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Ribas Latre, A. ; Hoffmann, A. ; Gebhardt, C. ; Weiner, J.* ; Arndt, L.* ; Raulien, N.* ; Gericke, M.* ; Ghosh, A.* ; Krause, K.* ; Klöting, N. ; Pfluger, P.T. ; Sheikh, B. ; Ebert, T.* ; Tönjes, A.* ; Stumvoll, M. ; Wolfrum, C.* ; Blüher, M. ; Wagner, U.* ; Vendrell, J.* ; Fernández-Veledo, S.* ; Heiker, J.T.

The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.

Metabolism 168:156239 (2025)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adipose Tissue ; Inflammation ; Metabolic Disease ; Obesity ; Protease ; Serpin; Kallikrein 7; Tenascin-c; 3t3-l1 Adipocytes; Gene-expression; Morbid-obesity; Inflammation; Vaspin; Skin; Fibronectin; Inhibition
ISSN (print) / ISBN 0026-0495
e-ISSN 1532-8600
Journal Metabolism: clinical and experimental
Quellenangaben Volume: 168, Issue: , Pages: , Article Number: 156239 Supplement: ,
Publisher Elsevier
Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Institute of Diabetes and Obesity (IDO)
Grants Generalitat de Catalunya
German Federal Ministry of Health (Berlin, Germany)
German Diabetes Association (DDG)
AstraZeneca
EFSD Mentorship Programme
Helmholtz Munich
Free State of Saxony
German Research Foundation)
Ministry of Culture and Science of the state North Rhine-Westphalia (Duesseldorf, Germany)
German Federal Ministry of Education and Research (BMBF) through the German Center for Diabetes Research
Agency for Management of University
Ministerio de Ciencia e Innovacion
Instituto de Salud Carlos III
CIBER-Consorcio Centro de Investigacion Biomedica en Red
The "La Caixa" Foundation
Spanish Ministry of Science and Innovation MCIN/AEI
European Research Council (ERC CoG)
Deutsche Forschungsgemeinschaft (DFG