In response to increases in fat mass, as seen in obesity, the adipose tissue undergoes distinct structural remodeling (1). Recent attention has focused on the importance of the extracellular matrix (ECM) in remodeling of adipose tissue during the development of obesity. The ECM not only provides structural support to the surrounding cells, but also plays a crucial role in the biological function of different organs. Components of the ECM include structural proteins, such as collagen and fibrillins, and various classes of adhesion proteins, such as fibronectin and proteoglycan.

Fibrillins are large proteins that form extracellular microfibril suprastructures ubiquitously found in elastic and nonelastic tissues. Constitutive components of the microfibrils also include the microfibril-associated glycoproteins (MAGPs) 1 and 2 (2,3). Microfibrils appear to have dual roles: They confer mechanical stability and limited elasticity to tissues and modulate the activity of members of the transforming growth factor-β (TGF-β) superfamily (46). The importance of microfibrils in regulating TGF-β activity is illustrated by the phenotype associated with fibrillin-1 mutations (e.g., Marfan syndrome), namely excess TGF-β activity resulting from an inability to sequester latent TGF-β in the ECM (7).

In obesity, it is believed that altered expression of ECM components may influence immune cell recruitment and activation, leading to increased inflammation in the adipose tissue. However, the exact mechanisms for these processes are still largely unknown. In this issue, Craft et al. (8) investigate how ECM components mediate metabolic pathways that are associated with obesity and identify MAGP1 as a key regulator. The MAGPs can bind the active form of TGF-β and thereby regulate its activity (46), and mice deficient in MAGP1 have a phenotype consistent with increased TGF-β activity (9). MAGP1-deficient mice have also previously been reported to display increased adiposity (9). The purpose of the study by Craft et al. therefore was to investigate if this increased adiposity and altered metabolic function results from increased TGF-β activity. Using MAGP1-deficient (Mfap2−/−) mice, Craft et al. demonstrate that MAGP1 has the capacity to regulate growth factor availability, which is important for maintaining normal metabolic function, and provide further support for the role of TGF-β in the etiology of obesity-associated metabolic disease (Fig. 1). The results also highlight the contribution that accessory proteins, such as MAGP1, provide to overall microfibril function and tissue homeostasis.

Figure 1

Lack of MAGP1 in Mfap2-deficient mice results in increased TGF-β signaling and obesity-associated metabolic disease. Treatment with a neutralizing TGF-β antibody enabled Mfap2-deficient mice to maintain normal metabolic function.

Figure 1

Lack of MAGP1 in Mfap2-deficient mice results in increased TGF-β signaling and obesity-associated metabolic disease. Treatment with a neutralizing TGF-β antibody enabled Mfap2-deficient mice to maintain normal metabolic function.

The relationship between ECM components, adipocyte size, and inflammation has been investigated previously. Khan et al. (10) recently explored the role of collagen VI in metabolic dysregulation. They demonstrated that weakening of the adipose tissue ECM by genetic disruption of collagen VI resulted in considerable improvement of the metabolic phenotype in the context of a high-fat diet and in mice with the ob/ob mutation. In addition, a study by Vaittinen et al. (11) showed that the microfibrillar-associated protein 5 (MFAP5) is highly expressed in human adipose tissue and is correlated with markers of insulin resistance, suggesting that MFAP5 is related to ECM remodeling during the development of obesity. Kolehmainen et al. (12) recently studied the effect of weight loss on gene expression in the adipose tissue of obese individuals with impaired metabolic function and found that genes regulating the ECM and cell death showed a strong downregulation after long-term weight reduction.

Several questions remain to be answered. Craft et al. show that MAGP1 mRNA expression is markedly increased in adipose tissue from obese humans. Why is this and what does it mean? In MAGP1-deficient mice, where MAGP1 expression is abolished, the mice display increased adiposity, suggesting that higher levels of MAGP1 are protective. It would be interesting to investigate if increased MAGP1 mRNA expression in obese human adipose tissue correlates with increased MAGP1 protein levels, or if increased mRNA levels are only compensatory. Would it be beneficial to induce expression of MAGP1 in obese human adipose tissue and would that result in a normalization of TGF-β activity? Furthermore, in contrast to proteins such as MAGP1 that inhibit TGF-β activity, other molecules are involved in releasing TGF-β from the ECM (13,14). How are these molecules regulated in adipose tissue and what are their roles in metabolic diseases?

