Inhibition of γ-secretase in adipocytes leads to altered IL-6 secretion and adipose inflammation

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