FIZZ1-Induced Myofibroblast Transdifferentiation from Adipocytes and Its Potential Role in Dermal Fibrosis and Lipoatrophy

Abstract

Subcutaneous lipoatrophy characteristically accompanies dermal fibrosis with de novo emergence of myofibroblasts such as in systemic sclerosis or scleroderma. Recently dermal adipocytes were shown to have the capacity to differentiate to myofibroblasts in an animal model. Transforming growth factor b can induce this phenomenon in vitro; however its in vivo significance is unclear. Because found in inflammatory zone 1 (FIZZ1) is an inducer of myofibroblast differentiation but an inhibitor of adipocyte differentiation, we investigated its potential role in adipocyte transdifferentiation to myofibroblast in dermal fibrosis. FIZZ1 caused significant and rapid suppression of the expression of fatty acid binding protein 4 and peroxisome proliferator-activated receptor-g in adipocytes, consistent with dedifferentiation with loss of lipid and Oil Red O staining. The suppression was accompanied subsequently with stimulation of a-smooth muscle actin and type I collagen expression, indicative of myofibroblast differentiation. In vivo FIZZ1 expression was significantly elevated in the murine bleomycin-induced dermal fibrosis model, which was associated with significant reduction in adipocyte marker gene expression and subcutaneous lipoatrophy. Finally, FIZZ1 knockout mice exhibited significantly reduced bleomycin-induced dermal fibrosis with greater preservation of the subcutaneous fat than wild-type mice. These findings suggested that the FIZZ1 induction of adipocyte transdifferentiation to myofibroblast might be a key pathogenic mechanism for the accumulation of myofibroblasts in dermal fibrosis. (Am J Pathol 2015 http://dx

Dendritic cells maintain dermal adipose–derived stromal cells in skin fibrosis

“…We found that ADSC numbers declined gradually starting at day 7 ( Figure 2E), correlating with the start of DWAT loss (Supplemental Figure 1C). As adipocytes differentiate into myofibroblasts during fibrosis (6,11), we asked whether ADSC loss might reflect differentiation into myofibroblasts and assessed myofibroblast numbers. Myofibroblasts are identified by their expression of α-smooth muscle actin (SMA) and express Sca1 at intermediate levels in BLM-induced lung fibrosis (25).…”

“…DWAT loss is also observed in murine scleroderma models (5)(6)(7)(8)(9)(10), which more readily allow evaluation of all skin layers upon sacrifice. DWAT loss involves loss of adipocytes, and this at least in part reflects a direct contribution of adipocytes to fibrosis, as recent studies have shown that adipocytes can transdifferentiate into myofibroblasts in vitro and in vivo in skin fibrosis (6,11). In addition to adipocytes, adipose tissue is also composed of a stromal-vascular fraction, and whether elements of this fraction are also lost with DWAT atrophy is not known.…”

Dermal Adipocytes: From Irrelevance to Metabolic Targets?

“…The authors proposed that dermal fibrosis might appear through transdifferentiation of dermal adipocytes. Recently, Martins and colleagues [27] reported that resistin-like molecule α(RELMα /FIZZ1) can cause the suppression of adipocyte-specific genes, leading to a de-differentiation, while in parallel inducing α-smooth muscle actin and type I collagen expression, reflecting a transition to myofibroblasts. RELMα is induced in the bleomycin-induced dermal fibrosis model also employed by Varga and colleagues.…”

Localization of RELM‐β/FIZZ2 Is Associated with Cementum Formation

“…On the other hand, RELM‐β/FIZZ2 has been reported to become localized in epithelial cells of intestinal and respiratory tracts (Artis et al, ; Mishra et al, ). RELM‐ α/FIZZ1 has multiple roles including those in cell proliferation, vascularization, and the induction of myofibroblast differentiation (Teng et al, ; Liu et al, ; Martins et al, ). Resistin/Fizz3 is known to regulate glucose metabolism (Steppan et al, ).…”