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.
Highlights
As sentinel cells of the body, macrophages play a pivotal role in host defense mechanisms
The efficiency of FetA knockdown was assessed by immunoblotting followed by densitometry of the protein expression of FetA in lysates of hepatocytes, adipocytes and stromal vascular fraction (SVF) isolated from standard diet (SD), high fat diet (HFD) and HFD+FetAKD mice (Supplementary Fig. S1)
We explored the effect of FetA silencing upon different M1/M2 markers in adipose-derived stromal vascular fraction (SVF)
Summary
As sentinel cells of the body, macrophages play a pivotal role in host defense mechanisms. Armed with multiple pattern recognition receptors including toll-like receptors (TLRs), C-type lectins (CTLs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) etc., macrophages can appropriately sense danger signals emanating from a variety of pathogens and damaged tissue [1]. That, these heterogeneous group of cells exhibit a wide range of plasticity and complex molecular program in coordinating efficient responses to an array of cues arising within the tissue microenvironment [2]. A couple of recent excellent reviews in the subject have put forth that factors and/or metabolic triggers that initiate ATM activation and induce sterile inflammation within AT remain largely unknown [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
