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

Fibrillin-1 is an extracellular glycoprotein present throughout the body. Mutations in fibrillin-1 cause a wide spectrum of type I fibrillinopathies, including Marfan syndrome characterized by clinical manifestations in adipose tissues, among others. This study addresses the hypothesis that fibrillin-1 regulates adipocyte development and plays a vital role in adipose tissue homeostasis. We employed two mouse models - Fbn1 (20-25% of normal fibrillin-1) and Fbn1 (missense mutation in fibrillin-1) to examine the role of fibrillin-1 in adipose tissue development and homeostasis. Fibrillin-1 was detected around mature adipocytes in both mouse and human white adipose tissues. As expected, Fbn1 mice displayed a significant reduction of fibrillin-1 in white adipose tissue, and no change was observed for Fbn1 mice, each compared to their respective littermates. Male Fbn1 mice had more white and brown adipose tissues, whereas female Fbn1 and both male and female Fbn1 showed no difference compared to their respective wild-type littermates. Consistent with this data, male Fbn1 mice displayed hyperinsulinemia and an insulin resistance phenotype with higher levels of cholesterol and high-density lipoproteins in the serum. Fibrillin-1 deficiency in male Fbn1 mice also promoted adipogenic gene expression and led to hypertrophic expansion of mature adipocytes. To further elucidate the fibrillin-1-dependent adipogenic mechanisms in cell culture, we used primary bone marrow derived mesenchymal stem/stromal cells (MSCs) from Fbn1, Fbn1 and wild-type mice. Increased lipid content, adipogenic differentiation and pAKT levels were observed when MSCs from both male and female Fbn1 mice were differentiated. Furthermore, a recombinant fragment spanning the C-terminal half of fibrillin-1 significantly reduced adipocyte differentiation i) by binding to MSCs and inhibiting adipogenic commitment, and ii) by sequestering insulin, together suppressing the AKT signaling pathway. This fibrillin-1 fragment also rescued enhanced adipogenic differentiation of MSCs derived from Fbn1 mice. Overall, this study shows that altered adipose tissue homeostasis observed in fibrillin-1 deficient mice depends on the type of fibrillin-1 deficiency and the biological sex, and it shows that fibrillin-1 is a negative regulator of adipogenesis.