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

Int J Obes (Lond). 2018 Jun;42(6):1140-1150. doi: 10.1038/s41366-018-0114-1. Epub 2018 Jun 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / pathology
  • Analysis of Variance
  • Animals
  • Disease Models, Animal
  • Inflammation / metabolism
  • Inflammation / physiopathology*
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / physiology*
  • Obesity / genetics
  • Obesity / metabolism*
  • Receptor, Notch1 / physiology*
  • Signal Transduction
  • Thinness / genetics
  • Thinness / metabolism*

Substances

  • MicroRNAs
  • Mirn30d microRNA, mouse
  • Notch1 protein, mouse
  • Receptor, Notch1