Extracellular Matrix Remodeling and Mechanical Stresses as Modulators of Adipose Tissue Metabolism and Inflammation - The Mechanobiology of Obesity and Related Diseases - page 113

6 Concluding Remarks
In this chapter, we reviewed a potential role for mechanical regulation of adipose
tissue function, focusing on ECM changes associated with cellular hypertrophy
(Fig. 1 ). The studies discussed in this chapter broadly agree that the fibrous ECM of
adipose tissue acts to constrain the expansion of adipocytes, as evidenced by blunted
weight gain in animal models lacking MMPs for ECM remodeling. While adipose
tissue normally exhibits a high degree of plasticity, the constraint imposed by the
ECM likely sets an upper limit (estimated to be ca. 1 lg lipid per cell [ 60 , 61 ]) to
the capacity for cell size expansion and lipid storage. It should be noted that the
evidence for this upper limit is based on observed trends of average adipocyte sizes
in selected adipose tissue depots of high BMI individuals. It remains unclear
whether there is a genetically determined maximal size for adipocytes. Comparisons
of adipose tissue growth in obesity-prone and obesity-resistant mice under a stan-
dard or a high-fat diet suggest that adipocyte size primarily depends on diet, whereas
the number increase of adipocytes depends on strain [ 12 ].
The lipid storage capacity of adipose tissue could be adjusted through tissue
remodeling involving the formation of new adipocytes through differentiation of
locally resident stem cells and preadipocytes, and formation of capillary networks
through neovascularization. Indeed, hypertrophic adipocytes are thought to secrete
a host of paracrine factors to promote adipogenic differentiation of precursor cells.
However, the addition of lipid storage capacity through adipogenesis is likely also
limited, as the total number of mature adipocytes remains relatively constant in
adult humans. Consequently, chronic overfeeding and/or genetic factors can
overwhelm the capacity for lipid storage via cellular expansion and tissue
remodeling, leading to ectopic lipid deposition in muscle and liver and elevation of
free fatty acids in circulation.
In addition to these systemic effects, adipose cellular hypertrophy also corre-
lates with the development of a pro-inflammatory state within the tissue, which in
turn could drive metabolic dysregulation, leading to insulin resistance and elevated
free fatty acid efflux. As discussed above, one leading biochemical explanation
involves hypoxia-induced fibrosis. Alternative hypotheses involving the recruit-
ment and/or polarization of activated macrophages have also been investigated.
Less well studied is the role of mechanical stresses that arise from hypertrophy. As
demonstrated by Hara et al., one type of stress is a persistent stretch in the cell
membrane, which could activate mechanotransduction pathways. Recent findings
reported by Hara et al. and others point to the RhoA/ROCK pathway as a key link
between mechanical stretch and the observed pro-inflammatory state. There is
now substantial evidence that RhoA/ROCK activation inhibits adipogenesis
through PPARc suppression while stimulating the production of pro-inflammatory
cytokines.
While few in number, studies have effectively demonstrated that external
mechanical influences experienced by adipocytes via the ECM and applied forces
have significant effects on adipocyte differentiation and function. These extracellular