Skin aging: Dermal adipocytes metabolically reprogram dermal fibroblasts.

Emerging data connects the aging process in dermal fibroblasts with metabolic reprogramming, provided by enhanced fatty acid oxidation and reduced glycolysis. This switch may be caused by a significant expansion of the dermal white adipose tissue (dWAT) layer in aged, hair-covered skin. Dermal adipocytes cycle through de-differentiation and re-differentiation. As a result, there is a strongly enhanced release of free fatty acids into the extracellular space during the de-differentiation of dermal adipocytes in the catagen phase of the hair follicle cycle. Both caveolin-1 and adiponectin are critical factors influencing these processes. Controlling the expression levels of these two factors also offers the ability to manipulate the metabolic preferences of the different cell types within the microenvironment of the skin, including dermal fibroblasts. Differential expression of adiponectin and caveolin-1 in the various cell types may also be responsible for the cellular metabolic heterogeneity within the cells of the skin.

Phenotypical Conversions of Dermal Adipocytes as Pathophysiological Steps in Inflammatory Cutaneous Disorders.

Adipocytes from the superficial layer of subcutaneous adipose tissue undergo cyclic de- and re-differentiation, which can significantly influence the development of skin inflammation under different cutaneous conditions. This inflammation can be connected with local loading of the reticular dermis with lipids released due to de-differentiation of adipocytes during the catagen phase of the hair follicle cycle. Alternatively, the inflammation parallels a widespread release of cathelicidin, which typically takes place in the anagen phase (especially in the presence of pathogens). Additionally, trans-differentiation of dermal adipocytes into myofibroblasts, which can occur under some pathological conditions, can be responsible for the development of collateral scarring in acne. Here, we provide an overview of such cellular conversions in the skin and discuss their possible involvement in the pathophysiology of inflammatory skin conditions, such as acne and psoriasis.

Dermal adipocytes contribute to the metabolic regulation of dermal fibroblasts.

Dermal fibroblasts are an essential population of skin cells. They are not only responsible for synthesis and remodelling of the extracellular matrix of the dermis, but also communicate with other skin cells via autocrine and paracrine interactions. Skin-associated dermal adipocytes reside below the reticular dermis. Strong lipolysis is observed during the regression of dermal adipocytes. However, the nature of the local intercellular crosstalk in which lipids released by dermal adipocytes affecting the metabolism of adjacent skin fibroblasts has not yet been examined. With the use of a series of novel mouse models that allow us to manipulate adipocytes, we demonstrate that dermal adipocytes can modulate the structure of the dermis through regulating extracellular matrix production in dermal fibroblasts. Fatty acids released by dermal adipocytes are involved in this process. Our observations offer new in vivo insights into the role of dermal adipocyte-derived lipids in influencing metabolism of adjacent local cells in the skin through a paracrine effect in the microenvironment of the dermal adipocyte.

Caveolin-1 as a possible target in the treatment for acne.

Expression of caveolin-1 (Cav-1) is an important pathophysiological factor in acne. Cav-1 strongly interacts with such well-recognized etiopathogenic factors such as hyperseborrhea, follicular hyperkeratinization and pathogenicity of Cutibacterium acnes. Cav-1 is a strong negative regulator of transforming growth factor beta (TGF-ß) expression. It acts as a critical determinant of autophagy, which is significantly induced in acne lesions through C. acnes and by absorption of fatty acids. Cav-1 also demonstrates different correlations with the development of innate immunity. We propose that normalization of Cav-1 expression can serve as a target in anti-acne therapy.

Caveolin as a Universal Target in Dermatology.

