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

Abstract

Background/ObjectivesObesity is a pandemic disorder that is characterized by accumulation of adipose tissue and chronic-low grade inflammation that is driven primarily by adipose tissue macrophages (ATMs). While ATM polarization from pro-(M1)to anti-(M2) inflammatory phenotype influences insulin sensitivity and energy expenditure, the mechanisms of such a switch are unclear. In the current study we identified epigenetic pathways including microRNAs (miR) in ATMs that regulate obesity-induced inflammation.Subjects/MethodsMale C57BL/6J mice were fed normal chow diet (NCD) or high-fat diet (HFD) for 16 weeks to develop lean and diet-induced obese mice respectively. Transcriptome microarrays, microRNA microarrays, and meDIP-Seq were performed on ATMs isolated from visceral fat. Pathway analysis and bone marrow derived macrophage (BMDM) transfections further allowed computational and functional analysis of miRNA-mediated ATM polarization.ResultsATMs from HFD-fed mice were skewed towards M1 inflammatory phenotype. Concurrently, the expression of miRs 30a-5p, 30c-5p, and 30e-5p was downregulated in ATMs from HFD mice when compared to mice fed NCD. The miR-30 family was shown to target Delta-like-4, a Notch1 ligand, whose expression was increased in HFD ATMs. Inhibition of miR-30 in conditioned BMDM triggered Notch1 signaling, pro-inflammatory cytokine production, and M1 macrophage polarization. In addition, DNA hypermethylation was observed in mir30-associated CpG islands suggesting HFD downregulates miR-30 through epigenetic modifications.ConclusionsHFD-induced obesity downregulates miR-30 by DNA methylation thereby inducing Notch1 signaling in ATMs and their polarization to M1 macrophages. These findings identify miR-30 as a regulator of pro-inflammatory ATM polarization and suggest miR-30 manipulation could be a therapeutic target for obesity-induced inflammation.