The Extracellular Matrix Protein MAGP1 Is a Key Regulator of Adipose Tissue Remodeling During Obesity
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Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Lab- oratory, Sahlgrenska University Hospital
,
Gothenburg
,
Sweden;
and Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at University of Gothenburg
,
Gothenburg
,
Sweden
-
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-b (TGF-b)
superfamily (46). The importance of microfibrils in
regulating TGF-b activity is illustrated by the phenotype
associated with fibrillin-1 mutations (e.g., Marfan syndrome),
namely excess TGF-b activity resulting from an inability to
sequester latent TGF-b 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-b and thereby regulate its activity (46),
and mice deficient in MAGP1 have a phenotype
consistent with increased TGF-b 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-b activity. Using MAGP1-deficient (Mfap22/2)
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-b 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.
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
microfibrillarassociated 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.
2014 by the American Diabetes Association. See http://creativecommons.org
/licenses/by-nc-nd/3.0/ for details.
Figure 1Lack of MAGP1 in Mfap2-deficient mice results in
increased TGF-b signaling and obesity-associated metabolic
disease. Treatment with a neutralizing TGF-b antibody enabled
Mfap2-deficient mice to maintain normal metabolic function.
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-b activity? Furthermore, in
contrast to proteins such as MAGP1 that inhibit (...truncated)