Caveolin-1 is strongly expressed in different dermal and subdermal cells and physically interacts with signaling molecules and receptors, among them with transforming growth factor beta (TGF-ß), matrix metalloproteinases, heat shock proteins, toll-like and glucocorticoid receptors. It should therefore be heavily involved in the regulation of cellular signaling in various hyperproliferative and inflammatory skin conditions. We provide an overview of the role of the caveolin-1 expression in different hyperproliferative and inflammatory skin diseases and discuss its possible active involvement in the therapeutic effects of different well-known drugs widely applied in dermatology. We also discuss the possible role of caveolin expression in development of the drug resistance in dermatology. Caveolin-1 is not only an important pathophysiological factor in different hyperproliferative and inflammatory dermatological conditions, but can also serve as a target for their treatment. Targeted regulation of caveolin is likely to serve as a new treatment strategy in dermatology.

Adipocyte-myofibroblast transition as a possible pathophysiological step in androgenetic alopecia.

Appearance of local fibrotic structures around and beneath hair follicles during their involution is a known hallmark of androgenetic alopecia (AGA). We hypothesise that this fibrosis can be connected with recently uncovered adipocyte-myofibroblast transition (AMT) involving the dermal adipocytes. This reflects that AMT is at least partially androgen-dependent, and we propose that AMT may play a role in AGA.

Interfacial Adipose Tissue in Systemic Sclerosis.

PURPOSE OF REVIEW: This review provides a summary of recent insights into the role of the local white adipose tissue (WAT) in systemic sclerosis. RECENT FINDINGS: Adipocytes located in an interfacial WAT area adjacent to fibrotic lesions have an intermediate phenotype and special properties implicated in fibrotic pathology in systemic sclerosis (SSc). The important role of these cells is recognized in different pathologies, such as wound healing, psoriasis, breast cancer, and prostate cancer. Additionally, both immature and mature adipocytes are involved in the appearance of fibroblast-like cells but exhibit different phenotypes and synthetic properties. Adipocytes from interfacial WAT adjacent to the fibrotic area in SSc are phenotypically different from bulk adipocytes and are involved in pathogenesis of SSc. Immature and mature adipocytes from this WAT layer differentiate into various types of fibroblast-like cells, making the local ratio of immature to mature adipocytes in interfacial WAT of particular importance in SSc pathogenesis.

Dermal adipocytes and hair cycling: is spatial heterogeneity a characteristic feature of the dermal adipose tissue depot?

Adipocytes are widely distributed in the dermis, in a unique fat depot referred to as dermal white adipose tissue (dWAT). In rodents, dWAT is present as widespread thin layers, whereas in pigs and humans, it is present in clusters referred to as 'dermal cones' around the pilosebaceous units. This distinct layer of fat cells located above the subcutaneous white adipose tissue is important for proper hair follicle (HF) cycling in rodents. Murine HFs produce spatially restricted synchronous patches after their second postnatal cycle which correlates with the spatial heterogeneity of murine dWAT. Similarly, the cycling of HFs in humans may also be related to the spatial distribution of dWAT, making the difference between murine and human HF cycling of more quantitative than of qualitative nature. This should allow the production of small spatially correlated HF patches in human skin, and we propose that this process can be regulated by paracrine signalling involving a number of signalling modules, including the hedgehog pathway. This pathway is an established player in HF cycling, but is also involved in the regulation of adipogenesis and may therefore be a key regulator of the process across species. We also suggest that the spatial heterogeneity of dWAT is connected not only to HF cycling, but may also be related to other physiological and pathological processes in the skin.

Are dermal adipocytes involved in psoriasis?

There is rapidly growing evidence that adipose tissue is involved in the pathophysiology of psoriasis. Recent results demonstrate that murine skin can react to pathogens with the expansion of its dermal adipose depot and an increased production of antimicrobial peptides, which in turn can cause exacerbation of psoriasis-associated inflammation. We hypothesize that dermal adipocytes rather than subcutaneous adipose tissues are involved in the pathophysiology of psoriasis. This model is supported by the observations that the use of a number of different therapeutic options to alleviate psoriasis invariably leads to a modulation of the dermal adipose tissue. We propose to test this hypothesis through a detailed profiling effort of adipocytes from psoriatic lesions prior to and after psoriasis-relevant therapies.

