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

Ji H. Han, Hanho Shin, Jun G. Rho, Jung Eun Kim, Dong H. Son, Juhwan Yoon, Yong J. Lee, Jung Hyuck Park, Byung J. Song, Chang Sik Choi, Seul G. Yoon, Il Y. Kim, Eun K. Lee, Je K. Seong, Ki W. Kim, Wook Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2179-2189
Number of pages11
JournalDiabetes, Obesity and Metabolism
Volume20
Issue number9
DOIs
Publication statusPublished - 2018 Sep

Fingerprint

rimonabant
Inflammasomes
Cannabinoid Receptors
Adipose Tissue
Obesity
Inflammation
Brain
Cannabinoid Receptor Antagonists
Diet
Obese Mice
White Adipose Tissue
Penetrance
Insulin Resistance
Macrophages
Cytokines

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Han, Ji H. ; Shin, Hanho ; Rho, Jun G. ; Kim, Jung Eun ; Son, Dong H. ; Yoon, Juhwan ; Lee, Yong J. ; Park, Jung Hyuck ; Song, Byung J. ; Choi, Chang Sik ; Yoon, Seul G. ; Kim, Il Y. ; Lee, Eun K. ; Seong, Je K. ; Kim, Ki W. ; Kim, Wook. / Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity. In: Diabetes, Obesity and Metabolism. 2018 ; Vol. 20, No. 9. pp. 2179-2189.
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title = "Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity",
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.",
author = "Han, {Ji H.} and Hanho Shin and Rho, {Jun G.} and Kim, {Jung Eun} and Son, {Dong H.} and Juhwan Yoon and Lee, {Yong J.} and Park, {Jung Hyuck} and Song, {Byung J.} and Choi, {Chang Sik} and Yoon, {Seul G.} and Kim, {Il Y.} and Lee, {Eun K.} and Seong, {Je K.} and Kim, {Ki W.} and Wook Kim",
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Han, JH, Shin, H, Rho, JG, Kim, JE, Son, DH, Yoon, J, Lee, YJ, Park, JH, Song, BJ, Choi, CS, Yoon, SG, Kim, IY, Lee, EK, Seong, JK, Kim, KW & Kim, W 2018, 'Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity', Diabetes, Obesity and Metabolism, vol. 20, no. 9, pp. 2179-2189. https://doi.org/10.1111/dom.13350

Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity. / Han, Ji H.; Shin, Hanho; Rho, Jun G.; Kim, Jung Eun; Son, Dong H.; Yoon, Juhwan; Lee, Yong J.; Park, Jung Hyuck; Song, Byung J.; Choi, Chang Sik; Yoon, Seul G.; Kim, Il Y.; Lee, Eun K.; Seong, Je K.; Kim, Ki W.; Kim, Wook.

In: Diabetes, Obesity and Metabolism, Vol. 20, No. 9, 09.2018, p. 2179-2189.

Research output: Contribution to journalArticle

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T1 - Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity

AU - Han, Ji H.

AU - Shin, Hanho

AU - Rho, Jun G.

AU - Kim, Jung Eun

AU - Son, Dong H.

AU - Yoon, Juhwan

AU - Lee, Yong J.

AU - Park, Jung Hyuck

AU - Song, Byung J.

AU - Choi, Chang Sik

AU - Yoon, Seul G.

AU - Kim, Il Y.

AU - Lee, Eun K.

AU - Seong, Je K.

AU - Kim, Ki W.

AU - Kim, Wook

PY - 2018/9

Y1 - 2018/9

N2 - 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.

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