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

Tibor Sághy,Miklós Antal,Krisztina Hegedűs,Csaba Bankó,Rinke Stienstra,Krisztina Köröskényi,Zsolt Bacsó,Zsuzsa Szondy,Attila Papp

doi:10.1038/s41419-019-1677-z

Tibor Sághy, Miklós Antal + Show 7 more

Open Access

https://doi.org/10.1038/s41419-019-1677-z

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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.

Highlights

Transglutaminase 2 (TG2) is a unique member of the transglutaminase family with various biological functions[1]
Since TG2 has been shown to participate in the apoptotic cell clearance[4,7], and obesity is associated with enhanced adipocyte apoptosis, we decided to investigate whether loss of TG2 affects diet-induced obesity-related pathologies
Data presented in this paper indicate that loss of TG2 enhances obesity-related pathologies such as adipose tissue inflammation, adipocyte death, hepatic steatosis and insulin resistance in mice exposed to either high sucrose diet (HSD) or to high fat diet (HFD), and all this is a result of the loss of TG2 from bone marrow-derived cells

Summary

Introduction

Transglutaminase 2 (TG2) is a unique member of the transglutaminase family with various biological functions[1]. TG2 is localized predominantly within the cell, substantial amounts of the protein is present on the surface of macrophages functioning as an integrin β3 coreceptor[2,3]. Increasing evidence indicate that impaired clearance of apoptotic cells is associated with the development of various chronic inflammatory diseases[6]. This is related to the fact that (1) uncleared apoptotic cells undergo secondary necrosis and induce inflammation, and (2) macrophages properly engulfing apoptotic cells would normally induce anti-inflammatory mechanisms that prevent tissue inflammation. In TG2 null mice following in vivo apoptosis induction, apoptotic cells are accumulated in tissues, but are surrounded by mononuclear cells[7], and their clearance is accompanied by production of pro-inflammatory cytokines[8]. TG2 knockout mice develop systemic lupus erythematosus-like autoimmunity on long term[7]

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