Adipocyte 4(1): 60-64

MAGP1, the extracellular matrix, and metabolism

^{Department of Cell Biology and Physiology; Washington University; School of Medicine; Saint Louis; MO USA}

Commentary To: Craft CS, Pietka TA, Schappe T, Coleman T, Combs MD, Klein S, Abumrad NA, Mecham, RP. The extracellular matrix protein MAGP1 supports thermogenesis and protects against obesity and diabetes through regulation of TGFβ. Diabetes 2014; 63:1920-32; PMID: 24458361; http://dx.doi.org/10.2337/db13-1604

^{Correspondence to: Clarissa S Craft; Email:}ude.ltsuw@tfarc.assiralc

Received 2014 May 2; Revised 2014 Jul 23; Accepted 2014 Jul 29.

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: MAGP, Microfibril, obesity, TGFβ, thermogenesis

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

Abstract

The extracellular matrix (ECM) of adipose tissue is a milieu of basement membrane components, fibrillar and non-fibrillar collagens, fibronectin, SPARC, microfibrils, and numerous other proteins.¹ Once considered an inert structure, the ECM is now considered a dynamic regulator of cellular processes. The ECM influences cellular processes through 2 broad mechanisms: mechanical force and biochemical cues.

ECM protein composition and crosslinking determines the physical properties (i.e. rigidity) of the ECM network, which in turn dictates the constraint on adipocyte expansion. When metabolic conditions change, such as weight gain or loss, the ECM must remodel to accommodate the change in adipocyte size and number.^1-3 Inactivation of adipose-associated ECM genes in mice has demonstrated that changing the composition of the ECM in ways that alter its physical properties has functional consequences for adipose integrity. For example, over-expression of fibrillar collagens (mainly types I, III, and V), or preventing the remodeling of fibrillar collagens by inactivating collagen-degrading proteases, leads to a stiffer, fibrotic matrix that restricts tissue function.⁴ In contrast, decreasing ECM rigidity by reducing collagen I content (as occurs in the SPARC-null mouse) or by subtracting collagen VI from the mix, results in a permissive environment that supports adipose tissue expansion.^5-7

The ECM can interact with cells by directly engaging cell surface receptors or by regulating the delivery of signaling molecules to cells. Microfibrils are an example of ECM structures that do both: they provide mechanical stability to tissues and regulate the bioavailability of several growth factors.^8-12 The microfibril core consists of polymers of fibrillin proteins. Fibrillin polymers then associate with several additional “accessory” proteins that confer functionality to the fiber. For example, fibrillin-1 interacts with latent TGFβ binding proteins (LTBPs) to covalently anchor the large latent complex (LLC) of TGFβ into the ECM where it is sequestered away from the cell.¹³ Loss of fibrillin-LTBP binding increases free “active” TGFβ levels, causes aberrant TGFβ signaling, and is pathologic.¹²

Acknowledgments

I thank Dr. Robert P Mecham for helpful discussion and manuscript review.

Acknowledgments

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