Hematopoietic Tissue Factor–Protease-Activated Receptor 2 Signaling Promotes Hepatic Inflammation and Contributes to Pathways of Gluconeogenesis and Steatosis in Obese Mice

• Published in: The American journal of pathology Vol. 185; no. 2; pp. 524 - 535
• Main Authors: Wang, Jing, Chakrabarty, Sagarika, Bui, Quyen, Ruf, Wolfram, Samad, Fahumiya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015; American Society for Investigative Pathology
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Gluconeogenesis; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Hepatitis - genetics; Hepatitis - metabolism; Hepatitis - pathology; Insulin Resistance - genetics; Mice; Mice, Knockout; Mice, Obese; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Pathology; Receptor, PAR-2 - genetics; Receptor, PAR-2 - metabolism; Regular; Signal Transduction; Thromboplastin - genetics; Thromboplastin - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2014.10.008

Failure to inhibit hepatic gluconeogenesis is a major mechanism contributing to fasting hyperglycemia in type 2 diabetes and, along with steatosis, is the hallmark of hepatic insulin resistance. Obesity is associated with chronic inflammation in multiple tissues, and hepatic inflammation is mechanistically linked to both steatosis and hepatic insulin resistance. Here, we delineate a role for coagulation signaling via tissue factor (TF) and proteinase-activated receptor 2 (PAR2) in obesity-mediated hepatic inflammation, steatosis, and gluconeogenesis. In diet-induced obese mice, TF tail signaling independent of PAR2 drives CD11b+ CD11c+ hepatic macrophage recruitment, and TF–PAR2 signaling contributes to the accumulation of hepatic CD8+ T cells. Transcripts of key pathways of gluconeogenesis, lipogenesis, and inflammatory cytokines were reduced in high-fat diet–fed mice that lack the cytoplasmic domain of TF ( F3 ) (TFΔCT ) or that are deficient in PAR2 ( F2rl1 ), as well as by pharmacological inhibition of TF–PAR2 signaling in diet-induced obese mice. These gluconeogenic, lipogenic, and inflammatory pathway transcripts were similarly reduced in response to genetic ablation or pharmacological inhibition of TF–PAR2 signaling in hematopoietic cells and were mechanistically associated with activation of AMP-activated protein kinase (AMPK). These findings indicate that hematopoietic TF–PAR2 signaling plays a pivotal role in the hepatic inflammatory responses, steatosis, and hepatic insulin resistance that lead to systemic insulin resistance and type 2 diabetes in obesity.