MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages Cell Biology/Molecular Biology

• Published in: International Journal of Obesity Vol. 42; no. 6; pp. 1140 - 1150
• Main Authors: Miranda, Kathryn, Yang, Xiaoming, Bam, Marpe, Murphy, E. Angela, Nagarkatti, Prakash S., Nagarkatti, Mitzi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2018
• Subjects: 13/1; 13/109; 13/21; 13/31; 13/51; 13/95; 14/19; 38/22; 38/23; 38/39; 38/61; 38/77; 38/90; 631/1647/334/1874/345; 631/250; 631/80; 64/60; 692/308/2778; 82/80; Epidemiology; Health Promotion and Disease Prevention; Internal Medicine; Medicine; Medicine & Public Health; Metabolic Diseases; Public Health
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/s41366-018-0114-1

Background/objectives: Obesity 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/methods: Male 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. Results: ATMs from HFD-fed mice were skewed toward 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 that HFD downregulates miR-30 through epigenetic modifications. Conclusions: HFD-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 that miR-30 manipulation could be a therapeutic target for obesity-induced inflammation.