Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells

Front Immunol. 2019 May 10:10:1049. doi: 10.3389/fimmu.2019.01049. eCollection 2019.

Abstract

Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders.

Keywords: CB1; DLL4; Notch; Th1; macrophage; miR-30e-5p; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adipose Tissue / pathology*
  • Animals
  • Calcium-Binding Proteins / metabolism*
  • Diet, High-Fat
  • Inflammation / immunology
  • Inflammation / pathology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • MicroRNAs / genetics
  • MicroRNAs / physiology
  • Obesity / pathology*
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Th1 Cells / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • CNR1 protein, mouse
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • MIRN30e microRNA, mouse
  • MicroRNAs
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251