GRP94 regulates M1 macrophage polarization and insulin resistance

Am J Physiol Endocrinol Metab. 2020 Jun 1;318(6):E1004-E1013. doi: 10.1152/ajpendo.00542.2019. Epub 2020 Mar 24.

Abstract

Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.

Keywords: GRP94; insulin sensitivity; macrophage polarization.

Publication types

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

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism
  • Animals
  • Coculture Techniques
  • Cytokines / genetics
  • Cytokines / immunology
  • Diet, High-Fat*
  • Glucose Tolerance Test
  • Inflammation / genetics
  • Inflammation / immunology
  • Insulin Resistance / genetics*
  • Insulin Resistance / immunology
  • Interferon-gamma / pharmacology
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation / genetics*
  • Macrophage Activation / immunology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Knockout
  • Obesity / genetics
  • Obesity / immunology*
  • Obesity / metabolism
  • RNA, Messenger / metabolism

Substances

  • Cytokines
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • RNA, Messenger
  • endoplasmin
  • Interferon-gamma