Role of microRNA in CB1 antagonist–mediated regulation of adipose tissue macrophage polarization and chemotaxis during diet-induced obesity

Abstract

Although cannabinoid receptor 1 (CB1) antagonists have been shown to attenuate diet-induced obesity (DIO) and associated inflammation, the precise molecular mechanisms involved are not clear. In the current study, we investigated the role of microRNA (miR) in the regulation of adipose tissue macrophage (ATM) phenotype following treatment of DIO mice with the CB1 antagonist SR141716A. DIO mice were fed high-fat diet (HFD) for 12 weeks and then treated daily with SR141716A (10 mg/kg) for 4 weeks while continuing HFD. Treated mice experienced weight loss, persistent reduction in fat mass, improvements in metabolic profile, and decreased adipose inflammation. CB1 blockade resulted in down-regulation of several miRs in ATMs, including the miR-466 family and miR-762. Reduced expression of the miR-466 family led to induction of anti-inflammatory M2 transcription factors KLF4 and STAT6, whereas down-regulation of miR-762 promoted induction of AGAP-2, a negative regulator of the neuroimmune retention cues, Netrin-1 and its coreceptor UNC5B. Furthermore, treatment of primary macrophages with SR141716A up-regulated KLF4 and STAT6, reduced secretion of Netrin-1, and increased migration toward the lymph node chemoattractant CCL19. These studies demonstrate for the first time that CB1 receptor blockade attenuates DIO-associated inflammation through alterations in ATM miR expression that promote M2 ATM polarization and macrophage egress from adipose tissue. The current study also identifies additional novel therapeutic targets for diet-induced obesity and metabolic disorder.

RETRACTED ARTICLE: microRNA-128 mediates CB1 expression and regulates NF-KB/p-JNK axis to influence the occurrence of diabetic bladder disease

“…We adopt miR-128 inhibition to significantly improve the occurrence of diabetic bladder disease in rats and we have found for the first time that miR-128 can target the inhibition of CB1 expression. Previous studies have shown that CB1 can cause Inflammation, inflammation plays an important role in the development of diabetes [27]. Our high expression of CB1 can antagonize the promotion of miR-128 on the occurrence of diabetic bladder disease.…”

“…miR-128 inhibits growth and mediates differentiation by targeting oncogenic receptor tyrosine kinase (RTK) epithelial growth factor receptor and platelet-derived growth factor receptor alpha. [12] miR-128 is a glioma tumor suppressor that targets RTK signaling to inhibit giNSC self-renewal and enhance differentiation [27]. These results suggest that miR-128 plays a key role in DCP.…”

A review on the biology and properties of adipose tissue macrophages involved in adipose tissue physiological and pathophysiological processes

“…It has been indicated that IL-25 stimulates alternatively activated macrophages and their interaction with adipocytes but promotes energy metabolism, enhances mitochondrial functions and attenuates lipid accumulation in the liver and adipose tissues [ 22 ]. In addition, cannabinoid receptor 1 (CB1) blockade resulted in downregulation of miR-466 family and miR-762 in ATMs, which promote M2 polarization and macrophage egress from adipose tissue [ 23 ]. Empagliflozin, a sodium-glucose cotransporter (SGLT) 2 inhibitor, repressed weight gain by enhancing browning of adipocytes and alleviated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and the liver [ 24 ].…”

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs

“…Reductions in weight and fat mass after four weeks were again significant in rimonabant-treated DIO mice fed a high-fat diet, yet lean tissue mass was retained and not significantly different to the vehicle treated-mice (20.08 ± 0.29 g vs. 22.9 ± 0.11 g). Furthermore, rimonabant proved to decrease inflammation by downregulating several microRNAs in adipose tissue macrophages, inducing an anti-inflammatory cascade [ 48 ].…”