CB2R agonist JWH-133 attenuates chronic inflammation by restraining M1 macrophage polarization via Nrf2/HO-1 pathway in diet-induced obese mice.

Abstract

AIMS:

Cannabinoid receptor 2 (CB2R) is an important regulator of immunoinflammatory responses. Interestingly, studies have demonstrated that CB2R was expressed in metabolically active tissue, so we speculated that CB2R might have a crucial impact on energy balance. We thus examined the anti-inflammatory activities of CB2R and a CB2R agonist, JWH-133, in diet-induced obese in mice as well as in cultured macrophages.

MATERIALS AND METHODS:

We evaluated the in vivo effect of JWH-133 on diet-induced adipose tissue inflammation. We also assessed the in vitro effects of JWH-133 on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages, with a focus on the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway.

KEY FINDINGS:

We found that JWH-133 reduced body weight gain, relieved glucose tolerance, and enhanced insulin sensitivity in a mouse model. It also down-regulated the expression of M1 macrophage biomarkers (tumor necrosis factor-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-1β, CC motif chemokine ligand 2, and C-X-C motif chemokine 10) in vivo and in vitro, but up-regulated levels of M2 macrophage biomarkers (IL-10 and arginase-1) in both mice and cultured macrophages. Furthermore, the underlying mechanisms were studied in an LPS-treated RAW264.7 cell line. We found a role for JWH-133 in controlling M1 macrophage polarization by activating the Nrf2/HO-1 pathway, while the effect of JWH-133 was diminished by a HO-1 inhibitor, Sn(IV) protoporphyrin IX dichloride.

SIGNIFICANCE:

JWH-133 showed anti-obesity effects that ameliorated pro-inflammatory M1 macrophage polarization through the Nrf2/HO-1 pathway. Therefore, our results provide a new proof for the potential use of the CB2R agonist, JWH-133, in the treatment of obesity.

• Authors: Qiong Wu, Yanan Ma, Yang Liu, Ningning Wang, Xin Zhao, Deliang Wen
• Journal: Life sciences (Life Sci) Vol. 260 Pg. 118424 (Nov 01 2020) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 32949586 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Cannabinoids
• Cytokines
• Lipopolysaccharides
• Membrane Proteins
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Receptor, Cannabinoid, CB2
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Glucose
• 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC

Topics

• Adipocytes (drug effects, pathology)
• Animals
• Body Weight (drug effects)
• Cannabinoids (pharmacology)
• Cell Polarity (drug effects)
• Cytokines (genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Gene Expression (drug effects)
• Glucose (metabolism)
• Heme Oxygenase-1 (metabolism)
• Inflammation (drug therapy, etiology)
• Lipopolysaccharides (toxicity)
• Macrophages (drug effects, metabolism, pathology)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• NF-E2-Related Factor 2 (metabolism)
• Obesity (complications, etiology, pathology)
• Panniculitis (drug therapy, pathology)
• RAW 264.7 Cells
• Receptor, Cannabinoid, CB2 (agonists)