Extracellular Matrix Remodeling and Mechanical Stresses as Modulators of Adipose Tissue Metabolism and Inflammation - The Mechanobiology of Obesity and Related Diseases - page 104

and type VI microfibers. The structural integrity and function of WAT are also
influenced by a number of other ECM proteins, including fibronectin [ 6 ], throm-
bospondin [ 7 ], secreted acidic cysteine-rich glycoprotein (SPARC) [ 8 ], and matrix
metalloproteinases (MMPs), which influence cell shape and regulate the assembly,
deposition, and degradation of collagen type I fibers.
In post-adolescent humans, the total number of mature adipocytes is thought to
remain constant, as does the rate of turnover (estimated to be approximately 10 %
per year) [ 9 ]. Formation of new adipocytes through the differentiation of locally
resident pool of precursor cells in the stromal fraction (reviewed in [ 10 ]) is
essential for adipose tissue lipid turnover [ 11 ]. However, net expansion of tissue
cellular mass is quantitatively driven by increases in the sizes of mature adipo-
cytes, as hyperplastic growth increases the number of small cells that have a much
smaller volume of fat stored [ 12 ]. Studies with transgenic mice indicate that the
ECM proteins generally act to constrain the size expansion of adipocytes. For
example, deletion of col6a1 and resultant lack of collagen type VI led to increased
adipocyte size in both high-fat diet (HFD)-fed and genetically obese mice com-
pared to their littermates with intact col6a1 [ 13 ]. A similar phenotype was
observed in SPARC-null mice [ 14 ]. Degradation of collagen fibers via MMP
activity is essential for adipose tissue development and remodeling, with MMP14,
a pericellular type I collagenase, playing a major role [ 15 ]. Wild-type mice fed a
HFD exhibited rapid cleavage and turnover of collagen type I fibers in fat pads
along with robust weight gain. In contrast, mice heterozygous for MMP14 were
unable to remodel fat pad collagen networks and showed blunted weight gain [ 16 ].
Adipose cellular hypertrophy is associated with significant changes in the ECM
in both genetic and diet-induced models of obesity. In diabetic (db/db) obese mice,
various types of collagens are overexpressed in visceral (epididymal) WAT depots.
Overfeeding studies involving healthy human subjects showed dramatic increases
in ECM-related gene expression as well as connective tissue deposition in subcu-
taneous WAT during weight gain [ 17 ]. The formation of excess fibrous connective
tissue resulting from excessive deposition of ECM proteins, termed fibrosis, is a
common tissue response to chronic inflammation [ 18 ], and is increasingly con-
sidered a hallmark of WAT in obesity. A recent study involving human subjects
used picrosirius red staining and histomorphometry to find greater total fibrosis as
well as pericellular fibrosis around adipocytes in visceral (omental) WAT of obese
individuals compared to lean controls [ 19 ]. The same study also reported a negative
correlation between fibrosis of subcutaneous WAT and reduction in fat mass fol-
lowing bariatric surgery, suggesting that the presence of excess ECM fibers
diminishes the plasticity of the tissue. Here, plasticity refers to the ability of the
adipose tissue to increase (or decrease) the lipid storage capacity in response to
changes in the bodily energy balance. Conversely, loss of collagen type VI in
knockout mice ameliorates tissue stiffness [ 13 ]. The col6a1-/- mice also expressed a
lower level of elastin, a key molecule in matrix elasticity whose main function is to
return cells to their original shape upon stretching. Reducing the level of elastin
would allow adipocytes to stretch and expand with less tension from the elastin
fibers, which would typically attempt to pull them back into their original state.