. Y., Rho, J. G., Son, D. H., Kim, K. W., ... & Kim, W. (2018). A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice. The FASEB Journal, 33(3), 4314-4326.
Approximately 35% of Americans suffer from obesity and its related health effects. The activation of cannabinoid 1 receptor [CB1R] has been shown to increase body weight, appetite, insulin resistance, and fat cell production. Thus, overactivity of CB1R is associated with obesity and the side effects that come with it, such as type II diabetes. Previously, rimonabant, a CB1R antagonist was developed and approved for use in Europe to improve eating habits as well as metabolic outcomes of patients with obesity. However, rimonabant blocked the activation of CB1R in the brain, which resulted in undesirable and serious neuropsychiatric side effects. This paper describes a new peripheral CB1R antagonist, AJ5012, which displays a significantly lower brain penetrance than rimonabant while remaining effective in improving glycemic control, adipose tissue inflammation, and insulin sensitivity. Multiple experiments on obese mice showed that AJ5012 improved metabolic outcomes independent of weight loss. The results indicate that blocking CB1R outside of the brain can help limit the biochemical repercussions of obesity while also avoiding the negative side effects of brain-penetrant drugs. Although promising, future research should focus on determining the oral bioavailability of AJ5012 and in-depth investigation of other peripheral CB1R antagonists that can more effectively break the connection between adipose tissue inflammation and obesity-induced insulin resistance.
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