The Facial Adipose Tissue: A Revision.

Recent advantages in the anatomical understanding of the face have turned the focus toward the subcutaneous and deep facial fat compartments. During facial aging, these fat-filled compartments undergo substantial changes along with other structures in the face. Soft tissue filler and fat grafting are valid methods to fight the signs of facial aging, but little is known about their precise effect on the facial fat. This narrative review summarizes the current knowledge about the facial fat compartments in terms of anatomical location, histologic appearance, immune-histochemical characteristics, cellular interactions, and therapeutic options. Three different types of facial adipose tissue can be identified, which are located either superficially (dermal white adipose tissue) or deep (subcutaneous white adipose tissue): fibrous (perioral locations), structural (major parts of the midface), and deposit (buccal fat pad and deep temporal fat pad). These various fat types differ in the size of the adipocytes and the collagenous composition of their extracellular matrix and thus in their mechanical properties. Minimal invasive (e.g., soft tissue fillers or fat grafting) and surgical interventions aiming to restore the youthful face have to account for the different fat properties in various facial areas. However, little is known about the macro- and microscopic characteristics of the facial fat tissue in different compartments and future studies are needed to reveal new insights to better understand the process of aging and how to fight its signs best.

Soft tissue fillers as non-specific modulators of adipogenesis: change of the paradigm?

Dermal filler injection is a cornerstone of facial rejuvenation procedures. Based on available data in animal and human studies, we suppose that the activation and proliferation of adipose-derived stem cells and expansion of mature adipocytes play a crucial role in long-term effects of volumizing, tissue tightening and beautification.

Is the endotoxin-complement cascade the major driver in lipedema?

Lipedema is a poorly understood disorder of adipose tissue characterized by abnormal but symmetrical deposition of subcutaneous white adipose tissue (WAT) in proximal extremities. Here, we propose that the underlying cause for lipedema could be triggered by a selective accumulation of bacterial lipopolysaccharides (LPS; also known as endotoxin) in gluteofemoral WAT. Together with a malfunctioning complement system, this induces low-grade inflammation in the depot and raises its uncontrollable expansion. Correspondingly, more attention should be paid in future research to the endotoxemia prevalent in patients with lipedema. We would like to propose that proper management of endotoxemia can reduce the progression and even improve the state of disease in patients with lipedema.

Pathophysiology of cellulite: Possible involvement of selective endotoxemia.

The most relevant hallmarks of cellulite include a massive protrusion of superficial adipose tissue into the dermis, reduced expression of the extracellular glycoprotein fibulin-3, and an unusually high presence of MUSE cells in gluteofemoral white adipose tissue (gfWAT) that displays cellulite. Also typical for this condition is the hypertrophic nature of the underlying adipose tissue, the interaction of adipocytes with sweat glands, and dysfunctional lymph and blood circulation as well as a low-grade inflammation in the areas of gfWAT affected by cellulite. Here, we propose a new pathophysiology of cellulite, which connects this skin condition with selective accumulation of endogenous lipopolysaccharides (LPS) in gfWAT. The accumulation of LPS within a specific WAT depot has so far not been considered as a possible pathophysiological mechanism triggering localized WAT modifications, but may very well be involved in conditions such as cellulite and, secondary to that, lipedema.

Assessment of Mechanical Stress Induced by Radiofrequency Currents on Skin Interfaces.

The epidermal-dermal (ED) and dermal-subcutaneous (DS) junctions are the most prominent skin interfaces, which are known to be of primary importance in different dermatological and aesthetic conditions. These interfaces are strongly modified in aging skin, and their effective targeting can lead to improvement of skin appearance in aging and by cellulite. Application of radiofrequency (RF) currents to the skin can selectively produce mechanical stress on these interfaces. Here, we assess the stresses induced by RF currents of different frequencies on EDJ and DSJ and discuss possible applications of the interfacial therapy in aesthetic medicine.

