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Inhibition of target proteases such as KLK7 has been shown to reduce adipose tissue inflammation in obesity, while vaspin binding to cell surface GRP78 has been linked to reduced obesity\u2010induced ER stress and insulin resistance in the liver. However, the molecular mechanisms by which vaspin directly affects cellular processes in adipocytes remain unknown. Using fluorescently labeled vaspin, we found that vaspin is rapidly internalized by mouse and human adipocytes, but less efficiently by endothelial, kidney, liver, and neuronal cells. Internalization occurs by active, clathrin\u2010mediated endocytosis, which is dependent on vaspin binding to the LRP1 receptor, rather than GRP78 as previously thought. This was demonstrated by competition experiments and RNAi\u2010mediated knock\u2010down in adipocytes and by rescuing vaspin internalization in LRP1\u2010deficient Pea13 cells after transfection with a functional LRP1 minireceptor. Vaspin internalization is further increased in mature adipocytes after insulin\u2010stimulated translocation of LRP1. Although vaspin has nanomolar affinity for LRP1 clusters II\u2010IV, binding to cell surface heparan sulfates is required for efficient LRP1\u2010mediated internalization. Native, but not cleaved vaspin, and also vaspin polymers are efficiently endocytosed, and ultimately targeted for lysosomal degradation. Our study provides mechanistic insight into the uptake and degradation of vaspin in adipocytes, thereby broadening our understanding of its functional repertoire. We hypothesize the vaspin\u2010LRP1 axis to be an important mediator of vaspin effects not only in adipose tissue but also in other LRP1\u2010expressing cells.<\/jats:p>","DOI":"10.1111\/febs.16991","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T05:37:47Z","timestamp":1698989867000},"page":"2134-2154","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["<scp>LRP1<\/scp>\n                    is the cell\u2010surface endocytosis receptor for vaspin in adipocytes"],"prefix":"10.1111","volume":"291","author":[{"given":"Catherine A.","family":"Tindall","sequence":"first","affiliation":[{"name":"Helmholtz Institute for Metabolic Obesity and Vascular Research (HI\u2010MAG) of the Helmholtz Zentrum M\u00fcnchen at the University of Leipzig and University Hospital Leipzig  Germany"},{"name":"Faculty of Life Sciences, Institute of Biochemistry University of Leipzig  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