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 microfibrilassociated 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 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.

Microfibril-associated glycoproteins MAGP-1 and MAGP-2 in disease

“…To date, no known skeletal diseases have been definitively linked to mutations in the human MAGP-1 gene. The MAGP-1 gene polymorphism rs2284746, discussed above, was associated with increased height in the GIANT consortium database [55], which is in agreement with skeletal studies in mice showing increased bone length in animals lacking MAGP-1 [56]. MAGP-1 deficiency in mice ( Mfap2 −/− ) results in numerous bone defects, supporting a connection between MAGP-1 and skeletal homeostasis.…”

“…A common trait in MAGP-1-deficient mice is the appearance of lesions on adult animal hind and forelimbs, which were determined to be abnormal healing fractures [13]. These bone lesions, along with increased overall body length, persisted in the MAGP-1-deficient animals through several back-crosses into inbred and outbred mouse strains [56, 57]. The prevalence of bone fractures suggested that bone strength and overall bone quality were compromised in the MAGP-1-deficient background.…”

“…DEXA scans confirmed that MAGP-1-deficient animals have age-dependent osteopenia associated with a reduction in whole-body bone mineral content as early as eight weeks of age and decreased bone mineral density by 12 weeks. μCT identified narrowing of the marrow cavity despite normal cortical bone thickness, and examination of cancellous and cortical bone identified the cancellous as most affected by MAGP-1 deficiency [56–58].…”

Structural and compositional diversity of fibrillin microfibrils in human tissues

“…MFAP2 (also known as MAGP-1) binds strongly to fibrillin microfibrils ( 63 , 77 ) and was found to interact directly with both TGF-β and BMP-7 ( 78 ). Disrupting this interaction in mice leads to a marked increase in TGF-β signaling attributed to the loss of its sequestration into the fibrillin microfibril network ( 79 ). As such, MFAP2 plays a key role in modulating fibrillin-growth factor signaling.…”

Overexpressed MAGP1 Is Associated With a Poor Prognosis and Promotes Cell Migration and Invasion in Gastric Cancer

“…KEGG pathway analysis of MAGP1 co-expressed genes further showed an enrichment of focal adhesion, PI3K-AKT signaling and TGF-β signaling. Previous studies showed MAGP1 was involved in several phenotypic abnormalities of the ECM by regulating TGF-β activity, not impact structural features of ECM (29). And Fibrillin-1 can indirectly mediate TGF-β pathway by binding MAGP1, which tethered the active form of TGF-β to the microfibril (30).…”