Fetuin-A regulates adipose tissue macrophage content and activation in insulin resistant mice through MCP-1 and iNOS: involvement of IFNγ-JAK2-STAT1 pathway

Abstract

In the context of obesity-induced adipose tissue (AT) inflammation, migration of macrophages and their polarization from predominantly anti-inflammatory to proinflammatory subtype is considered a pivotal event in the loss of adipose insulin sensitivity. Two major chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and Fetuin-A (FetA), have been reported to stimulate macrophage migration into inflamed AT instigating inflammation. Moreover, FetA could notably modulate macrophage polarization, yet the mechanism(s) is unknown. The present study was undertaken to elucidate the mechanistic pathway involved in the actions of FetA and MCP-1 in obese AT. We found that FetA knockdown in high fat diet (HFD) fed mice could significantly subdue the augmented MCP-1 expression and reduce adipose tissue macrophage (ATM) content thereby indicating that MCP-1 is being regulated by FetA. Additionally, knockdown of FetA in HFD mice impeded the expression of inducible nitric oxide synthase (iNOS) reverting macrophage activation from mostly proinflammatory to anti-inflammatory state. It was observed that the stimulating effect of FetA on MCP-1 and iNOS was mediated through interferon γ (IFNγ) induced activation of JAK2-STAT1-NOX4 pathway. Furthermore, we detected that the enhanced IFNγ expression was accounted by the stimulatory effect of FetA upon the activities of both cJun and JNK. Taken together, our findings revealed that obesity-induced FetA acts as a master upstream regulator of AT inflammation by regulating MCP-1 and iNOS expression through JNK-cJun-IFNγ-JAK2-STAT1 signaling pathway. This study opened a new horizon in understanding the regulation of ATM content and activation in conditions of obesity-induced insulin resistance.

Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation

“…Moreover, FetA promotes the pro-inflammatory M1 polarization of macrophages ( 298 ). Mechanistically, FetA promotes M1 macrophage polarization via c-Jun and JNK- mediated IFNγ upregulation, which induces the expression of MCP-1 and iNOS in adipocytes via the JAK2-STAT1 pathway ( 299 ). Taken together, these studies show that FetA is an upstream regulator of FFA-induced TLR4 activation in adipocytes and promotes M1 macrophage polarization.…”

The Combined Partial Knockdown of CBS and MPST Genes Induces Inflammation, Impairs Adipocyte Function-Related Gene Expression and Disrupts Protein Persulfidation in Human Adipocytes

“…RELA is a relevant transcription factor associated with adipocyte inflammation [ 81 ] that inhibits adipogenesis and accumulation of lipids in adipocytes [ 82 ]. The activation of STAT1 transcription factor inhibits adipogenesis and promotes adipocyte and adipose tissue inflammation [ 83 , 84 , 85 , 86 , 87 , 88 ]. Isolated mature adipocytes from obese individuals had increased expression of mitogen-activated protein 4 kinase 4 (MAP4K4), which is known to inhibit PPARγ transcriptional activity, adipogenesis, and insulin-stimulated glucose transport [ 89 , 90 ].…”

Immunometabolic profiling ofin vitroandex vivo Leishmania-infected macrophages (LIMs) reveals unique polarization and bioenergetic signatures

“…CCL2, (Rollins et al)), the classical complement cascade (e.g. PENTRAXIN 2, (Haapasalo and Meri, 2019)), iNOS (IL33, CCL2, AHSG and CD40 (Bingaman et al, 2000; Brandonisio et al, 2002; Chattopadhyay et al, 2021; Xu et al, 2019)), (iii) drivers of the Th1 response (e.g. sRAGE, (Chen et al, 2008) and (iv) other factors known to control Leishmania elimination (IL3, IL7, G-CSF, and CD40) (Brandonisio et al, 2002; Gessner et al, 1993; Ho et al, 1992; Kamanaka et al, 1996; McDowell et al, 2002; Murray et al, 1995; Ritter and Moll, 2000).…”