Contributions of macrophage and adipocyte TF signaling to obesity and insulin resistance. In adipocytes, FVIIa inhibits both basal and insulin-mediated activation of Akt through a mechanism that requires the TF cytoplasmic domain. Suppression of Akt activity increases insulin resistance and decreases adiponectin synthesis by adipocytes. Reduced systemic levels of adiponectin further blunt insulin signaling and additionally inhibits AMPK and PPARα pathways of energy expenditure and β-oxidation, causing obesity. PAR2 is known to suppress AMPK in a manner dependent on β-arrestin recruitment, and this receptor may therefore contribute to the TF–FVIIa signaling pathway through this specific link. PAR2 may also have an opposing effect through G protein–mediated activation of AMPK in the absence of β-arrestin.73 In adipose tissue, TF–FVIIa–PAR2 signaling may regulate macrophage recruitment and/or retention via phosphorylation-dependent crosstalk between integrins and the cytoplasmic domain of TF. TF–FVIIa–PAR2 signaling and/or TF–integrin interactions activate and sustain M1 polarization of ATMs, contributing to insulin resistance.
