# Foxn1 Control of Skin Function
## 5 Foxn1 in Permeability Barrier Function, dWAT Physiology, and Resistance to Obesity  
The epidermis serves as a barrier to pathogen entry and a permeability barrier protecting from water and heat loss; thus, providing thermoregulatory functions. All these functions are mediated by keratinocytes and lipid-containing extracellular matrix. Lipids in the epidermis consist of ceramides (50% by weight), cholesterol (27%), and fatty acids (10%) that are synthesized by keratinocytes but in part come from circulation (essential fatty acids) [75]. A detailed comparative analysis of the lipidome of skin biopsies from Foxn1\({}^{-/-}\) and Foxn1\({}^{+/+}\) mice showed that mutation in the Foxn1 gene modifies the lipid profile [76]. Non-activity of Foxn1 in nude mouse skin leads to an increase in fatty acids, cholesterol sulphate, phospholipids, and sphingolipids with a concurrent decrease in triacylglycerlevels and diacylglycerols. The detected differences may explain the high rate (72%) of newborn inv-whn transgenic mouse mortality due to the inability to retain water [41]. Moreover, downregulation of PLC81, which is the target gene of Foxn1, impairs the barrier function of the epidermis due to dysregulation of Ca\({}^{2+}\) and p38 mitogen-activated protein kinase (MAPK) signaling [77].  
The modification of the skin lipidome profile in Foxn1\({}^{-/-}\) mice suggests dysregulation of thermoregulatory skin function, which at least partially may explain the resistance of Foxn1\({}^{-/-}\) mice to diet-induced obesity. A study by [PERSON] et al. showed that even mild cold stress (ambient housing temperature) increased energy expenditure, protecting Foxn1\({}^{-/-}\) mice from high-fat diet-induced obesity, compared with obesity-prone Foxn1\({}^{+/+}\) mice [78]. Similar observations were made by [PERSON] et al., examining PLC81 KO resistance to diet-induced obesity [79]. Both Foxn1\({}^{-/-}\) and PLC81 KO mice are hairless, which causes changes in thermoregulatory mechanisms to maintain body temperature [59]. It requires an increase in oxygen consumption and heat production that consequently may affect their resistance to diet-induced obesity. Although a central (hypothalamic) role of Foxn1 in controlling food intake should also be considered [78].  
However, a study performed on Foxn1\({}^{+/+}\) and Foxn1\({}^{+/-}\) mice, which have two (Foxn1\({}^{+/+}\)) or one (Foxn1\({}^{+/-}\)) active allele of Foxn1 but both have regular fur coats, revealed substantial differences between them in susceptibility to diet-induced obesity [80]. Foxn1\({}^{+/-}\) mice fed a high-fat diet for a period of eight weeks gained significantly less body weight than Foxn1\({}^{+/+}\) mice regardless of age or sex. Analysis of skin isolated from Foxn1\({}^{+/+}\) and Foxn1\({}^{+/-}\) mice showed abrogated expression of master regulators of adipogenesis (_Ppary_, _Fabp4_, _lepttin_, and _Mest_) in the skin of Foxn1\({}^{+/-}\) mice [80]. Moreover, the differences in dWAT adipogenesis between Foxn1\({}^{+/+}\) and Foxn1\({}^{+/-}\) mice were detected particularly during the skin wound healing process, supporting the important role of skin adipocytes in the restoration of skin integrity [80; 81]. Currently, it is known that the epidermal Wnt/\(\beta\)-catenin signaling pathway is a key initiator of the cascade that includes the Bmp (Bmp2/Bmp6) and insulin (Igf2) signaling pathways and stimulates the process of adipogenesis in the skin [82]. Recent data showed that gradual inactivation of Foxn1 in the skin of Foxn1\({}^{+/+}\), Foxn1\({}^{+/-}\), and Foxn1\({}^{-/-}\) mice is accompanied by a gradual decrease in Bmp2, Igf2, and Mest mRNA expression levels [80]. Whether Foxn1 is a mediator in the adipogenic cascade associated with Wnt/\(\beta\)-catenin and Bmp2/Igf2; thereby, affecting skin homeostasis, wound healing, and susceptibility to diet-induced obesity, is currently under investigation.