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

Han, Ji Hye; Shin, Hanho; Rho, Jun Gi; Kim, Jung Eun; Son, Dong Hoon; Yoon, Jong Han; Lee, Yong J.; Park, Jung Hyuck; Song, Byeong Jun; Choi, Chang Sik; Yoon, Seul Gi; Kim, Il Y.; Lee, Eun K.; Seong, Je Kyung; Kim, Ki Woo; Kim, Wook

doi:10.1111/dom.13350

Cited by 28 publications

(30 citation statements)

References 39 publications

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“…Monocyte chemotactic protein 1 secretion was not affected by the knockdown of IRF5 (25). Similar to the previous reports (25,33), our results also showed that and the CB1Rinduced expression of Mcp1, Nlrp3, and Il1b in macrophages was regulated by the p38 MAPK-dependent pathways. In addition to affecting the expression levels of Nlrp3 and Il1b, it is likely that CB1R can directly cause NLRP3 inflammasome activation.…”

Section: Discussionsupporting

confidence: 91%

“…S6A-E). Similar to previous reports (24,25,33), AEA-induced expression of Mcp1, Nlrp3, and Il1b were suppressed by the p38 MAPK inhibitor, SB202190 (Supplemental Fig. S6C-E).…”

Section: Increased Energy Expenditure By Aj5012 In Dio Micesupporting

confidence: 90%

“…It was reported that the CB1R-induced elevation in TNF-a and IL-1b production and NLRP3 expression is mediated by the transcription factor IRF5 and that this effect was dependent on the pertussis toxin (25,33). We also found that the increased levels of IRF5 in the eWAT of DIO mice were reduced by AJ5012 and rimonabant.…”

Section: Discussionsupporting

confidence: 67%

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A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice

et al. 2018

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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). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 91%

“…S6A-E). Similar to previous reports (24,25,33), AEA-induced expression of Mcp1, Nlrp3, and Il1b were suppressed by the p38 MAPK inhibitor, SB202190 (Supplemental Fig. S6C-E).…”

Section: Increased Energy Expenditure By Aj5012 In Dio Micesupporting

confidence: 90%

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A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice

et al. 2018

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“…For instance, AJ5012 (10-20 mg/kg/day), a peripheral CB1 antagonist, was reported to cause a significant weight loss, increase energy expenditure, ameliorate glycemic control and insulin sensitivity, and to reduce inflammation in rodent model [219]. Similarly, AJ5018 (10 mg/kg/day) was shown to improve metabolic abnormalities and suppress adipose tissue inflammation via moderation of macrophage infiltration, activation of the NLRP3 inflammasome, and reducing production of pro-inflammatory cytokines in mice [220]. Neither compound elicits neurobehavioral adverse effects due to low brain penetrance.…”

Section: Obesitymentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

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“…In addition, researchers could induce activation of the NLRP3 inflammasome directly via the TLR4 signaling pathway without the need for other secondary activators [13]. NLRP3 inflammasome responds to a variety of infectious and endogenous ligands and is involved in a variety of autoimmune diseases, such as obesity [14], diabetes mellitus [15,16], arthritis [17,18], and Alzheimer's disease [19]. for life [6].…”

Section: The Nlrp3 Inflammasomementioning

confidence: 99%

Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes

Ding

et al. 2019

Biomolecules

157

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The inflammasome is a multiprotein complex that acts to enhance inflammatory responses by promoting the production and secretion of key cytokines. The best-known inflammasome is the NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome. The evidence has shown that the NLRP3 inflammasome, IL-1β, thioredoxin-interacting protein (TXNIP), and pyroptosis play vital roles in the development of diabetes. This review summarizes the regulation of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) by NLRP3 via modulation of glucose tolerance, insulin resistance, inflammation, and apoptosis mediated by endoplasmic reticulum stress in adipose tissue. Moreover, NLRP3 participates in intestinal homeostasis and inflammatory conditions, and NLRP3-deficient mice experience intestinal lesions. The diversity of an individual’s gut microbiome and the resultant microbial metabolites determines the extent of their involvement in the physiological and pathological mechanisms within the gut. As such, further study of the interaction between the NLRP3 inflammasome and the complex intestinal environment in disease development is warranted to discover novel therapies for the treatment of diabetes.

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

Abstract: These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.

Cited by 28 publications

References 39 publications

A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice

A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice

A Guide to Targeting the Endocannabinoid System in Drug Design

Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes

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