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The thrombin receptor PAR4 supports visceral adipose tissue inflammation

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Title: The thrombin receptor PAR4 supports visceral adipose tissue inflammation
Authors: Sonja Kleeschulte, Vivien Fischinger, Lisa Öhlke, Johannes Bode, Markus Kamler, Dobromir Dobrev, Maria Grandoch, Anke C. Fender
Source: Naunyn Schmiedebergs Arch Pharmacol
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Male, Inflammation, Mice, Knockout, 0301 basic medicine, 0303 health sciences, Research, Medizin, U937 Cells, Intra-Abdominal Fat, Middle Aged, Diet, High-Fat, Mice, Inbred C57BL, Mice, 03 medical and health sciences, Mice, Inbred C57BL [MeSH], Protease-activated receptor, Adipocytes/pathology [MeSH], Receptors, Thrombin/genetics [MeSH], Obesity/pathology [MeSH], Obesity/metabolism [MeSH], Male [MeSH], Diet, High-Fat/adverse effects [MeSH], Intra-Abdominal Fat/metabolism [MeSH], Glucose intolerance, Obesity, U937 Cells [MeSH], Intra-Abdominal Fat/pathology [MeSH], Humans [MeSH], Adipose tissue, Middle Aged [MeSH], Animals [MeSH], Mice, Knockout [MeSH], Mice [MeSH], Inflammation/pathology [MeSH], 3T3-L1 Cells [MeSH], Inflammation/metabolism [MeSH], Adipocytes/metabolism [MeSH], Receptors, Thrombin/metabolism [MeSH], Thrombin, 3T3-L1 Cells, Adipocytes, Animals, Humans, Receptors, Thrombin
Description: 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.
Document Type: Article
Other literature type
Language: English
ISSN: 1432-1912
0028-1298
DOI: 10.1007/s00210-024-03097-5
Access URL: https://pubmed.ncbi.nlm.nih.gov/38652276
https://repository.publisso.de/resource/frl:6521277
https://www.ncbi.nlm.nih.gov/pubmed/38652276
https://doi.org/10.1007/s00210-024-03097-5
https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&origin=inward&scp=85191077331
Rights: CC BY
Accession Number: edsair.doi.dedup.....233e8b5411e967af99cef2a115d02f1a
Database: OpenAIRE
Description
Abstract: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.
ISSN:14321912
00281298
DOI:10.1007/s00210-024-03097-5