The Transcription Factor FOXN1 Regulates Skin Adipogenesis and Affects Susceptibility to Diet-Induced Obesity

Abstract

FOXN1, a transcription factor expressed in the epidermis, regulates keratinocyte differentiation and participates in skin wound healing. In this study, we explored the impact of FOXN1 insufficiency on diet-stimulated weight gain and dermal white adipose tissue regulation in the intact and wounded skin of FOXN1 eGFP/þ (heterozygotes, FOXN1-insufficient) mice in the context of age and diet. The results showed that on a high-fat diet, FOXN1 eGFP/þ mice gained significantly less body weight than their FOXN1 þ/þ counterparts (FOXN1-sufficient mice). The intact and wounded skin of FOXN1 eGFP/þ mice displayed abrogated expression of the master regulators of adipogenesis, PPARg, FABP4, and leptin, which decreased with age in FOXN1 þ/þ mice. FOXN1 insufficiency also resulted in a decreased percentage of adipocyte-committed precursor cells (CD24 þ) in the skin. The proadipogenic pathway genes Bmp2, Igf2, and Mest showed a gradual decrease in expression that accompanied the gradual inactivation of FOXN1 in the skin of FOXN1 þ/þ , FOXN1 eGFP/þ , and FOXN1 eGFP/eGFP (lack of FOXN1) mice. Bone morphogenetic protein 2 and insulin-like growth factor 2 signals colocalized with FOXN1-eGFP in the epidermis and in hair follicles. These data demonstrated that FOXN1 initiates the cascade of adipogenic signaling that regulates skin homeostasis and wound healing and affects susceptibility to dietinduced obesity.

Impairment of the Hif-1α regulatory pathway in Foxn1-deficient (Foxn1−/−) mice affects the skin wound healing process

“…regulates the adipogenic potential of the skin (dermal white adipose tissues; dWAT), thereby contributing to the skin wound healing process (Walendzik et al, 2019). The present data suggest that Foxn1 may modulate skin homeostasis (keratinocyte proliferation/differentiation) and the skin response to wounding through the regulation of the skin response to different (normoxia vs hypoxia) levels of oxygenation.…”

“…Our previous study revealed that Foxn1 is one of the key regulators in the skin wound healing process (Gawronska-Kozak et al, 2016;M. M. Kopcewicz et al, 2017;Walendzik et al, 2019).…”

“…The slides were counterstained with haematoxylin (Sigma-Aldrich by Merck). The sections were visualized using an Olympus microscope (BX43), photographed with an Olympus digital camera(XC50)and analysed with Olympus CellSens Software.Immunofluorescence detection and colocalization of Foxn1 and Trx-1 were performed on skin samples from young Foxn1::eGFP transgenic mice at day 3 post-wounding(Walendzik et al, 2019). The samples were fixed in 4% PFA for 2 h, washed in 0.1 M PB overnight at 4°C and stored in 18% sucrose/0.1 M PB solution prior to cryosectioning.…”

Impairment of the Hif‐1α regulatory pathway in Foxn1‐deficient (Foxn1 −/− ) mice affects the skin wound healing process

“…Immunofluorescence detection and colocalization of Foxn1 and Trx-1 were performed on skin samples from young Foxn1::Egfp transgenic mice at day 3 postwounding. 41 The samples were fixed in 4% PFA for 2 hours, washed in 0.1 M PB (Sigma-Aldrich) overnight at 4°C and stored in 18% sucrose (Chempur, Poland)/0.1 M PB solution prior to cryosectioning. Immunofluorescence assays were performed with the following primary antibodies: anti-Trx-1 (1:50, Cat# 24295, Cell Signaling) and anti-eGFP (1:400, Cat# 6673, Abcam).…”

Exosomes from Gastric Cancer Suppressed Adipo-differentiation of Adipose Mesenchymal Stem Cells to Promote Cancer-associated Cachexia via miR-155/ C/EPBβ pathway

“…Members of the CCAAT/enhancer-binding protein (C/EBP) family and the preceding peroxisoe proliferator-activated receptors (PPARs) family are the two most critical transcription factors associated to adipogenic-speci c program, among which C/EPBβ plays an essential role [8][9][10]. During A-MSCs adipo-differentiation, activated C/EBPβ triggers transcription of C/EPBα and PPARγ, which in turn coordinately activate genes, such as fatty acid-binding proteins (FABPs), fatty acid transport proteins (FATPs), whose expression produces for terminal adipocyte [11,12].…”