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Diabetes Obes Metab. 2018 Sep;20(9):2179-2189. doi: 10.1111/dom.13350. Epub 2018 Jun 5.

Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity.

Author information

1
Department of Molecular Science & Technology, Ajou University, Suwon, South Korea.
2
Department of Oral Biology, BK21 PLUS, Yonsei University College of Dentistry, Seoul, South Korea.
3
Department of Pharmacology, CKD Research Institute, Yongin, South Korea.
4
JW Pharmaceutical, Seoul, South Korea.
5
Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
6
Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, South Korea.
7
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
8
Interdisciplinary Program for Bioinformatics, Program for Cancer Biology and BIO-MAX/N-Bio Institute, Seoul National University, Seoul, South Korea.

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.

KEYWORDS:

adipose tissue inflammation; insulin resistance; obesity; peripheral cannabinoid 1 receptor

PMID:
29740969
DOI:
10.1111/dom.13350
[Indexed for MEDLINE]

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