In conclusion, the study by Craft et al. (8) highlights the fact that the ECM protein MAGP1 is extremely important in modulating adipocyte physiology. Further studies will be required to define the molecular mechanisms through which the ECM environment regulates adipocyte remodeling. It is likely that particular constituents of the ECM environment may provide possible targets for pharmacological intervention for the treatment of metabolic disorders.

See accompanying article, p. 1920.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
Lee
MJ
,
Wu
Y
,
Fried
SK
.
Adipose tissue remodeling in pathophysiology of obesity
.
Curr Opin Clin Nutr Metab Care
2010
;
13
:
371
376
[PubMed]
2.
Cleary
EG
,
Gibson
MA
.
Elastin-associated microfibrils and microfibrillar proteins
.
Int Rev Connect Tissue Res
1983
;
10
:
97
209
[PubMed]
3.
Sakai
LY
,
Keene
DR
,
Engvall
E
.
Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils
.
J Cell Biol
1986
;
103
:
2499
2509
[PubMed]
4.
Ramirez
F
,
Dietz
HC
.
Extracellular microfibrils in vertebrate development and disease processes
.
J Biol Chem
2009
;
284
:
14677
14681
[PubMed]
5.
Ramirez
F
,
Sakai
LY
,
Dietz
HC
,
Rifkin
DB
.
Fibrillin microfibrils: multipurpose extracellular networks in organismal physiology
.
Physiol Genomics
2004
;
19
:
151
154
[PubMed]
6.
Hubmacher
D
,
Tiedemann
K
,
Reinhardt
DP
.
Fibrillins: from biogenesis of microfibrils to signaling functions
.
Curr Top Dev Biol
2006
;
75
:
93
123
[PubMed]
7.
Ramirez
F
,
Carta
L
,
Lee-Arteaga
S
,
Liu
C
,
Nistala
H
,
Smaldone
S
.
Fibrillin-rich microfibrils—structural and instructive determinants of mammalian development and physiology
.
Connect Tissue Res
2008
;
49
:
1
6
[PubMed]
8.
Craft CS, Pietka TA, Schappe T, et al. The extracellular matrix protein MAGP1 supports thermogenesis and protects against obesity and diabetes through regulation of TGF-β. Diabetes 2014;63:1920–1932
9.
Weinbaum
JS
,
Broekelmann
TJ
,
Pierce
RA
, et al
.
Deficiency in microfibril-associated glycoprotein-1 leads to complex phenotypes in multiple organ systems
.
J Biol Chem
2008
;
283
:
25533
25543
[PubMed]
10.
Khan
T
,
Muise
ES
,
Iyengar
P
, et al
.
Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI
.
Mol Cell Biol
2009
;
29
:
1575
1591
[PubMed]
11.
Vaittinen M, Kolehmainen M, Schwab U, Uusitupa M, Pulkkinen L: Microfibrillar-associated protein 5 is linked with markers of obesity-related extracellular matrix remodeling and inflammation. Nutr Diabetes 2011;1:e15
12.
Kolehmainen
M
,
Salopuro
T
,
Schwab
US
, et al
.
Weight reduction modulates expression of genes involved in extracellular matrix and cell death: the GENOBIN study
.
Int J Obes (Lond)
2008
;
32
:
292
303
[PubMed]
13.
Rifkin
DB
.
Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability
.
J Biol Chem
2005
;
280
:
7409
7412
[PubMed]
14.
ten Dijke
P
,
Arthur
HM
.
Extracellular control of TGFbeta signalling in vascular development and disease
.
Nat Rev Mol Cell Biol
2007
;
8
:
857
869
[PubMed]
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.