Anti-inflammatory role of cannabinoid receptor type 1 antagonist AM251 in high fat diet-induced obesity— a focus on microRNAs

Obesity is a major health problem in the U.S. that continues to increase in prevalence. Excessive calorie consumption leads to expansion of adipose tissue through both hypertrophy and hyperplasia. As a result, adipocytes die and macrophages infiltrate into the adipose tissue to repair damage. Activation and infiltration of immune cells contribute to the chronic low-grade inflammation present in obesity. Immune cells express cannabinoid receptors that regulate inflammation. In this study, a mouse model of high fat diet-induced obesity was used to determine the effect the CB1 receptor antagonist AM251 has on adipose tissue inflammation. C57BL6 mice were fed a high fat diet (HFD) for twelve weeks to induce obesity and then given AM251 (10mg/kg/day) oral gavage for four weeks while continuing HFD. Treatment improved metabolic parameters while reducing fat mass and pro-inflammatory cytokine production. To further investigate the anti-inflammatory effects of AM251, infiltrating F4/80+ cells were isolated from epididymal fat and used for microRNA microarray. Nine miRNAs were differentially expressed as a result of AM251 treatment. These miRNAs were analyzed using Ingenuity Pathway Analysis software (Qiagen) and were found to significantly affect the “Inflammatory Disease and Inflammatory Response” pathways. Upregulated miRNAs such as miR-466i-3p were found to target macrophage polarization genes including Pik3r1. The current study suggests that CB1 antagonists may mediate anti-inflammatory effects and amelioration of obesity through regulation of miRNA expression. (Supported in parts by NIH grants P01AT003961, R01AT006888, R01ES019313, R01MH094755, P20GM103641, and Veterans Affairs Merit Award BX001357.)