Collagens Regulating Adipose Tissue Formation and Functions

Abstract

The globally increasing prevalence of obesity is associated with the development of metabolic diseases such as type 2 diabetes, dyslipidemia, and fatty liver. Excess adipose tissue (AT) often leads to its malfunction and to a systemic metabolic dysfunction because, in addition to storing lipids, AT is an active endocrine system. Adipocytes are embedded in a unique extracellular matrix (ECM), which provides structural support to the cells as well as participating in the regulation of their functions, such as proliferation and differentiation. Adipocytes have a thin pericellular layer of a specialized ECM, referred to as the basement membrane (BM), which is an important functional unit that lies between cells and tissue stroma. Collagens form a major group of proteins in the ECM, and some of them, especially the BM-associated collagens, support AT functions and participate in the regulation of adipocyte differentiation. In pathological conditions such as obesity, AT often proceeds to fibrosis, characterized by the accumulation of large collagen bundles, which disturbs the natural functions of the AT. In this review, we summarize the current knowledge on the vertebrate collagens that are important for AT development and function and include basic information on some other important ECM components, principally fibronectin, of the AT. We also briefly discuss the function of AT collagens in certain metabolic diseases in which they have been shown to play central roles.

Keywords: adipogenesis; basement membrane; collagen; diabetes; dyslipidemia; extracellular matrix; fibronectin; fibrosis; lipodystrophy; obesity.

Figure 1

Structure and supramolecular assembly of the collagen types reported to contribute to AT physiology and pathology. Domain organizations of collagen α chains of different subfamilies are depicted in boxes. Collagens I, III, and V form collagen fibrils. Collagens XII and XIV bind to the fibrils and regulate their organization. Collagen XVIII binds to collagen IV network in the BM. Collagen XV resides at the interphase of the BM and collagen fibrils. Collagen IV forms beaded filaments at the fibrillar matrix-BM interphase. Collagen VIII forms hexagonal lattices at the BM. Triple helix, collagenous domains. Non-collagenous domains of different collagens are shown with different colours. Endotrophin domain of collagen VI and frizzled domain of collagen XVIII are indicated. The sizes of collagens and their assemblies are not presented at their correct scale. Post-translational modifications such as glycosaminoglycan chains in collagens XII, XIV, XV, and XVIII are not illustrated.

Figure 2

Key collagens associated with white adipocyte differentiation. During the adipogenic differentiation of adipocyte stem cells to mature adipocytes, the expression of collagens shifts from the fibrillar collagens I and III to the BM-associated collagens IV, VI, XV, and XVIII. This view is largely based on the in vitro model of murine 3T3-L1 preadipocytes, as discussed in the main text. The gray boxes present some common cell markers expressed at different stages of adipocyte differentiation. Abbreviations: αSMA—α smooth muscle actin; BM—basement membrane; C/EBP—CCAAT/enhancer-binding proteins; Col—collagen; GLUT4—glucose transporter 4; PDGFR—platelet-derived growth factor receptor; PPARγ—peroxisome proliferation-activated receptor γ; ZFP423—Zinc-finger protein 423.

Figure 3

Summary of collagens in AT dysfunction. (A) Upregulated collagens (arrows) in the WAT of obese humans. (B) Upregulated collagens (arrows) in the WAT of mice fed with a high-fat diet (HFD), or in obese ob/ob or diabetic db/db mouse models, or in the Hif1a+ mice with constitutively active HIF-1α. (C) Left: Key collagens forming large collagen bundles (blue) in hypoxic (pink) and fibrotic AT. Collagens which are reported to be associated with insulin resistance (right upper corner), or with AT inflammation (bottom, a macrophage depicted).