Acoustic Waves in Axonal Membrane and Caveolins are the New Targets for Pain Treatment with High Frequency Ultrasound.

Reciprocal interaction between electrical and mechanical waves observed in axonal membrane during its excitation leads to a paradigm shift in pain research making the uncoupling of electro-mechanical signals an interesting target in pain treatment. This uncoupling can be realized either through direct disturbance of the mechanical surface waves in axonal membrane or through shifting of the thermodynamic state of this membrane far from its phase transition point. Both effects can be effectively realized through application of the very high frequency ultrasound waves. Additional target for application of ultrasound in pain treatment is the caveolin-1, which is abundantly present in Schwann cells as well as in the non-axonal tissues. Both targets demonstrate frequency-dependent reactions, thus making a very high frequency ultrasound a promising treatment modality in pain treatment.

Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral-bacterial interactions.

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.

The MMP14-caveolin axis and its potential relevance for lipoedema.

Lipoedema is associated with widespread adipose tissue expansion, particularly in the proximal extremities. The mechanisms that drive the development of lipoedema are unclear. In this Perspective article, we propose a new model for the pathophysiology of lipoedema. We suggest that lipoedema is an oestrogen-dependent disorder of adipose tissue, which is triggered by a dysfunction of caveolin 1 (CAV1) and subsequent uncoupling of feedback mechanisms between CAV1, the matrix metalloproteinase MMP14 and oestrogen receptors. In addition, reduced CAV1 activity also leads to the activation of ERα and impaired regulation of the lymphatic system through the transcription factor prospero homeobox 1 (PROX1). The resulting upregulation of these factors could effectively explain the main known features of lipoedema, such as adipose hypertrophy, dysfunction of blood and lymphatic vessels, the overall oestrogen dependence and the associated sexual dimorphism, and the mechanical compliance of adipose tissue.

The Role of Adipocytes and Adipocyte-Like Cells in the Severity of COVID-19 Infections.

Coronavirus disease-2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrates high morbidity and mortality caused by development of a severe acute respiratory syndrome connected with extensive pulmonary fibrosis. In this Perspective, we argue that adipocytes and adipocyte-like cells, such as pulmonary lipofibroblasts, may play an important role in the pathogenic response to SARS-CoV-2. Expression of angiotensin-converting enzyme 2 (the functional receptor for SARS-CoV) is upregulated in adipocytes of patients with obesity and diabetes, which turns adipose tissue into a potential target and viral reservoir. This may explain why obesity and diabetes are potential comorbidities for COVID-19 infections. Similar to the recently established adipocyte-myofibroblast transition, pulmonary lipofibroblasts located in the alveolar interstitium and closely related to classical adipocytes demonstrate the ability to transdifferentiate into myofibroblasts that play an integral part of pulmonary fibrosis. This may significantly increase the severity of the local response to SARS-CoV-2 in the lung. To reduce the severity and mortality associated with COVID-19, we propose to probe for the clinical response to thiazolidinediones, peroxisome proliferator activated receptor γ agonists that are well-known antidiabetic drugs. Thiazolidinediones are able to stabilize lipofibroblasts in their "inactive" state, preventing the transition to myofibroblasts and thereby reducing the development of pulmonary fibrosis and stimulating its resolution.

Caveolin-1 as a target in prevention and treatment of hypertrophic scarring.

Reduced expression of caveolin-1 (Cav-1) is an important pathogenic factor in hypertrophic scarring (HTS). Such a reduction can be found in connection with the main known risk factors for HTS, including dark skin, female gender, young age, burn site and severity of the injury. The degree of overexpression of Cav-1 associated with different therapeutic options for HTS correlates with clinical improvements in HTS. This makes endo- or exogenous induction of Cav-1 not only an important therapeutic target for HTS, but also highlights its use as a preventive target to reduce or avoid HTS formation.