Rho and Rho-Kinase Activity in Adipocytes Contributes to a Vicious Cycle in Obesity That May Involve Mechanical Stretch

Abstract

The development of obesity involves multiple mechanisms. Here, we identify adipocyte signaling through the guanosine triphosphatase Rho and its effector Rho-kinase as one such mechanism. Mice fed a high-fat diet (HFD) showed increased Rho-kinase activity in adipose tissue compared to mice fed a low-fat diet. Treatment with the Rho-kinase inhibitor fasudil attenuated weight gain and insulin resistance in mice on a HFD. Transgenic mice overexpressing an adipocyte-specific, dominant-negative form of RhoA (DN-RhoA TG mice) showed decreased Rho-kinase activity in adipocytes, decreased HFD-induced weight gain, and improved glucose metabolism compared to wild-type littermates. Furthermore, compared to HFD-fed wild-type littermates, DN-RhoA TG mice on a HFD showed decreased adipocyte hypertrophy, reduced macrophage recruitment to adipose tissue, and lower expression of mRNAs encoding various adipocytokines. Lipid accumulation in cultured adipocytes was associated with increased Rho-kinase activity and increased abundance of adipocytokine transcripts, which was reversed by a Rho-kinase inhibitor. Direct application of mechanical stretch to mature adipocytes increased Rho-kinase activity and stress fiber formation. Stress fiber formation, which was also observed in adipocytes from HFD-fed mice, was prevented by Rho-kinase inhibition and in DN-RhoA TG mice. Our findings indicate that lipid accumulation in adipocytes activates Rho to Rho-kinase (Rho-Rho-kinase) signaling at least in part through mechanical stretch and implicate Rho-Rho-kinase signaling in inflammatory changes in adipose tissue in obesity. Thus, inhibition of Rho-Rho-kinase signaling may provide a therapeutic strategy for disrupting a vicious cycle of adipocyte stretch, Rho-Rho-kinase signaling, and inflammation of adipose tissue that contributes to and aggravates obesity.

Polycaprolactone nanofibrous mesh reduces foreign body reaction and induces adipose flap expansion in tissue engineering chamber

“…Low extracellular matrix stiffness and stretching (ie, decreased intracellular tension) promote adipogenesis, but compression impedes it. [60][61][62][63][64][65] In our study, less collagen deposition and capsule formation were found in the PCL group at the early and middle stages compared with the control group, which indicated lower extracellular matrix stiffness and intracellular tension in the tissue of the PCL group in this period. This collective finding explains why there were more adipogenic gene (PPARγ) expression at week 4 and larger volume of adipose tissue in the following weeks in the PCL group.…”

Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis

“…MLC 20 and myosin phosphatase target subunit 1 (MYPT-1) are ROCK-specific substrates (42)(43)(44). Previously, we reported that phosphorylation of MLC 20 at serine 19 residue is increased in the fibroblastic foci in human IPF (45).…”

“…(Myo)fibroblasts isolated from IPF lungs and lungs of mice after bleomycin injury demonstrated high constitutive ROCK activity, as indicated by ELISA-based ROCK activity assay, in comparison to their respective controls ( Figure 5B). Immunoblot analysis for phosphorylation of ezrin Thr567 /radixin Thr564 /moesin Thr558 (ERM), a group of ROCK-specific substrates that function as linkers between plasma membrane and actin cytoskeleton (42,46), demonstrated high baseline levels of phosphorylated ERM in fibrotic lung fibroblasts from mice and humans ( Figure 5C). Rhotekin pulldown assays, based on affinity precipitation of GTP-bound (i.e., active) RhoA using glutathione S-transferase-rhotekin (GST-RBD) fusion proteins and immunoblot analysis, demonstrated that (myo)fibroblasts isolated from fibrotic lungs expressed higher levels of active RhoA than cells isolated from control uninjured lungs ( Figure 5D).…”

Mechanical Regulation and Maintenance of Organismal Homeostasis - Scientific Basis for Health Promotion by Physical Motility and Exercise

“…Although there are very limited experimental findings concerning relaxing mechanical stress, inhibition of myosin II 21) 22) or Rho kinase 23) , both of which decrease actomyosin contractility, reportedly has antiinflammatory effects. Furthermore, adhesion to softer substrates has been reported to downregulate the NF-κB activity as well as the expression of pro-inflammatory cytokines 24) .…”