Dermal Adipocytes Research Articles

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

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 β can induce this phenomenon invitro; however its invivo 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-γ in adipocytes, consistent with dedifferentiation with loss of lipid and Oil Red O staining. The suppression was accompanied subsequently with stimulation of α-smooth muscle actin and type I collagen expression, indicative of myofibroblast differentiation. Invivo 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.

In vivo second-harmonic generation and ex vivo coherent anti-stokes raman scattering microscopy to study the effect of obesity to fibroblast cell function using an Yb-fiber laser-based CARS extension unit.

Nonlinear microscopy techniques are being increasingly used to perform in vivo studies in dermatology. These methods enable us to investigate the morphology and monitor the physiological process in the skin by the use of femtosecond lasers operating in the red, near-infrared spectral range (680-1,300 nm). In this work we used two different techniques that require no labeling: second harmonic generation (SHG) for collagen detection and coherent anti-Stokes Raman scattering (CARS) to assess lipid distribution in genetically obese murine skin. Obesity is one of the most serious public health problems due to its high and increasing prevalence and the associated risk of type 2 diabetes and cardiovascular diseases. Other than these diseases, nearly half of patients with diabetes mellitus suffer from dermatological complications such as delayed wound healing, foot ulcers and several other skin changes. In our experiment we investigated and followed the effects of obesity on dermal collagen alterations and adipocyte enlargement using a technique not reported in the literature so far. Our results indicate that the in vivo SHG and ex vivo CARS imaging technique might be an important tool for diagnosis of diabetes-related skin disorders in the near future.

Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection.

Adipocytes have been suggested to be immunologically active, but their role in host defense is unclear. We observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423(nur12) mice or in mice given inhibitors of peroxisome proliferator-activated receptor γ. This host defense function was mediated through the production of cathelicidin antimicrobial peptide from adipocytes because cathelicidin expression was decreased by inhibition of adipogenesis, and adipocytes from Camp(-/-) mice lost the capacity to inhibit bacterial growth. Together, these findings show that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin.

Skin infection triggers fat responses

Obesity is associated with chronic inflammation, but does fat tissue offer protection during infection? Zhang et al . noticed that the fat layers in the skin of mice thickened after inoculation with the pathogenic bacterium Staphylococcus aureus (see the Perspective by Alcorn and Kolls). Mutant mice incapable of forming new fat cells were more susceptible to infection. The differentiating fat cells secreted a small-molecule peptide called cathelicidin, specifically in response to the infection. By contrast, mature fat cells produce less cathelicidin, and are thus less protective. L.-j. Zhang, C. F. Guerrero-Juarez, T. Hata, S. P. Bapat, R. Ramos, M. V. Plikus, R. L. Gallo, Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347 , 67–71 (2015).[Abstract][Full Text] J. F. Alcorn, J. K. Kolls, Killer fat. Science 347 , 26–27 (2015).[Summary][Full Text]

Unwiring the transcriptional heat circuit.

Mature adipocytes are postmitotic (1), and therefore development of adipocytes requires the proliferation and differentiation of progenitor cells into mature adipocytes. The identity of adipose precursor cells and the molecular mechanisms that control their proliferation and differentiation are only partially understood. Brown adipose tissue (BAT) is specialized for energy expenditure through a process mediated by uncoupling protein 1 (UCP1) that uncouples respiration from ATP synthesis and generates heat (2). Current knowledge defines two types of thermogenic adipocytes based on their distinct origins, anatomical locations, and differential abilities to respond to stimuli. The classical brown adipocytes mainly develop during embryonic stage, form a discrete depot, and exert a high level of basal thermogenic capacity. The other type of brown fat-like cells, called beige or brite adipocytes, are dispersed in white adipose tissue (WAT) and are recruited and induced in response to certain stimuli. Although beige adipocytes also generate heat by UCP1-mediated proton leak, they arise from a myogenic factor 5-negative (Myf5−) developmental lineage distinct from brown adipocytes, which develop from Myf5+ progenitors (Fig. 1) (3, 4). Aside from the adrenergic pathways that activate thermogenesis in both brown and beige adipocytes, whether there exists a common factor that marks and specifies the fate of these thermo-competent cells remains unknown. In PNAS, Wang et al. (5) identify early B-cell factor 2 (Ebf2) as a marker that specifies the brown and beige adipocyte lineage from muscle, dermal, and white adipocyte lineages and provide new insight into transcriptional targets of Ebf2 that may play a role in activating the thermogenic gene program.

Adipocytes in Skin Health and Disease

Adipocytes are intimately associated with the dermal compartment of the skin, existing in a specialized dermal depot and displaying dynamic changes in size during tissue homeostasis. However, the roles of adipocytes in cutaneous biology and disease are not well understood. Traditionally, adipocytes within tissues were thought to act as reservoirs of energy, as thermal, or as structural support. In this review, we discuss recent studies revealing the cellular basis of the dynamic development and regenerative capacity of dermal adipocytes associated with the hair cycle and following injury. We discuss and speculate on potential roles of dermal adipocytes in cutaneous biology with an emphasis on communication during hair follicle growth and wound healing. Finally, we explore how alterations in the dermal adipose tissue may support clinical manifestations of cutaneous diseases such as lipodystrophy, obesity, and alopecia.

Epidermal Wnt/beta-catenin signalling promotes dermal adipocyte differentiation during hair follicle morphogenesis and regeneration

Epidermal Wnt/beta-catenin signalling promotes dermal adipocyte differentiation during hair follicle morphogenesis and regeneration