MAGP1, the extracellular matrix, and metabolism

Abstract

Adipose tissue and the extracellular matrix were once considered passive players in regulating physiological processes. Now, both entities are acknowledged for their capacity to engage signal transduction pathways, and for their involvement in maintaining normal tissue homeostasis. We recently published a series of studies that identified a novel mechanism whereby an extracellular matrix molecule, MAGP1 (microfibril associated glycoprotein 1), can regulate energy metabolism in adipose tissue. MAGP1 is a component of extracellular microfibrils and plays a supportive role in maintaining thermoregulation by indirectly regulating expression of the thermogenic uncoupling proteins (UCPs). The focus of this commentary is to draw attention to the role of the extracellular matrix in regulating the bioavailability of signaling molecules, like transforming growth factor β (TGFβ), and exemplify that a better understanding of the extracellular matrix's biological properties could unveil a new source of therapeutic targets for metabolic diseases.

Keywords: BMP, bone morphogenetic protein; ECM, extracellular matrix; MAGP; MAGP, microfibril-associated glycoprotein; Microfibril; PGC-1α, peroxisome proliferative activated receptor-γ coactivator 1α; TGFβ; TGFβ, transforming growth factor β; UCP-1, uncoupling protein-1; obesity; thermogenesis.

Figure 1.

MAGP1 structure and hypothesized function. (A) Protein domain composition of MAGP1. (B) Schematic of MAGP1s proposed method of action. Fibrillin-1 self-associates to form the microfibril backbone. The N-terminus of fibrillin-1 contains a binding site for TGFβ's large latent complex (LLC). This interaction allows fibrillin-rich microfibrils to sequester inactive TGFβ in the ECM. Fibrillin-1 also has 2 binding sites for MAGP1. We hypothesize that MAGP1 functions to prevent aberrant TGFβ signaling by capturing liberated-active TGFβ.

Figure 2.

Assembly of a MAGP1-rich extracellular matrix by adipose tissue stromal cells. The stromal-vascular cell fraction of subcutaneous white adipose tissue from wild-type mice was cultured in growth media (DMEM/F12 media supplemented with 10% FBS and antibiotics) for 7 d Cells were fixed using cold methanol. MAGP1 was visualized using a primary antibody targeting murine MAGP1 and Alexa Fluor 555-conjugated secondary antibody (green). Nuclei were visualized using Hoechst nuclear dye (blue).