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

Abstract

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

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Recently, significant research has been conducted on peripherally restricted CB1 antagonists or inverse agonists [218]. 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].…”

CB1 Receptor-Dependent and Independent Induction of Lipolysis in Primary Rat Adipocytes by the Inverse Agonist Rimonabant (SR141716A)

“…Those exceed the C max of Rimonabant in the serum of treated mice by two to three orders of magnitude and may be sufficient for initiation of its direct CB1R-dependent and/or independent lipolytic activity. Nevertheless, the direct CB1R-independent lipolytic activity of Rimonabant as detectable in vitro might be of minor importance in vivo since (i) Rimonabant has been shown to exert no significant effects on body weight gain, adipose tissue mass and cellular adiposity in CB1R knockout mice fed a high-fat diet, which are lean and resistant to diet-induced obesity [54], (ii) the transcriptional patterns in white adipose tissue and lipolysis stimulation are similar between Rimonabant-treated obese and high fat diet-fed CB1R knockout mice [55] and (iii) other known direct Rimonabant effects on adipocytes, as manifested in the induction of mRNA and protein expression, as well as in the secretion of adiponectin in cultured mouse 3T3 F442A adipocytes, were recapitulated in the adipose tissue of Rimonabant-treated wild type, but not CB1R knockout mice [28]. Thus, the available animal data favour a CB1R-mediated mechanism for the upregulation of adipocyte lipolysis during acute Rimonabant treatment, such as nervous stimulation in response to antagonism of hypothalamic CB1R, albeit a comparative analysis of serum FA levels between Rimonabant-treated wild type and CB1R knockout mice is still missing.…”

“…Addressing the CB1R and/ or LD at adipose tissue, exclusively, has the crucial advantage of bypassing putative psychiatric side effects in course of engagement of hypothalamic CB1R. In fact, a novel potent CB1R antagonist, which has a low brain-to-plasma concentration distribution and does not exhibit centrally mediated neurobehavioral effects, was recently found to trigger significant weight loss and improvement of glycemic control, insulin sensitivity and adipose tissue inflammation in the absence of relevant reduction of food intake [55]. In addition, a different and strictly peripheral CB1R antagonist was demonstrated to increase the expression of genes involved in brown adipose tissue thermogenesis, to decrease the LD size in brown adipocytes and to enhance uncoupled respiration [19].…”

Flufenamic acid alleviates sepsis‐induced lung injury by up‐regulating CBR1

“…Tat‐CBR1 reduced the expression of pro‐inflammatory cytokines by suppressing the expression of NF‐κB and mitogen activated protein kinase (MAPK) (Kim et al, 2015). Many studies also demonstrated that CBR1 could reduce inflammation in ocular (Thapa and Cairns 2020), obesity (Han et al, 2019; Grunewald et al, 2019) and rheumatoid arthritis synovial fibroblasts (Fechtner and Ahmeds 2017). Therefore, FFA alleviated the inflammation and oxidative stress partially by up‐regulating the CBR1 expression.…”