Tissue factor pathways linking obesity and inflammation

Abstract

Obesity is a major cause for a spectrum of metabolic syndrome-related diseases that include insulin resistance, type 2 diabetes, and steatosis of the liver. Inflammation elicited by macrophages and other immune cells contributes to the metabolic abnormalities in obesity. In addition, coagulation activation following tissue factor (TF) upregulation in adipose tissue is frequently found in obese patients and particularly associated with diabetic complications. Genetic and pharmacological evidence indicates that TF makes significant contributions to the development of the metabolic syndrome by signaling through G protein-coupled protease activated receptors (PARs). Adipocyte TF–PAR2 signaling contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas hematopoietic TF–PAR2 signaling is a major cause for adipose tissue inflammation, hepatic steatosis and inflammation, as well as insulin resistance. In the liver of mice on a high fat diet, PAR2 signaling increases transcripts of key regulators of gluconeogenesis, lipogenesis and inflammatory cytokines. Increased markers of hepatic gluconeogenesis correlate with decreased activation of AMP-activated protein kinase (AMPK), a known regulator of these pathways and a target for PAR2 signaling. Clinical markers of a TF-induced prothrombotic state may thus indicate a risk in obese patient for developing complications of the metabolic syndrome.

Cross Talk Pathways Between Coagulation and Inflammation

“…In mice, this pathway contributes to diet-induced obesity by decreasing metabolism and energy expenditure and augmenting adipose tissue inflammation and insulin resistance. 18 In spite of the preceding observations, caution must be exercised before drawing the conclusion that all TF-mediated pathways are damaging. To that point, although blocking TF/ thrombin/PAR1 signaling is protective in mouse models of myocardial ischemia-reperfusion injury, it is detrimental in Coxsackievirus B3-induced viral myocarditis.…”

Targeting Liver Fibrosis with a Cell-penetrating Protease-activated Receptor-2 (PAR2) Pepducin

“…There are no effective therapies yet available to treat the potentially lifethreatening complications resulting from liver fibrosis (5), pointing to an urgent need to more deeply understand the pathophysiology of NASH and identify new points of therapeutic intervention. Emerging evidence points to a novel mechanism linking the development of NASH fibrosis with PAR2, a cell surface protease-activated receptor highly expressed in liver stellate cells, hepatocytes, inflammatory cells, and other mesenchymal cells that regulates the response to tissue injury (13,14,42,43). Here, we demonstrate that the PAR2 pepducin PZ-235 suppresses collagen production, fibrosis, steatosis, triglycerides, and lobular inflammation in mouse models of NASH.…”

Coagulation Profile Dynamics in Pediatric Patients with Cushing Syndrome: A Prospective, Observational Comparative Study

“…15 Patients with obesity have an increased production of inflammatory factors, including increased levels of FVIII, thrombin activity, and circulating monocyte tissue factor procoagulant compared with their counterparts of normal weight. 16 This increased inflammatory response can lead to hypercoagulability, insulin resistance, and hepatic dysfunction. 16 Similarly, hyperlipidemia also is associated with Cushing syndrome, yet another risk factor for VTE.…”

“…16 This increased inflammatory response can lead to hypercoagulability, insulin resistance, and hepatic dysfunction. 16 Similarly, hyperlipidemia also is associated with Cushing syndrome, yet another risk factor for VTE. 15,17 …”