Netrin-1 mediates macrophage retention in adipose tissue through AGAP-2 interaction with the dependence receptor UNC5B via miR-762 and miR-346

Abstract

Abstract Retention of Macrophages in adipose tissue is associated with high expression of neuroimmune guidance cue Netrin-1 and its receptor UNC5B which are involved in chemotaxis. Cannabinoid receptor1 (CB1) receptors are known to regulate the immune response. We have shown previously that treatment of mice with SR141716A, a CB1 antagonist, attenuates obesity. To further investigate the mechanisms, Diet-Induced Obesity (DIO) was generated by feeding C57BL/6J mice with high-fat diet (HFD) whereas their lean, age-matched controls were fed low-fat diet (LFD). HFD-fed mice were treated with either SR141716A (10mg/kg/day) or vehicle by daily oral gavage for 4 weeks starting at week 12. Our data demonstrated that SR141716A suppressed diet intake transiently, however weight loss and reduction in fat mass was persistent. Suppression of pro-inflammatory macrophages was observed in SR141716A-treated HFD-fed group followed by down regulation of Netrin-1 and UNC5B in macrophages. In silico analysis demonstrated that miRs induced by SR141716A regulated several pathways including macrophage migration. miR-762 and miR-346 which were down regulated following SR141716A treatment were found to be complementary to the 3′-UTR of AGAP-2 gene. SR141716A regulated AGAP-2 expression and its association with UNC5B and inhibited UNC5B-provoked macrophage retention in adipose tissue, and subsequently ameliorated insulin resistance. Thus, for the first time we demonstrate that blockade of CB1 receptors leads to altered chemotaxis balance of adipose tissue macrophages leading to amelioration of obesity.