Deficiency of Stat1 in CD11c + Cells Alters Adipose Tissue Inflammation and Improves Metabolic Dysfunctions in Mice Fed a High-Fat Diet

Diabetes. 2021 Mar;70(3):720-732. doi: 10.2337/db20-0634. Epub 2020 Dec 15.

Abstract

CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 weeks) had reductions in MDC (mainly CD11c+ macrophage) M1-like polarization and interferon-γ-expressing T-helper type 1 (Th1) cells but increases in interleukin 5-expressing Th2 cells and eosinophils in perigonadal and inguinal AT, and enhanced inguinal AT browning, with increased energy expenditure. cKO mice compared with controls also had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance. Taken together, our results demonstrate that Stat1 in MDCs plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.

Publication types

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

MeSH terms

  • Adipose Tissue / metabolism*
  • Adult
  • Animals
  • Blotting, Western
  • CD11c Antigen / genetics
  • CD11c Antigen / metabolism*
  • Cells, Cultured
  • Diet, High-Fat / adverse effects*
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Interleukin-5 / metabolism
  • Male
  • Mice
  • Obesity / genetics
  • Obesity / immunology*
  • Obesity / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*

Substances

  • CD11c Antigen
  • Interleukin-5
  • STAT1 Transcription Factor

Associated data

  • figshare/10.2337/figshare.13348094