title: Characterization of metabolic health in mouse models of fibrillin-1 perturbation.
abstract: Mutations in the microfibrillar protein fibrillin-1 or the absence of its binding partner microfibril-associated glycoprotein (MAGP1) lead to increased TGFβ signaling due to an inability to sequester latent or active forms of TGFβ, respectively. Mouse models of excess TGFβ signaling display increased adiposity and predisposition to type-2 diabetes. It is therefore interesting that individuals with Marfan syndrome, a disease in which fibrillin-1 mutation leads to aberrant TGFβ signaling, typically present with extreme fat hypoplasia. The goal of this project was to characterize multiple fibrillin-1 mutant mouse strains to understand how fibrillin-1 contributes to metabolic health. The results of this study demonstrate that fibrillin-1 contributes little to lipid storage and metabolic homeostasis, which is in contrast to the obesity and metabolic changes associated with MAGP1 deficiency. MAGP1 but not fibrillin-1 mutant mice had elevated TGFβ signaling in their adipose tissue, which is consistent with the difference in obesity phenotypes. However, fibrillin-1 mutant strains and MAGP1-deficient mice all exhibit increased bone length and reduced bone mineralization which are characteristic of Marfan syndrome. Our findings suggest that Marfan-associated adipocyte hypoplasia is likely not due to microfibril-associated changes in adipose tissue, and provide evidence that MAGP1 may function independently of fibrillin in some tissues.
authors.affiliation: Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Tezin A
authors.initials: TA
authors.lastname: Walji
authors.affiliation: Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Turecamo
authors.affiliation: Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Antea J
authors.initials: AJ
authors.lastname: DeMarsilis
authors.affiliation: Department of Biochemistry & Molecular Biology, Molecular & Medical Genetics, Oregon Health & Science University, Shriners Hospital for Children, Portland, OR 97201, USA.
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
authors.affiliation: Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.affiliation: Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: clarissa.craft@wustl.edu.
authors.forename: Clarissa S
authors.initials: CS
authors.lastname: Craft
mesh_terms: D002001:Adipose Tissue, Brown / Q000473:pathology; D000818:Animals; D001823:Body Composition; D002113:Calcification, Physiologic; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D000071838:Fibrillin-1 / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020894:Microfibrils / Q000378:metabolism; D009929:Organ Size; D009928:Organ Specificity; D000072260:RNA Splicing Factors; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology; D054392:Adipokines
chemical_list: D003285:Contractile Proteins; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000072260:RNA Splicing Factors; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C016598:microfibrillar protein
keywords: Adipose tissue; Diabetes; Fibrillin; MAGP; Microfibril; TGFβ