1. Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity
- Author
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Eun Kyung Lee, Seul Gi Yoon, Chang Sik Choi, Hanho Shin, Dong H. Son, Jung Hyuck Park, Ki Woo Kim, Jung Eun Kim, Jun Gi Rho, Wook Kim, Ji H. Han, Juhwan Yoon, Je K. Seong, Il Yong Kim, Byung Joo Song, and Yong J. Lee
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Inflammasomes ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,Mice, Obese ,Inflammation ,White adipose tissue ,Proinflammatory cytokine ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Mice ,Endocrinology ,Insulin resistance ,Rimonabant ,Internal medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,Internal Medicine ,Medicine ,Animals ,Obesity ,Cannabinoid Receptor Antagonists ,business.industry ,Macrophages ,Antagonist ,Brain ,Inflammasome ,medicine.disease ,030104 developmental biology ,Adipose Tissue ,medicine.symptom ,Insulin Resistance ,business ,medicine.drug - Abstract
Aim To analyze the metabolic parameters and adipose tissue inflammation via NLRP3 inflammasome following chronic treatment of mouse models of obesity with AJ5018 as the peripherally restricted cannabinoid 1 receptor (CB1R) antagonist. Materials and methods The selectivity for CB1R over CB2R, brain/plasma concentration ratio, and centrally mediated neurobehavioural effects of AJ5018, were assessed. The long-term effects of AJ5018 and rimonabant on the metabolic parameters and adipose tissue inflammation were analyzed in diet-induced obese (DIO) mice and diabetic db/db mice. Results AJ5018 had a higher degree of selectivity for CB1R over CB2R and markedly reduced brain penetrance, as reflected by the lower brain/plasma concentration ratio and the attenuated centrally mediated neurobehavioural effects, compared with its brain-penetrant parent compound rimonabant. In DIO and db/db mice, AJ5018 exhibited comparable effects to rimonabant in improving metabolic abnormalities and suppressing macrophage infiltration into white adipose tissue, activation of the NLRP3 inflammasome, and production of proinflammatory cytokines. Conclusions These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.
- Published
- 2017