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

Abstract

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^mgR/mgR (20-25% of normal fibrillin-1) and Fbn1^C1041G/+ (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^mgR/mgR mice displayed a significant reduction of fibrillin-1 in white adipose tissue, and no change was observed for Fbn1^C1041G/+ mice, each compared to their respective littermates. Male Fbn1^mgR/mgR mice had more white and brown adipose tissues, whereas female Fbn1^mgR/mgR and both male and female Fbn1^C1041G/+ showed no difference compared to their respective wild-type littermates. Consistent with this data, male Fbn1^mgR/mgR 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^mgR/mgR 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^mgR/mgR, Fbn1^C1041G/+ and wild-type mice. Increased lipid content, adipogenic differentiation and pAKT levels were observed when MSCs from both male and female Fbn1^mgR/mgR 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^mgR/mgR 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.

Keywords: Adipocyte differentiation; Adipose tissue; Extracellular matrix; Fibrillin-1; Marfan syndrome; Microfibrils.