The thrombin receptor PAR4 supports visceral adipose tissue inflammation.

Autor: Kleeschulte S; Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany., Fischinger V; Institute for Pharmacology and Clinical Pharmacology, University Hospital Düsseldorf, Düsseldorf, Germany., Öhlke L; Institute for Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Duisburg, Germany., Bode J; Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany., Kamler M; Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany., Dobrev D; Institute for Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Duisburg, Germany.; Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Canada.; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA., Grandoch M; Institute for Translational Pharmacology and CARID Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Fender AC; Institute for Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Duisburg, Germany. anke.fender@uk-essen.de.
Jazyk: angličtina
Zdroj: Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2024 Sep; Vol. 397 (9), pp. 7187-7200. Date of Electronic Publication: 2024 Apr 23.
DOI: 10.1007/s00210-024-03097-5
Abstrakt: Thrombin inhibition suppresses adiposity, WAT inflammation and metabolic dysfunction in mice. Protease-activated receptor (PAR)1 does not account for thrombin-driven obesity, so we explored the culprit role of PAR4 in this context. Male WT and PAR-4 -/- mice received a high fat diet (HFD) for 8 weeks, WT controls received standard chow. Body fat was quantified by NMR. Epididymal WAT was assessed by histology, immunohistochemistry, qPCR and lipase activity assay. 3T3-L1 preadipocytes were differentiated ± thrombin, acutely stimulated ± PAR4 activating peptide (AP) and assessed by immunoblot, qPCR and U937 monocyte adhesion. Epicardial adipose tissue (EAT) from obese and lean patients was assessed by immunoblot. PAR4 was upregulated in mouse WAT under HFD. PAR4 -/- mice developed less visceral adiposity and glucose intolerance under HFD, featuring smaller adipocytes, fewer macrophages and lower expression of adipogenic (leptin, PPARγ) and pro-inflammatory genes (CCL2, IL-1β) in WAT. HFD-modified activity and expression of lipases or perilipin were unaffected by PAR4 deletion. 3T3-L1 adipocytes differentiated with thrombin retained Ki67 expression, further upregulated IL-1β and CCL2 and were more adhesive for monocytes. In mature adipocytes, PAR4-AP increased phosphorylated ERK1/2 and AKT, upregulated Ki67, CCl2, IL-β and hyaluronan synthase 1 but not TNF-α mRNA, and augmented hyaluronidase-sensitive monocyte adhesion. Obese human EAT expressed more PAR4, CD68 and CD54 than lean EAT. PAR4 upregulated in obesity supports adipocyte hypertrophy, WAT expansion and thrombo-inflammation. The emerging PAR4 antagonists provide a therapeutic perspective in this context beyond their canonical antiplatelet action.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: