The overactivity of cannabinoid 1 receptor (CB1R) is associated with obesity and type 2 diabetes. First-generation CB1R antagonists, such as rimonabant, offered therapeutic advantages for the control of obesity and related metabolic abnormalities, but their therapeutic potential was limited by undesirable neuropsychiatrie side effects. Here, we evaluated AJ5012 as a novel potent peripheral CB1R antagonist and, using this antagonist, investigated the role of peripheral CB1R on adipose tissue inflammation in obese mouse models. AJ5012 had a high degree of CB1R and cannabinoid 2 receptor selectivity but a low brain:plasma concentration ratio without eliciting centrally mediated neurobehavioral effects. In diet-induced obese (DIO) mice, AJ5012 did not reduce food intake but did induce a significant weight loss, likely owing to an increased energy expenditure. It was as effective as rimonabant for the improvement of hormonal or metabolic abnormalities, glycemic control, and insulin sensitivity. The treatment of DIO and leptin receptor–deficient mice with AJ5012 also exhibited effects comparable to rimonabant for the prevention of macrophage infiltration, activation of the nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome, and production of proinflammatory cytokines, which resulted in the suppression of adipose tissue inflammation. In addition to macrophage, activation of CB1R in 3T3-L1 adipocytes induced the expression of proinflammatory genes, which was fully inhibited by AJ5012. Our findings identified AJ5012 as a novel peripheral CB1R antagonist and suggest that peripheral CB1R blockade might break the links between insulin resistance and adipose tissue inflammation.—Han, J. H., Shin, H., Park, J.-Y., Rho, J. G., Son, D. H., Kim, K. W., Seong, J. K., Yoon, S.-H., Kim, W. A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice. FASEB J. 33, 4314–4326 (2019). www.fasebj.org.
Bibliographical noteFunding Information:
The authors thank the Korea Mouse Phenotyping Center for support with indirect calorimetry; Jung-Hyuck Park, Byungjeong Song, and Chang-Sik Choi (JW Pharmaceutical, Seoul, South Korea) for assistance with the measurement of antagonist levels; and JaeSung Yang and JaeSung Hwang (Dong-A ST Research Center, Youngin, South Korea) for assistance with the measurement of polar surface area and atom-based logarithm of the partition coefficient between n-octanol and water. J.K.S. was supported by the BK21 PLUS Program for Creative Veterinary Science Research, Interdisciplinary Program for Bioinformatics, and Program for Cancer Biology and Bio-Max/N-Bio Institute of Seoul National University. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science and ICT (Grants 2013M3A9D5072550 and 2016R1E1A1A01941213) and the Ministry of Education (Grant 2009-0093826). The authors declare no conflicts of interest.
All Science Journal Classification (ASJC) codes
- Molecular Biology