Native adiponectin plays a role in the adipocyte-mediated conversion of fibroblasts to myofibroblasts

Abstract

Adipocytes regulate tissues through production of adipokines that can act both locally and systemically. Adipocytes also have been found to play a critical role in regulating the healing process. To better understand this role, we developed a three-dimensional human adipocyte spheroid system that has an adipokine profile similar to in vivo adipose tissues. Previously, we found that conditioned medium from these spheroids induces human dermal fibroblast conversion into highly contractile, collagen-producing myofibroblasts through a transforming growth factor beta-1 (TGF-β1) independent pathway. Here, we sought to identify how mature adipocytes signal to dermal fibroblasts through adipokines to induce myofibroblast conversion. By using molecular weight fractionation, heat inactivation and lipid depletion, we determined mature adipocytes secrete a factor that is 30–100 kDa, heat labile and lipid associated that induces myofibroblast conversion. We also show that the depletion of the adipokine adiponectin, which fits those physico-chemical parameters, eliminates the ability of adipocyte-conditioned media to induce fibroblast to myofibroblast conversion. Interestingly, native adiponectin secreted by cultured adipocytes consistently elicited a stronger level of α-smooth muscle actin expression than exogenously added adiponectin. Thus, adiponectin secreted by mature adipocytes induces fibroblast to myofibroblast conversion and may lead to a phenotype of myofibroblasts distinct from TGF-β1-induced myofibroblasts.

Development and analysis of scaffold-free adipose spheroids

“…Herein we have presented two options for forming spheroids using either a 96-well spheroid plate or agarose micromolds. These are not the only methods for producing spheroids, indeed we have previously used hanging drop method as well [ 10 , 22 , 23 ], but these two options are highly accessible to a large number of labs and are suitable for many experimental needs. The largest trade-off between the two options are whether one needs a large number of spheroids or precise control over the size and variability of spheroids.…”

“…In addition, spheroid cultures developed large unilocular droplets >20 µm in diameter [ 10 ]. We have since used this method to uncover novel ways in which secreted factors from adipocytes alter fibroblast behaviour [ 22 , 23 ]. In addition, this technique has been adapted by other groups to investigate differences between spheroid and monolayer phenotypes in different species and cell types [ 24 ] and to incorporate immune cells [ 19 ].…”

The association between adipokines and pulmonary diseases: a mendelian randomization study

“…A previous investigation reported that individuals with an elevated adiponectin-to-leptin ratio demonstrated poorer survival outcomes compared to those with severe IPF and a reduced adiponectin-to-leptin ratio [ 24 ]. Nonetheless, experimental research has demonstrated that adiponectin can suppress the expression of alpha-smooth muscle actin (α-SMA), type I collagen, and pro-inflammatory cytokines [ 25 – 26 ]. Adiponectin has been proposed as a potential therapeutic agent for fibrosis-associated pathologies, its antifibrotic properties potentially mediated through the inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway [ 27 ].…”