MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice

Cell Metab. 2021 Apr 6;33(4):781-790.e5. doi: 10.1016/j.cmet.2020.12.019. Epub 2021 Jan 14.

Abstract

Insulin resistance is a major pathophysiologic defect in type 2 diabetes and obesity, while anti-inflammatory M2-like macrophages are important in maintaining normal metabolic homeostasis. Here, we show that M2 polarized bone marrow-derived macrophages (BMDMs) secrete miRNA-containing exosomes (Exos), which improve glucose tolerance and insulin sensitivity when given to obese mice. Depletion of their miRNA cargo blocks the ability of M2 BMDM Exos to enhance insulin sensitivity. We found that miR-690 is highly expressed in M2 BMDM Exos and functions as an insulin sensitizer both in vivo and in vitro. Expressing an miR-690 mimic in miRNA-depleted BMDMs generates Exos that recapitulate the effects of M2 BMDM Exos on metabolic phenotypes. Nadk is a bona fide target mRNA of miR-690, and Nadk plays a role in modulating macrophage inflammation and insulin signaling. Taken together, these data suggest miR-690 could be a new therapeutic insulin-sensitizing agent for metabolic disease.

Keywords: exosomes; insulin sensitivity; macrophages; miR-690; obesity.

Publication types

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

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Animals
  • Antagomirs / metabolism
  • DEAD-box RNA Helicases / deficiency
  • DEAD-box RNA Helicases / genetics
  • Diet, High-Fat
  • Exosomes / metabolism*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Insulin / metabolism
  • Insulin Resistance
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism
  • Obesity / metabolism
  • Obesity / pathology
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Ribonuclease III / deficiency
  • Ribonuclease III / genetics

Substances

  • Antagomirs
  • Insulin
  • MIRN690 microRNA, mouse
  • MicroRNAs
  • RNA, Small Interfering
  • Phosphotransferases (Alcohol Group Acceptor)
  • NAD kinase
  • Dicer1 protein, mouse
  • Ribonuclease III
  • DEAD-box RNA Helicases