Abstract
ABSTRACT Adipocyte-mediated inflammatory signalling has been proposed to alter adipose physiology in obesity and Type 2 diabetes mellitus. Novel targets for alteration of inflammatory signalling are needed to improve obesity-related outcomes. The γ-secretase enzyme complex has been suggested to play a role both in adipocyte function as well as in immune regulation. We hypothesized that adipocyte-specific γ-secretase inhibition could alter the inflammatory makeup of adipose tissue. We found that genetic blockade of γ-secretase in adipocytes leads to a decrease in EMR1 (F4/80) expression, as a marker of macrophage presence, in adipose tissue without changes in expression of markers of other inflammatory cell types. To explore the mechanism by which adipocytes can alter macrophage function in vitro, fully differentiated 3T3-L1 adipocytes were treated with a γ-secretase inhibitor in the presence of lipopolysaccharide (LPS) and transcription of IL6 and ccl2 (MCP1) were quantified. IL-6 expression and secretion were significantly inhibited by γ-secretase blockade, with little effect on MCP1. Preconditioned media from 3T3-L1 adipocytes treated with a γ-secretase inhibitor also alters macrophage activation but did not affect macrophage translocation in vitro. Therefore, γ-secretase inhibition in fully differentiated adipocytes can alter IL-6 signalling to macrophages, consistent with our hypothesis that that γ-secretase is involved in adipocyte-initiated inflammatory signalling cascades.
Highlights
The proximal cause of obesity-induced insulin resis tance is excessive adipose mass [1] and one factor that can affect adipose function is inflammation
Emr1 (F4/80), a well-known marker of adipose tissue macrophages, which increases in response to HFD (Figure 1(a)), was lower in A-Nicastrin eWAT adipose tissue compared to that from cre-negative littermates independent of diet (Figure 1(b))
Adipose inflammation has long been associated with insulin resistance and Type 2 diabetes [34]
Summary
The proximal cause of obesity-induced insulin resis tance is excessive adipose mass [1] and one factor that can affect adipose function is inflammation. The γ-secretase enzyme complex is a heterotetramer of four obligate components – Nicastrin, PSEN1, APH-1, and PEN-2 – that regulates intramembranous cleavage of type-I transmembrane proteins termed regulated intramembrane proteolysis. This process releases the C-terminal intracel lular domain of the transmembrane protein, which may go on to mediate downstream effects [10]. A novel function of γ-secretase could be in regulat ing immune signalling cascades initiated by adipocytes themselves in either Notch dependent or independent manners. We further studied adipocyte-specific alterations and mechanisms of known adipokines’ secretion, exploring an initial pathway in which γ-secretase functions in regulation of adipose tissue inflammation
Sign-in/Register to view highlights & summary 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.
