Mechanical Stretching and Signaling Pathways in Adipogenesis - The Mechanobiology of Obesity and Related Diseases - page 47

4 Possible Pharmacological Intervention
As mentioned above, the cyclic stretching perturbs a cascade-like expression of
adipogenic transcription factors during the induction (determination) period of
adipocyte differentiation. The cyclic stretching was substantially effective con-
cerning a reduced differentiation efficacy, which is caused mainly by down-reg-
ulation of PPARc during the late phase of the induction period [ 14 ]. We further
investigated whether or not any other agents may cooperate with the stretching
[ 15 ].
A variety of endogenous and exogenous lipids and/or fatty acids play important
roles in adipocyte differentiation; at least some of their functions are attributable to
their regulation of C/EBPs and PPARc [ 135 ]. Eicosapentaenoic acid (EPA,
[5Z,8Z,11Z,14Z,17Z]-5,8,11,14,17-icosapentaenoic acid) and docosahexaenoic
acid (DHA, [4Z,7Z,10Z,13Z,16Z,19Z]-docosa-4,7,10,13,16,19-hexaenoic acid)
are fish-oil-derived x-3 PUFA. Ingestion of x-3 PUFA, including EPA and DHA,
is considerably attractive for their potential to lower the risk of cardiovascular
events, especially with respect to their anti-thrombotic, anti-inflammatory, anti-
atherogenic, and anti-arrhythmic actions [ 136 , 137 ]. The majority of the beneficial
effects are attributed to changes in lipid metabolism in hepatic tissues [ 138 , 139 ].
Moreover, x-3 PUFA can modulate gene expression involved in lipid homeostasis
in adipocytes [ 138 - 141 ]; however, the administration of either EPA or DHA in a
static culture of 3T3-L1 cells showed only a marginal or weak effect on adipocyte
differentiation [ 110 ], although substantial suppressive action of EPA, at the
pharmacologically highest concentration (100 lM), on lipid droplet formation in
differentiating 3T3-L1 cells was recently reported [ 142 ].
It is considered that EPA can be a good substrate for COX-2 both in vitro and
in vivo but is only a poor substrate for COX-1 under the particular condition of an
increased peroxide tone [ 143 ]. In contrast, DHA cannot be a direct substrate for
both COXs. Thus, EPA, but not DHA [ 144 ], will be converted into the 3-series
PGs, namely PGH 3 and its metabolites, resulting in either same or altered bio-
logical activities depending on the class of PGs [ 143 ]. The exact molecular
mechanism(s) of this combined effect is yet to be further clarified. The cyclic
stretching significantly up-regulates COX-2 expression; thus the addition of EPA,
but not DHA, would be efficiently converted into PGH 3 and the inhibitory 3-series
PGs as well as endogenous 2-series PGs (Fig. 3 ), leading to an efficient inhibition
of 3T3-L1 adipogenesis [ 15 ].
Mechanosensing mechanisms in adipocytes would be expected to be a direct
pharmacological target for the purpose of anti-obesity and other adipocyte-related
pathogenicity including impaired glucose tolerance and hypercholesterolemia, or
cell/tissue-regenerating medicine. For example, compounds that interact with
integrin-ECM binding may modulate adipogenesis either positively or negatively
[ 145 - 147 ].
Furthermore, Hara et al. [ 35 ] demonstrated that lipid accumulation in mature
adipocytes would activate Rho-Rho-kinase signaling possibly through mechanical