Age, Diet and Epidermal Signaling Modulate Dermal Fibroblasts’ Adipogenic Potential

Abstract

The recognition of a distinct fat depot, the dermal white adipose tissue (dWAT), points out the complexity of the interaction among skin resident cells: keratinocytes, dermal fibroblasts (DFs) and adipocytes in response to physiological (diet, age) and pathological (injury) stimulations. dWAT has been recognized as a significant contributor to thermoregulation, hair cycle, immune response, wound healing and scarring. In this study, we examined age- and diet-related changes in dWAT modulation and DFs’ adipogenic potential. The data showed that diet modulates dWAT expansion predominantly by hypertrophy, whereas age affects the pool of adipocyte progenitor cells in the skin indicating its role in dWAT hyperplasia. Analysis of DFs’ migratory abilities in the model of skin explants isolated from the skin of young, old, low (LFD)- or high (HFD)-fat diet C56BL/6 mice revealed that HFD, regardless of animal age has the most profound stimulatory impact of DF migration. We determined that the adipogenic potential of DFs is comparable to stromal vascular fraction (SVF) of inguinal fat depot and ear mesenchymal stem cells (EMSC). We also showed the stimulatory role of epidermally expressed transcription factor Foxn1 on adipogenic signaling: bone morphogenetic protein 2 (Bmp2) and insulin-like growth factor 2 (Igf2) in keratinocytes.

Dermal White Adipose Tissue (dWAT) Is Regulated by Foxn1 and Hif-1α during the Early Phase of Skin Wound Healing

“…Although the classic studies by Chase et al [ 6 ], in the 1950s, demonstrated the synchrony between dermal adipocytes and hair follicle cycling, it was the work of Wojciechowicz et al [ 7 ], focusing on adipocyte development in mouse dorsal skin, that firmly established the presence of adipocyte tissue within the dermis that the authors named the dermal white adipose tissue (dWAT). The dWAT is a type of white adipose tissue and, similar to other fat depots, its content is regulated by the diet and increases in an obesogenic environment in both young and old mice that are fed a high-fat diet (HFD) [ 8 , 9 ]. In old mice, an increase in dWAT, due to 8 weeks of HFD feeding, seems to compensate for age-related skin (fibroblast-rich dermis) thinning [ 8 ].…”

“…They also determined that mature adipocytes after skin injury undergo lipolysis to release fatty acids (FAs), which in turn stimulate macrophage infiltration, whereas post-lipolytic adipocytes change their identity to become myofibroblasts. Walendzik et al demonstrated that the migration of dermal fibroblasts (DFs) from skin explants collected from HFD mice is much more robust than that from mice fed a low-fat diet (LFD), regardless of animal age (young vs. old) [ 9 ]. Follow-up analysis of DFs isolated from the skin of young and old mice fed a low-fat diet (LFD) or HFD, revealed differences in their adipogenic potential, particularly related to animal age, with respect to Zfp423 (determinant of preadipocyte commitment) and Zfp521 (negative regulator of adipogenesis) [ 9 ].…”

“…Walendzik et al demonstrated that the migration of dermal fibroblasts (DFs) from skin explants collected from HFD mice is much more robust than that from mice fed a low-fat diet (LFD), regardless of animal age (young vs. old) [ 9 ]. Follow-up analysis of DFs isolated from the skin of young and old mice fed a low-fat diet (LFD) or HFD, revealed differences in their adipogenic potential, particularly related to animal age, with respect to Zfp423 (determinant of preadipocyte commitment) and Zfp521 (negative regulator of adipogenesis) [ 9 ]. Moreover, it was also shown that the subpopulation of PDGFRα + /CD24 + /Sca1 + DFs, recognized as adipocyte progenitors [ 20 ], decreased with animal age, particularly in the group fed the LFD [ 9 ].…”

“…Follow-up analysis of DFs isolated from the skin of young and old mice fed a low-fat diet (LFD) or HFD, revealed differences in their adipogenic potential, particularly related to animal age, with respect to Zfp423 (determinant of preadipocyte commitment) and Zfp521 (negative regulator of adipogenesis) [ 9 ]. Moreover, it was also shown that the subpopulation of PDGFRα + /CD24 + /Sca1 + DFs, recognized as adipocyte progenitors [ 20 ], decreased with animal age, particularly in the group fed the LFD [ 9 ]. The origin of intradermal adipocytes, during development and during post-wounding skin reconstruction, are still under debate [ 20 , 21 ].…”

“…The broad spectrum of dWAT function has prompted research on its molecular regulation, particularly through signals derived from the epidermis [ 9 , 10 , 11 , 12 ]. Although limited, this research shows that the epidermal Wnt/β-catenin pathway, through the secretion of ligands for the BMP2 and insulin signaling pathways, regulates adipocyte differentiation [ 10 ].…”