Extracellular Matrix Remodeling and Mechanical Stresses as Modulators of Adipose Tissue Metabolism and Inflammation - The Mechanobiology of Obesity and Related Diseases - page 110

of adipogenesis will continue to be identified, and that specific mechanisms and
signaling events associated with each cue will be resolved, furthering our
understanding of adipogenesis and possibly leading to advanced therapies to treat
adipose tissue-related disease and dysfunction.
5.2 Applied Mechanical Loading
In addition to matrix stiffness, individual WAT depots as well as WAT inter-
spersed within other tissues are subjected to various types of mechanical loads
in vivo. Subcutaneous, intramuscular and visceral adipose tissue may experience a
combination of tension, compression, and torsion due bodily motion depending on
the location of the depot. For instance, adipose tissue in the buttocks may expe-
rience compression during sitting, while intramuscular depots in the limbs may
experience tension during walking or running, though magnitudes of these forces
are unknown. Several studies involving the application of dynamic or static loads
on cultured stem cells and preadipocytes (also reviewed in [ 48 ]) suggest that cyclic
mechanical loads generally act to inhibit adipogenesis. For example, uniaxial
cyclic stretching of mouse 3T3-L1 preadipocytes to 130 % of their original length
at 1 Hz for 15 or 45 h inhibited their differentiation through activation of the
mitogen activated protein kinase (MAPK/ERK) signaling pathway [ 49 ]. Similarly,
cyclical stretching of human umbilical cord perivascular cells to 10 % equibiaxial
strain at 0.5 Hz for 24 and 60 h reduced adipogenesis under adipogenic culture
conditions. However, unlike the earlier study with preadipocytes, this reduction
seemed to occur through TGFb1/Smad signaling, rather than ERK activation [ 50 ].
Another study examined the differentiation of bovine mesenchymal stem cells
(MSCs) and multipotent mouse C3H10T1/2 cells subjected to 300 cycles of stretch
at 1 Hz for up to 2 weeks under culture conditions permissive for both osteo-
genesis and adipogenesis [ 51 ]. This study found that the cyclical stretch inhibited
adipogenesis but induced osteogenesis in both cell types by suppressing the
activation of PPARc. A subsequent study found that intermittent cyclical
stretching (2 % equibiaxial strain at 0.17 Hz and 6 h/day for 5 days) also inhibited
adipogenesis of C3H10T1/2 cells via downregulation of PPARc, while enhancing
osteogenesis [ 52 ]. These effects were observed whether the cells were cultured in
adipogenic or osteogenic medium. Follow-up studies applying the same loading on
C3H10T1/2 cells as well as murine marrow-derived MSCs while knocking down
various components of the b-catenin signaling pathway with siRNA implicated
this pathway in mechanically regulated inhibition of adipogenesis [ 53 , 54 ].
Interestingly, comparison of cyclic loading and vibration found that both modes
inhibited adipogenic differentiation of C3H10T1/2 cells, and that b-catenin was
activated under both mechanical loading conditions [ 55 ].
Despite variance in magnitude, frequency and cycle numbers between studies,
dynamic loading (stretch or vibrational) seems to generally inhibit adipogenesis,
although a consensus mechanism has not emerged. One potential quantitative