Fibrillin-1 regulates white adipose tissue development, homeostasis, and function

Muthu, Muthu L.; Tiedemann, Kerstin; Fradette, Julie; Komarova, Svetlana V.; Reinhardt, Dieter P.

doi:10.1016/j.matbio.2022.05.002

Cited by 15 publications

(16 citation statements)

References 86 publications

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“…Heterozygous mice were crossed with C57BL/6 mice for more than 10 generations and maintained on this background to ensure that the colonies were genetically similar. Fbn1 mgR/mgR mice were obtained from Dr. Francesco Ramirez and were described previously [ 19 , 27 ]. For preventive treatment, starting at 4 weeks of age, WT and Fbn1 C1041G/+ mice were given losartan ad libitum in the drinking water at a final concentration of 0.3 g/L (20–30 mg/kg/day), or left untreated.…”

Section: Methodsmentioning

confidence: 99%

Fibrillin-1 Regulates Arteriole Integrity in the Retina

Alonso

Frémaux

et al. 2022

Biomolecules

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Fibrillin-1 is an extracellular matrix protein that assembles into microfibrils that provide critical functions in large blood vessels and other tissues. Mutations in the fibrillin-1 gene are associated with cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Fibrillin-1 is a component of the wall of large arteries but has been poorly described in other vessels. We examined the microvasculature in the retina using wild type mice and two models of Marfan syndrome, Fbn1C1041G/+ and Fbn1mgR/mgR. In the mouse retina, fibrillin-1 was detected around arterioles, in close contact with the basement membrane, where it colocalized with MAGP1. Both a mutation in fibrillin-1 or fibrillin-1 underexpression characteristically altered the microvasculature. In Fbn1C1041G/+ and Fbn1mgR/mgR mice, arterioles were enlarged with reduced MAGP1 deposition and focal loss of smooth muscle cell coverage. Losartan, which prevents aortic enlargement in Fbn1C1041G/+mice, prevented smooth muscle cell loss and vessel leakiness when administrated in a preventive mode. Moreover, losartan also partially rescued the defects in a curative mode. Thus, fibrillin-1/MAGP1 performs essential functions in arteriolar integrity and mutant fibrillin-1-induced defects can be prevented or partially rescued pharmacologically. These new findings could have implications for people with Marfan syndrome.

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Section: Methodsmentioning

confidence: 99%

Fibrillin-1 Regulates Arteriole Integrity in the Retina

Alonso

Frémaux

et al. 2022

Biomolecules

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“…These rapid-responding proteins were further illustrated by the known and predicted functional interactions of insulin (Figure D). Out of the 32 proteins, 16 (pink circle), including PODXL2, SEMA3C, FBN1, were annotated as interactors of insulin/growth factors, − the remaining 16, including LGR4, MYADM, and CNNM3, mostly have been reported to play critical roles in regulating glucose/lipid homeostasis or molecule transport (Figure D and Table S7). These data consistently support that our proposed strategy has sufficient temporal resolution to detect early events in insulin signaling.…”

Section: Resultsmentioning

confidence: 99%

Temporal Tracking of Insulin Action on the Cell Surface of Proteins at a Resolution of Ten Seconds

Wang

Fang

et al. 2023

Anal. Chem.

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The ligand–receptor signaling occurring on the cell surface governs cell growth, proliferation, and survival via rapidly triggering a cascade of events. Here, we for the first time report an in situ perturbation-free and rapid surface proteomic profiling at a temporal resolution of ten seconds. By this innovation, about 1022 cell surface-associated proteins were reproducibly identified and quantified. It is noteworthy that, upon a model ligand insulin stimulus, a few rapid-responding proteins at 10 s to 2 min were identified, e.g., CNNM3. Moreover, temporal response patterns were established for the members of GLUT4 storage vesicles (GSVs; responsible for glucose transportation) and confirmed with five known GSV proteins. This pattern was then exploited to uncover seven new regulatory proteins (LDLR, HFE, ECE1, MRC2, CORO1C, CPD, and BST2). Collectively, we showed a powerful surface proteomic tool to decipher rapid signaling of cell-surface proteins and to uncover new subunits involved in rapidly trafficking vesicles.

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“…Of note, Fbn1 mgR/mgR males were heavier than wild-type males (Figure 2B), which is unexpected considering the human MFS phenotype but has been previously observed in this mouse model and is attributed to altered adipose tissue homeostasis. 29…”

Section: Resultsmentioning

confidence: 99%

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Dubacher,

Sugiyama,

Smith

et al. 2023

Preprint

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OBJECTIVE: Hereditary aortic diseases (hADs) increase the risk of aortic dissections and ruptures. Recently, we have established an objective approach to measure the rupture force of the murine aorta, thereby explaining the outcomes of clinical studies and assessing the added value of approved drugs in vascular Ehlers-Danlos syndrome (vEDS). Here, we applied our approach to six additional mouse hAD models. APPROACH AND RESULT: We used two mouse models of Marfan syndrome (MFS) as well as one smooth-muscle-cell-specific knockout (SMKO) of Efemp2 and three CRISPR/Cas9-engineered knock-in models (Ltbp1, Mfap4, and Timp1). Moreover, one of the two MFS models was subjected to 4-week-long losartan treatment. Per mouse, three rings of the thoracic aorta were prepared, mounted on a tissue puller, and uniaxially stretched until rupture. The aortic rupture force of the SMKO and both MFS models was significantly lower compared with wild-type mice but in both MFS models higher than in mice modeling vEDS. In contrast, the Ltbp1, Mfap4, and Timp1 knock-in models presented no impaired aortic integrity. As expected, losartan treatment reduced aneurysm formation but surprisingly had no impact on the aortic rupture force of our MFS mice. CONCLUSIONS: We demonstrate for the first time that our read-out system is able to characterize the aortic biomechanical integrity of mice modeling not only vEDS but also related hADs, allowing the aortic-rupture-force-focused comparison of mouse models. Furthermore, aneurysm progression alone may not be a sufficient read-out for aortic rupture, as blood-pressure-lowering therapies preventing aortic aneurysms might not strengthen the weakened aortic wall. These results may contribute to better medical therapies of hADs.

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Fibrillin-1 regulates white adipose tissue development, homeostasis, and function

Cited by 15 publications

References 86 publications

Fibrillin-1 Regulates Arteriole Integrity in the Retina

Fibrillin-1 Regulates Arteriole Integrity in the Retina

Temporal Tracking of Insulin Action on the Cell Surface of Proteins at a Resolution of Ten Seconds

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

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