Mechanical Stretching and Signaling Pathways in Adipogenesis - The Mechanobiology of Obesity and Related Diseases - page 43

The role of ERK/MAPK as to the adipogenic differentiation has been found to
have both stimulatory [ 40 , 87 - 92 ] and inhibitory [ 13 , 14 , 93 - 98 ] effects. As for
these apparently contradictory observations, Prusty and colleagues suggested that a
stimulation of the ERK/MAPK pathway could both promote and attenuate adi-
pogenesis depending on its time of activation during the differentiation process
[ 91 ]. In the early phase of 3T3-L1 adipocyte differentiation program, sequential
phosphorylation of C/EBPb by ERK/MAPK and glycogen synthase kinase 3b
(GSK3b) is required for the ability of C/EBPb to bind DNA [ 3 , 90 , 99 ]. On the
other hand, prolonged or continuous activation of the ERK/MAPK pathway during
the late stages is expected to block adipogenic gene expression due to the MAPK-
dependent inhibitory phosphorylation of PPARc decreasing its transcriptional
activity [ 94 , 100 - 103 ], or MEK-dependent redistribution from the nucleus to the
cytosol [ 104 , 105 ], or decreasing its expression level [ 13 - 15 ], all of these leading
to a downregulation of the PPARc's function in adipogenesis.
We have reported that the activated state of ERK1/2 was significantly pro-
longed during the induction period in response to the cyclic (1 Hz) uniaxial
stretching (up to 130 % of the original length = 100 %) than it was during the
same period under the unstretched condition [ 14 ]. Only the inhibitory function of
the ERK/MAPK pathway in the adipocyte differentiation of 3T3-L1 cells was
elicited in response to cyclic stretching, suggesting that prolonged or sustained
activation of the ERK/MAPK pathway acts in an inhibitory manner in the context
of adipocyte differentiation [ 14 ]. Inhibition of adipocyte differentiation through the
sustained ERK/MAPK activity was also demonstrated by Sakaue and colleagues;
blockade of endogenous MAPK phosphatase-1 (MKP-1), a negative regulator of
ERK/MAPK, resulted in persistence of ERK/MAPK activation and blocked the
differentiation even in the static condition [ 13 ]. The influence of the mechanical
stretching on the MKP-1 expression is yet to be examined.
The effects of the cyclic stretching were also examined in differentiation models
of mesenchymal stem cells (MSCs) [ 27 , 30 , 34 ], in which suppressed adipogenesis
through ERK/MAPK activation and down-regulation of PPARc were commonly
observed irrespective of the presence of adipogenic medium. In some cases, it has
been demonstrated that anti-adipogenic actions of the cyclic stretching were
devoted into osteoblastogenesis through increased expression of Runx2, a key
transcription factor associated with osteoblast differentiation [ 27 , 34 ]. However,
cyclic stretching alone induced neither osteoblastogenesis nor adipogenesis in
MSCs culture, though it apparently induced smooth muscle cells (SMCs) evi-
denced by the augmented expression of typical SMCs markers, such as alpha-
smooth muscle actin and calponin [ 31 ]. These results suggest that cyclic stretching
did not trigger the differentiation programs, but may perturb and/or modulate the
'hub' signal to direct a specific cell fate, such as adipogenic-osteogenic lineage
determination (Fig. 3 ).
On the other hand, it was reported that static and equibi- or multiaxial stretching
at 106-112 % of the original, which assumed to correspond a physiological tensile
strain distribution in weight-bearing adipose tissues during sitting and lying,
accelerates

lipid droplet formation in differentiating 3T3-L1 adipocytes by