Loss of transglutaminase 2 sensitizes for diet-induced obesity-related inflammation and insulin resistance due to enhanced macrophage c-Src signaling

Tibor Sághy, Krisztina Köröskényi, Krisztina Hegedűs, M. Antal, Csaba Bankó, Z. Bacsó, Attila Papp, Rinke Stienstra, Z. Szondy

Research output: Contribution to journalArticle

Abstract

Transglutaminase 2 (TG2) is a multifunctional protein that promotes clearance of apoptotic cells (efferocytosis) acting as integrin β3 coreceptor. Accumulating evidence indicates that defective efferocytosis contributes to the development of chronic inflammatory diseases. Obesity is characterized by the accumulation of dead adipocytes and inflammatory macrophages in the adipose tissue leading to obesity-related metabolic syndrome. Here, we report that loss of TG2 from bone marrow-derived cells sensitizes for high fat diet (HFD)-induced pathologies. We find that metabolically activated TG2 null macrophages express more phospho-Src and integrin β3, unexpectedly clear dying adipocytes more efficiently via lysosomal exocytosis, but produce more pro-inflammatory cytokines than the wild type ones. Anti-inflammatory treatment with an LXR agonist reverts the HFD-induced phenotype in mice lacking TG2 in bone marrow-derived cells with less hepatic steatosis than in wild type mice proving enhanced lipid clearance. Thus it is interesting to speculate whether LXR agonist treatment together with enhancing lysosomal exocytosis could be a beneficial therapeutic strategy in obesity.

Original languageEnglish
Article number439
JournalCell Death and Disease
Volume10
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

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Insulin Resistance
Obesity
Macrophages
Diet
Inflammation
Exocytosis
High Fat Diet
Adipocytes
Integrins
Bone Marrow Cells
Adipose Tissue
Chronic Disease
Anti-Inflammatory Agents
Therapeutics
Pathology
Cytokines
Phenotype
Lipids
transglutaminase 2
Liver

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Loss of transglutaminase 2 sensitizes for diet-induced obesity-related inflammation and insulin resistance due to enhanced macrophage c-Src signaling. / Sághy, Tibor; Köröskényi, Krisztina; Hegedűs, Krisztina; Antal, M.; Bankó, Csaba; Bacsó, Z.; Papp, Attila; Stienstra, Rinke; Szondy, Z.

In: Cell Death and Disease, Vol. 10, No. 6, 439, 01.06.2019.

Research output: Contribution to journalArticle

Sághy, Tibor ; Köröskényi, Krisztina ; Hegedűs, Krisztina ; Antal, M. ; Bankó, Csaba ; Bacsó, Z. ; Papp, Attila ; Stienstra, Rinke ; Szondy, Z. / Loss of transglutaminase 2 sensitizes for diet-induced obesity-related inflammation and insulin resistance due to enhanced macrophage c-Src signaling. In: Cell Death and Disease. 2019 ; Vol. 10, No. 6.
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