title: Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition.
abstract: Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ∼ 50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzled-like sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu.
authors.forename: Mari
authors.initials: M
authors.lastname: Aikio
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu.
authors.forename: Harri
authors.initials: H
authors.lastname: Elamaa
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu.
authors.forename: David
authors.initials: D
authors.lastname: Vicente
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu.
authors.forename: Valerio
authors.initials: V
authors.lastname: Izzi
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu.
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Kaur
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu.
authors.forename: Lotta
authors.initials: L
authors.lastname: Seppinen
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London and Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom;
authors.forename: Helen E
authors.initials: HE
authors.lastname: Speedy
authors.affiliation: Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70211 Kuopio, Finland;
authors.forename: Dorota
authors.initials: D
authors.lastname: Kaminska
authors.affiliation: Biocenter Oulu,Department of Internal Medicine, Clinical Research Center, Institute of Clinical Medicine, and.
authors.forename: Sanna
authors.initials: S
authors.lastname: Kuusisto
authors.affiliation: Biocenter Oulu,Department of Pathology, Oulu University Hospital, University of Oulu, FI-90014 Oulu, Finland;
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu.
authors.forename: Ritva
authors.initials: R
authors.lastname: Heljasvaara
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London and Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom;
authors.forename: Emma L
authors.initials: EL
authors.lastname: Jones
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, FI-00290 Helsinki, Finland; and.
authors.forename: Mikko
authors.initials: M
authors.lastname: Muilu
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, FI-00290 Helsinki, Finland; and.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70211 Kuopio, Finland;Department of Medicine, Clinical Nutrition and Obesity Center, Kuopio University Hospital, FI-70211 Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.affiliation: Biocenter Oulu,Department of Internal Medicine, Clinical Research Center, Institute of Clinical Medicine, and.
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London and Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom; taina.pihlajaniemi@oulu.fi c.shoulders@qmul.ac.uk.
authors.forename: Carol C
authors.initials: CC
authors.lastname: Shoulders
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research,Biocenter Oulu, taina.pihlajaniemi@oulu.fi c.shoulders@qmul.ac.uk.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D050154:Adiposity / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D043170:Collagen Type XVIII / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D043170:Collagen Type XVIII; D005227:Fatty Acids