MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages.

Abstract

Abstract Macrophages are innate immune cells that play integral roles in maintenance of adipose tissue homeostasis. Visceral obesity stimulates pro-inflammatory macrophages to infiltrate into adipose tissue causing chronic low-grade inflammation that can lead to insulin resistance and cardiometabolic disorders. Notch signaling is elevated in obesity and serves as a form of communication between macrophages and adipocytes. Blockade of this pathway promotes adipose tissue browning while reducing inflammation and therefore, has therapeutic potential. MicroRNAs (miRNA, miR) are non-coding RNAs that bind the 3′UTR of target mRNAs to repress their translation and miRNA based therapies are presently being developed for clinical purposes. In the current study, we identified differentially expressed miRNAs in adipose tissue macrophages (ATMs) between lean and obese mice by microarray. Array analysis and PCR validation revealed miRNAs -30a-5p, -30c-5p, and -30e-5p were downregulated in obese ATMs suggesting the miR-30 family plays an important role in macrophage phenotype. Pathway analysis demonstrated that miR-30 targeted Notch signaling genes including Delta-like ligand-4 (DLL4), a previously identified therapeutic target for cardiometabolic disorders. It was noted that DLL4 expression was increased on obese ATMs and in vitro miRNA transfection studies further demonstrated that miR-30 modulates Notch signaling-induced inflammation. These data demonstrate for the first time that the miR-30 family may play a critical role in the regulation of DLL4-mediated Notch signaling in ATMs, thereby modulating metabolic inflammation. (Supported in part by NIH grants P01AT003961, R01AT006888, R01ES019313, R01MH094755 and P20GM103641).