Thrombin promotes diet-induced obesity through fibrin-driven inflammation

Kopec, Anna K.; Abrahams, Sara R.; Thornton, Sherry; Palumbo, Joseph S.; Mullins, Eric S.; Divanovic, Senad; Weiler, Hartmut; Owens, A. Phillip; Mackman, Nigel; Goss, Ashley; Ryn, Joanne van; Luyendyk, James P.; Flick, Matthew J.

doi:10.1172/jci92744

Cited by 104 publications

(105 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TF is upregulated in the obese visceral adipose tissue and fibrin deposition is prominent, surrounding the ‘crown‐like’ structure where macrophages interact with stressed adipocytes. In mouse models, a genetically induced hyper‐thrombotic state promotes obesity, but a mutant of fibrinogen devoid of interaction with the macrophage‐expressed integrin αMβ2 (CD11b/CD18) is protected from diet‐induced obesity with diminished systemic and adipose inflammation .…”

Section: Tf‐par2 Signaling In Inflammatory Diseases and Cancermentioning

confidence: 99%

“…In the liver, TF‐PAR2 signaling drives the accumulation of CD8 + T cells and promotes pathways of hepatic lipogenesis and gluconeogenesis that contribute to steatosis and hepatic insulin resistance . Hepatic inflammation is also reduced in mice treated with the thrombin inhibitor dabigatran or defective macrophage fibrin interaction . Thus, coagulation‐induced fibrin deposition participates in inflammatory TF‐PAR2 signaling in prevalent diseases of metabolic inflammation.…”

Section: Tf‐par2 Signaling In Inflammatory Diseases and Cancermentioning

confidence: 99%

See 1 more Smart Citation

Tissue factor at the crossroad of coagulation and cell signaling

Zelaya

Rothmeier

Ruf

2018

Journal of Thrombosis and Haemostasis

125

123

View full text Add to dashboard Cite

The tissue factor (TF) pathway plays a central role in hemostasis and thrombo-inflammatory diseases. Although structure-function relationships of the TF initiation complex are elucidated, new facets of the dynamic regulation of TF's activities in cells continue to emerge. Cellular pathways that render TF non-coagulant participate in signaling of distinct TF complexes with associated proteases through the protease-activated receptor (PAR) family of G protein-coupled receptors. Additional co-receptors, including the endothelial protein C receptor (EPCR) and integrins, confer signaling specificity by directing subcellular localization and trafficking. We here review how TF is switched between its role in coagulation and cell signaling through thiol-disulfide exchange reactions in the context of physiologically relevant lipid microdomains. Inflammatory mediators, including reactive oxygen species, activators of the inflammasome, and the complement cascade play pivotal roles in TF procoagulant activation on monocytes, macrophages and endothelial cells. We furthermore discuss how TF, intracellular ligands, co-receptors and associated proteases are integrated in PAR-dependent cell signaling pathways controlling innate immunity, cancer and metabolic inflammation. Knowledge of the precise interactions of TF in coagulation and cell signaling is important for understanding effects of new anticoagulants beyond thrombosis and identification of new applications of these drugs for potential additional therapeutic benefits.

show abstract

Section: Tf‐par2 Signaling In Inflammatory Diseases and Cancermentioning

confidence: 99%

Section: Tf‐par2 Signaling In Inflammatory Diseases and Cancermentioning

confidence: 99%

Tissue factor at the crossroad of coagulation and cell signaling

Zelaya

Rothmeier

Ruf

2018

Journal of Thrombosis and Haemostasis

125

123

View full text Add to dashboard Cite

show abstract

“…Our data showing reduced glucose levels, in combination with unchanged insulin levels, after vorapaxar treatment substantiate these findings and suggest that thrombin-mediated insulin resistance is facilitated by PAR-1. Moreover, dabigatran etexilate-dependent thrombin inhibition during high-fat diet-induced obesity reduced blood glucose levels, even when thrombin inhibition was initiated after obesity was established (16).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological PAR‐1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy

et al. 2019

View full text Add to dashboard Cite

Vorapaxar‐dependent protease‐activated receptor (PAR)‐1 inhibition diminishes diabetic nephropathy in experimental type 1 diabetes. As most patients with diabetic nephropathy suffer from type 2 diabetes, the aim of this study was to investigate whether PAR‐1 inhibition also limits diabetic nephropathy in experimental type 2 diabetes. Consequently, leptin‐deficient black and tan brachyuric (BTBRob/ob) mice were randomly assigned to vorapaxar (1.75 mg/kg; twice weekly via oral gavage) or vehicle treatment, whereas matched wild‐type (WT) BTBR (BTBRWT) mice served as nondiabetic controls. Weight and (non‐fasting) blood glucose levels were monitored for up to 18 wk, after which kidney function and histologic damage was evaluated postmortem. We show that blood glucose levels and body weight increased in diabetic BTBRob/ob mice compared with nondiabetic BTBRWT controls. Vorapaxar‐dependent PAR‐1 inhibition reduced but did not normalize blood glucose levels in BTBRob/ob mice, whereas it potentiated the increase in body weight. Vorapaxar did not, however, preserve kidney function, whereas it only minimally reduced histopathological signs of kidney injury. Overall, we thus show that PAR‐1 inhibition reduces blood glucose levels during the progression of diabetic nephropathy in experimental type 2 diabetes but does not improve renal function. This is in contrast to the therapeutic potential of vorapaxar in type 1 diabetes‐induced nephropathy, highlighting the importance of disease‐dependent treatment modalities.—Waasdorp, M., Florquin, S., Duitman, J., Spek, C. A. Pharmacological PAR‐1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy. FASEB J. 33, 10966–10972 (2019). http://www.fasebj.org

show abstract

“…Is this because the types of clot differ between these models? Also, in a model of fatty liver disease, crosslinked fibrin(ogen) deposits have been identified in the liver and adipose tissue , and again it would be of interest to identify the make‐up of these deposits. Is parenchymal extinction, i.e. the progression of liver injury by intrahepatic microthrombi, not a relevant pathological mechanism at all, or does this depend on the nature, extent and phase of liver injury?…”

mentioning

confidence: 99%

mentioning

confidence: 99%