Biomedical Engineering Reference
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adipogenesis in cultured 3T3-L1 cells by preventing the up-regulation of peroxi-
some proliferator-activated receptor-c (PPARc), pointing to a direct link between
RhoA/ROCK signaling and transcriptional regulation of the adipocyte differenti-
ation program [
34
]. Treatment with the ROCK inhibitor Y-27632 reversed these
anti-adipogenic effects, confirming the suppressive effect of RhoA/ROCK acti-
vation on adipogenesis. A recent study by Noguchi et al. showed that treatment of
cultured 3T3-L1 cells with Y-27632 disrupted actin stress fibers, corroborating the
previous study that ROCK activity targets cytoskeletal reorganization [
35
]. The
same study also found that the RhoA/ROCK pathway interfered with insulin
signaling mediated by Akt phosphorylation, highlighting another potential point of
integration between mechanical and biochemical signaling.
While there is strong in vitro evidence that Rho/ROCK activation inhibits the
cytoskeletal reorganization necessary for adipocyte differentiation, there has been
less clarity regarding the role of this pathway in mediating mechanical cues
in vivo. An important clue pointing to the involvement of RhoA/ROCK signaling
in the development of obesity was provided by a study showing that long-term
treatment of obese Zucker rats with the ROCK inhibitor fasudil reduced blood
glucose, triglyceride, and free fatty acid levels, while blunting weight gain and
attenuating the increase in visceral adipose tissue mass [
36
]. More recently, pull-
down assays confirmed RhoA expression and activity in white adipose tissue of
C57BL/6 mice [
37
]. In the same study, overexpression of RhoA in differentiated
3T3-L1 adipocytes up-regulated the expression of monocyte chemoattractant
protein-1 (MCP-1), a major recruitment factor of monocytes and macrophages.
The most direct evidence to date linking RhoA/ROCK activation with cellular
hypertrophy and adipose tissue inflammation was provided in a recent report
authored by Hara et al., who proposed that the stretch experienced by lipid-laden
adipocytes could trigger RhoA/ROCK activity [
38
]. Mice fed a high-fat diet
(HFD) showed enlarged adipocytes as well as increased macrophage infiltration,
MCP-1 and TNF expression, and ROCK activity in adipose tissue compared to
mice fed a low-fat diet (LFD). The HFD mice also exhibited phenotypes char-
acteristic of diet-induced obesity, including increased adiposity and compromised
glucose tolerance. Treatment with fasudil attenuated these changes in a dose-
dependent manner, indicating that HFD-associated metabolic dysregulation, adi-
pocyte hypertrophy, and adipose tissue inflammation depend on RhoA/ROCK
signaling. The same study also showed that ROCK activity correlated with adi-
pocyte size in cultured 3T3-L1 adipocytes. Moreover, ROCK could be activated
by mechanically stretching mature adipocytes grown on a silicone substrate.
Interestingly, the degree of stretching required to elicit significant biochemical
responses was comparable to the size increase of adipocytes in HFD mice relative
to LDF mice. A constant, 72-h stretch to 120 % of non-stretched cell diameter was
sufficient to significantly increase ROCK activity and induce stress fiber formation.
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