Coagulation Signalling and Metabolic Disorders: Lessons Learned from Animal Models

Abstract

Nutrient excess in obesity drives metabolic reprogramming in multiple tissues involving extensive interorgan and intercellular crosstalk. Experimental and clinical studies show that prolonged nutrient excess often compromises metabolic adaptation propagating proobesogenic and proinflammatory responses. Chronic inflammation further promotes insulin resistance and associated comorbidities. Obesity and type 2 diabetes are characterized by a hypercoagulable state and clinical studies show a strong correlation of markers of coagulation activation in metabolic disorders. Coagulation protease-dependent signalling via protease-activated receptors is intimately associated with inflammation. The experimental evidence supports roles of tissue factor and G protein coupled protease-activated receptor-2 signalling in the regulation of insulin resistance and metabolic inflammation in diet-induced obesity. Likewise, increases in plasminogen activator inhibitor-1 levels and fibrin-driven inflammation promote insulin resistance in obesity. Additionally, impaired thrombomodulin-dependent protein C activation is mechanistically linked to diabetic kidney disease. Given the increased usage of direct oral anticoagulants, understanding the role of specific coagulation proteases in regulation of metabolic inflammation is highly relevant and might provide insights into the design of novel treatment regimens for patients suffering from thromboinflammatory and cardiometabolic disorders.

Zusammenfassung

Durch Nährstoffüberschuss ausgelöste Adipositas führt zur Veränderung von metabolischen Prozessen in einer Vielzahl von Geweben mit der Konsequenz von komplexen pathologischen Wechselwirkungen auf zellulärer Ebene. So zeigen experimentelle und klinische Studien, dass ein über längeren Zeitraum aufgenommener Nährstoffüberschuss adipogene und proinflammatorischen Reaktionen fördert und eine Anpassung des Stoffwechsels kompromittieren. Durch die Manifestierung chronisch entzündlicher Prozesse werden Insulinresistenz und damit verbundene Komorbiditäten verstärkt. Außerdem gehen Adipositas und Typ-2-Diabetes mit einer Hyperkoagulabilität einher. In klinische Studien konnte gezeigt werden, dass Gerinnungsaktivierungsmarker mit Stoffwechselstörungen korrelieren. Dabei vermitteln von der Gerinnungskaskade aktivierte Protease-aktivierte-Rezeptoren (PARs) entzündliche Prozesse. Es konnte experimentell gezeigt werden, dass das Gewebethromboplastin (tissue factor, TF) und die Signale des G Protein gekoppelten Rezeptors PAR2 an den pathologischen Regulationsprozessen in ernährungsbedingter Adipositas, wie die Insulinresistenz beteiligt sind. Ebenso werden Fettleibigkeit und Insulinresistenz durch einen Anstieg des Plasminogenaktivator-Inhibitor-1 und fibringesteuerte Entzündungen gefördert. Darüber hinaus ist die beeinträchtigte Thrombomodulin-abhängige Protein C Aktivierung mechanistisch mit einer diabetischen Nephrophathie verbunden. Angesichts des zunehmenden Einsatzes oraler Antikoagulantien benötigt es ein verbessertes Verständnis, wie spezifische Gerinnungsfaktoren entzündliche Prozesse in Stoffwechselerkrankungen regulieren. Dies könnte Einblicke geben, die zu neuartigen Behandlungsansätze für Patienten mit Gerinnung-Störungen und kardio-metabolischen Erkrankungen führen.

Keywords

coagulation proteases - metabolic diseases - protease-activated receptors

Schlüsselwörter

Gerinnungsproteasen - metabilsche Erkrankungen - Protease-aktivierte Rezeptoren

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