Mechanical Stretching and Signaling Pathways in Adipogenesis - The Mechanobiology of Obesity and Related Diseases - page 41

indicated that integrins a 5 and a 6 are differentially regulated during adipocyte
differentiation; a 5 expression is gradually diminished, but a 6 is increased during
adipogenesis [ 64 ]. On the other hand, b 1 integrin was constitutively expressed in
both preadipocytes and mature adipocytes [ 64 ].
It has been indicated that integrin-ECM interaction is one of the mechano-
sensing apparatuses, which could transmit cellular mechanical signals to both the
inside and outside of cells. Two pathways concerning mechanosensitive integrin
signaling have been proposed so far (Fig. 3 ), and it is likely that the activation of
ERK/MAPK is a convergent point of mechanotransduction pathways irrespective
of the types of cells [ 65 ]. One pathway is RhoA-dependent stress fiber formation
and phospholipase C activation, which lead to IP 3 -mediated intracellular Ca 2+
release and ERK/MAPK activation [ 65 , 66 ]. Another pathway involves focal
adhesion, where different kinds of mechanosensitive protein kinases, such as focal
adhesion kinase (FAK) and c-Src along with a set of adapter proteins such as Grb2
and Sos are recruited, and would eventually transit into the Ras-directed ERK/
MAPK pathway [ 65 , 67 ].
Ectopic integrin a 6 expression decreases the level of active ERK/MAPK and
cell growth. Integrin a 6 is critically involved in clustering growth-arrested pre-
adipocytes, where RhoA activity is negatively affected [ 64 ]. In contrast, ectopic
integrin a 5 expression significantly activates Rac, another member of the Rho
family, and greatly decreases adipogenic potential of preadipocytes, which would
induce proliferation of preadipocytes, promoting cell adhesion and spreading, and
chromatin remodeling [ 64 ]. This is consistent with the observation of decreased
expression of a 5 integrin and down-regulation of Rac activity during differentia-
tion of 3T3-L1 cells [ 64 ]. Of note, Sul and colleagues have demonstrated that Pref-
1/Dlk1, which acts to maintain the preadipocytes state and to prevent adipocyte
differentiation [ 68 ], directly interacts with fibronectin via the Pref-1 juxtamem-
brane domain and fibronectin C-terminal domain [ 69 ]. Disrupting fibronectin
binding to integrin by treating with RGD-peptide or knockdown of a 5 integrin
subunit and inhibition of Rac by knockdown or its dominant negative expression,
all serve to abolish ERK/MAPK activation [ 69 ]. Pref-1 does not prevent adipocyte
differentiation of such treated cells [ 69 ]. Thus, it seems likely that the integrin and
its downstream signaling FAK-Rac-ERK/MAPK pathway is a responsible
mechanism for the differentiation inhibitory action of Pref-1 via interaction with
fibronectin [ 69 ]. Therefore, perturbation of this integrin-ECM interaction would
activate RhoA and/or FAK-Rac, leading to an activation of ERK/MAPK and a
proliferation of preadipocytes as an anti-adipogenic response (Fig. 3 ). These
mechanisms may be implicated, at least in part, in the suppressive effect of
mechanical stresses on the adipogenesis.
Collectively, physical deformation caused by the stretching of membrane
components and/or cytoskeletal components (both of which interact directly or
indirectly with the ECM) is involved in the inhibitory mechanism of adipocyte
differentiation in response to cyclic stretching.