Biomedical Engineering Reference
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factor-null mice showed that HFD induced adipocyte death can occur independently
of macrophage infiltration and activation [ 29 ], which suggests that macrophage
recruitment and activation could result from, rather than cause, adipocyte hyper-
trophy and cell death.
In addition to metabolic stress from tissue stiffening, other direct signaling
mechanisms could be active to couple inflammation and ECM changes in obesity.
A transcriptional profiling study found strong correlation between up-regulation of
ECM components and markers for immune cell recruitment, activation, and
secretion of pro-inflammatory cytokines in subcutaneous WAT from obese human
subjects [ 30 ]. In particular, several subunits of integrin (alpha V, alpha M, beta 1,
beta 2, and beta 3) were significantly overexpressed in obese WAT relative to lean
controls, as were other cell adhesion molecules (e.g. syndecan binding protein) and
cytoskeletal regulatory proteins (e.g. actin related protein 2/3 complex). Impor-
tantly, histological examination performed in the same study confirmed the
presence of interstitial fibrosis around adipocytes, consistent with an earlier report
on the presence of inflammatory lesions in WAT of obese children [ 31 ]. These
co-expression patterns suggest an intriguing connection between WAT fibrosis,
inflammation, and classical mechanosensing and signal transduction pathways.
4 Pathways Activated by Mechanical Stimuli
Likely candidates involved in mediating the response of adipocytes to mechanical
stimuli are members of the Rho family of small GTPases that direct reorganization
of actin cytoskeleton. During terminal differentiation, adipocytes morphologically
change from fibroblastic cells to round, lipid-laden cells. This change depends on
the conversion of filamentous actin (F-actin) from stress fibers and lamellipodia to
cortical actin structures [ 32 ]. In a seminal study, McBeath et al. demonstrated the
essential role of RhoA-mediated cell shape regulation in lineage commitment of
human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate [ 33 ].
Controlling cell morphology using micropatterned substrates showed increased
activity of RhoA in spread cells. Direct manipulation of RhoA signaling super-
seded the effects of soluble factors in the culture medium. Inactivating RhoA
caused differentiation into adipocytes, whereas activating RhoA promoted osteo-
genesis. Further underscoring the critical role of mechanical cues, the effects of
RhoA manipulation depended on cell shape. Expression of a dominant-negative
RhoA led to adipogenesis only if cells were round.
In the same study, experiments with inhibitors of actin polymerization showed
that lineage specification signaling by RhoA occurs through the effector
Rho-associated protein kinase (ROCK) and its effects on myosin generated cyto-
skeletal tension. Elucidating the role of ROCK in adipogenesis has been facilitated
by the introduction of inhibitors Y-27632 and fasudil as well as discoveries of
bacterial dermonecrotic toxins that act through G-protein targets. Recently, Bannai
et al. reported that toxins from several bacterial species completely blocked
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