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Cell Biology/Molecular Biology

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

International Journal of Obesity volume 42, pages 1140–1150 (2018)Cite this article

Subjects

Abstract

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.

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Acknowledgements

The authors would like to thank Dr. Robert Price, Ph.D., and Director of the University of South Carolina Instrumentation Resource Facility for his kind assistance with confocal microscopy acquisition.

Author contributions

Conceptualization: KM, PSN, and MN; methodology: KM, EAM, PSN, and MN; validation: KM; formal analysis: KM and XY; investigation: KM, XY, and MB; resources: PSN and MN; writing—original draft: KM; writing—review and editing: KM, MB, PSN, and MN; visualization: KM; supervision: PSN and MN; funding acquisition: PSN and MN.

Funding

The authors would also like to acknowledge funding sources from the NIH: R01ES019313, R01MH094755, R01AI123947, R01AI129788, P01AT003961, P20GM103641, R01AT006888.

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Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA

    Kathryn Miranda, Xiaoming Yang, Marpe Bam, E. Angela Murphy, Prakash S. Nagarkatti & Mitzi Nagarkatti

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  1. Kathryn Miranda
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Correspondence to Mitzi Nagarkatti.

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Miranda, K., Yang, X., Bam, M. et al. MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages. Int J Obes 42, 1140–1150 (2018). https://doi.org/10.1038/s41366-018-0114-1

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