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Extracellular matrix synthesis and remodelling are significantly altered in these tissues in obesity and type 2 diabetes. Collagen XVIII is a ubiquitous extracellular matrix component, and it occurs in three isoforms which differ in terms of molecular size, domain structure and tissue distribution. We recently showed that, in mice, the lack of collagen XVIII, and especially its medium and long isoforms, leads to reduced adiposity and dyslipidaemia. To address the metabolic consequences of these intriguing observations, we assessed whole\u2010body glucose homeostasis in mice challenged with a high\u2010fat diet and in normal physiological conditions. We observed that, in the high caloric diet, the overall adiposity was decreased by 30%, serum triglyceride values were threefold higher and the steatotic area in liver was twofold larger in collagen XVIII knockout mice compared with controls. We demonstrated that mice lacking either all three collagen XVIII isoforms, or specifically, the medium and long isoforms develop insulin resistance and glucose intolerance. Furthermore, we found that ablation of collagen XVIII leads to increased heat production in low temperatures and to reduction of the high blood triglyceride levels of the knockout mice to the level of wild\u2010type mice. Our data indicate that collagen XVIII plays a role in the regulation of glucose tolerance, insulin sensitivity and lipid homeostasis, principally through its ability to regulate the expansion of the adipose tissue. These findings advance the understanding of metabolic disorders.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp279559","type":"journal-article","created":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T10:36:31Z","timestamp":1590402991000},"page":"3373-3393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Lack of collagen XVIII leads to lipodystrophy and perturbs hepatic glucose and lipid homeostasis"],"prefix":"10.1113","volume":"598","author":[{"given":"Tiina","family":"Pet\u00e4ist\u00f6","sequence":"first","affiliation":[{"name":"Oulu Center for Cell\u2010Matrix Research Faculty of Biochemistry and Molecular Medicine University of Oulu  Oulu Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Vicente","sequence":"additional","affiliation":[{"name":"Oulu Center for Cell\u2010Matrix Research Faculty of Biochemistry and Molecular Medicine University of Oulu  Oulu 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