Inflammation, obesity, and thrombosis

Abstract

Clinical and epidemiological studies support a connection between obesity and thrombosis, involving elevated expression of the prothrombotic molecules plasminogen activator inhibitor-1 and tissue factor (TF) and increased platelet activation. Cardiovascular diseases and metabolic syndrome-associated disorders, including obesity, insulin resistance, type 2 diabetes, and hepatic steatosis, involve inflammation elicited by infiltration and activation of immune cells, particularly macrophages, into adipose tissue. Although TF has been clearly linked to a procoagulant state in obesity, emerging genetic and pharmacologic evidence indicate that TF signaling via G protein-coupled protease-activated receptors (PAR2, PAR1) additionally drives multiple aspects of the metabolic syndrome. TF-PAR2 signaling in adipocytes contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas TF-PAR2 signaling in hematopoietic and myeloid cells drives adipose tissue inflammation, hepatic steatosis, and insulin resistance. TF-initiated coagulation leading to thrombin-PAR1 signaling also contributes to diet-induced hepatic steatosis and inflammation in certain models. Thus, in obese patients, clinical markers of a prothrombotic state may indicate a risk for the development of complications of the metabolic syndrome. Furthermore, TF-induced signaling could provide new therapeutic targets for drug development at the intersection between obesity, inflammation, and thrombosis.

Figure 1

Schematic overview of TF signaling complexes. The TF–FVIIa binary signaling complex signals via PAR2, whereas the ternary TF–FVIIa–FXa coagulation signaling complex activates both PAR2 and PAR1. TF pathway inhibitor inhibits the coagulation and signaling function of the ternary complex. Thrombin signals through PAR1 to induce inflammatory responses. Binding of aPC to EPCR switches the specificity of PAR1–thrombin signaling to mediate protective anti-inflammatory responses. Antibody 10H10 targets the TF–FVIIa binary signaling complex and disrupts the TF–integrin interaction.

Figure 2

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. 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.

Figure 3

Obesity-associated adipose inflammation. In the lean state, immune cells in adipose tissues (primarily resident M2-like macrophages together with T regulatory (Treg) cells and eosinophils) synthesize IL-10, IL-4, and IL-13 and help to maintain an anti-inflammatory environment that contributes to the insulin-sensitive state. Obesity drives a shift in the number and phenotype of immune cells.^, Monocytes are recruited from the blood into the obese adipose tissue, where they become M1 polarized and produce proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, which contribute to insulin resistance. Other changes contributing to the proinflammatory state include decreased numbers of eosinophils and Tregs, and increased numbers of neutrophils, B cells, mast cells, and interferon γ–producing Th1 and CD8+ T cells. The proinflammatory cytokines and chemokines act in autocrine, paracrine, and endocrine manners to promote inflammation and insulin resistance in adipose and other target tissues.

Figure 4

Fibrin deposition in adipose tissue in obesity. Immunohistochemical staining for fibrin in paraffin sections of adipose tissue, showing increased fibrin deposition (reddish-brown color) in obese mice (A,B) compared with lean mice (C). (D) Negative control staining without the primary anti-fibrin antibody. Slides were counterstained with hematoxylin. Original magnification in all panels, ×400.