Ultraviolet (UV) irradiation to the skin downregulates lipid synthesis and adipokine production in subcutaneous fat. Recent evidence also suggests that UV exposure limits body weight gain in obesity models. However, it is still unclear how chronic UV irradiation modulates the energy metabolism of the whole body. High fat- or normal diet-fed female C57BL/6 mice were treated with UV or sham irradiation for 12 weeks. UV exposure stimulated food intake but prevented body weight gain. Leptin, an appetite-suppressing hormone, was significantly reduced in serum, skin, and inguinal subcutaneous fat of high fat diet-fed UV-irradiated mice. Besides, UV irradiation significantly promoted the orexigenic pathway involving neuropeptide Y and agouti-related peptide in hypothalamus. Mice with UV irradiation showed browning of subcutaneous white adipose tissues and increased thermogenesis without increased physical activity. Notably, liquid chromatography/mass spectrometer analyses in the skin revealed that norepinephrine was among the most significantly increased neurotransmitters in UV-irradiated mice, and downregulation of norepinephrine production by dopamine β-hydroxylase inhibitor nepicastat reversed the effects of UV on food intake and body weight. In conclusion, chronic UV irradiation induces NE release resulting in stimulating food intake due to the downregulation of the anorexigenic hormone leptin, but preventing weight gain through the elevation of energy expenditure.

Endoplasmic reticulum (ER) stress is defined as a perturbation affecting ER homeostasis, which is caused by multiple factors such as UV, hypoxia, metabolic alteration, and dysregulated Ca2+ signal. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an ER membrane protein that mainly converts inactive glucocorticoid (GC) into the active form. 11β-HSD1 hyperactivation causing local GC excess has been implicated in various adverse effects on the skin. Although ER stress inducers have a common point with positive regulators of 11β-HSD1 such as GC, UV, and aging in keratinocytes, however, the underlying molecular mechanisms by which ER stress regulates the 11β-HSD1 expression and/or activity are currently unknown. Here, we show that ER stress is a key signaling pathway regulating 11β-HSD1 in keratinocytes. Multiple ER stress inducers including thapsigargin, a SERCA inhibitor, UVB, and high glucose evoked ER stress and increased 11β-HSD1 expression. Moreover, elevated GC levels also increased 11β-HSD1 expression supporting the notion that ER stress amplifies 11β-HSD1 expression via its positive feedback signaling. Mechanically, ER stress-induced upregulation of 11β-HSD1 was restored by 4-phenyl butyric acid (4-PBA), an inhibitor of ER stress, acting as a chemical chaperone. On the other hand, ER Ca2+ depletion is a common mechanism evoking ER stress. Restoring ER Ca2+by CDN1163, a SERCA activator, ameliorated disturbed ER homeostasis and overexpression of 11β-HSD1. Functionally, the increased expression of epidermal differentiation markers including filaggrin, loricrin, and involucrin by ER stress inducers was also rescued by co-treatment with 4-PBA or CDN1163. Taken together, these findings provide evidence that ER stress has a vital role in 11β-HSD1 upregulation, and suggest a new avenue for a potential therapeutic strategy for various chronic GC overactivation conditions such as skin aging, GC-, and diabetes-induced skin changes.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone, an inactive form of glucocorticoid (GC) into cortisol, the active form in human. It is expressed by several tissues including the skin. Excessive active GC deteriorates skin barrier function. Aged skin presents skin barrier impairment. This study was conducted in human and mice to determine if 11β-HSD1 affects the impaired barrier function of aged skin. For human study, elderly and young peoples were enrolled. Mice were divided into the wild aged mice, wild aged mice treated by topical 11β-HSD1 inhibitor, 11β-HSD1 knockout (KO) mice, wild young mice, and wild young mice treated by 11β-HSD1 inhibitor. Cortisol levels were elevated in the stratum corneum (SC) and oral epithelium of the elderly rather than the young. The 11β-HSD1 expression was increased in immunohistochemistry staining of aged mouse skin. Aged mice showed higher transepidermal water loss (TEWL) and lower SC hydration than young ones. Serum inflammatory cytokines such as interleukin-1α, -4, -31 and tumor necrosis factor-α were significantly increased in aged mice than in young mice. SC corticosterone was suppressed in aged 11β-HSD1 KO mice and topical 11β-HSD1 inhibitor applied wild-type mice. Horneodesmosome density was suppressed in aged wild mice, but elevated in aged 11β-HSD1 KO mice and in aged wild mice treated by topical 11β-HSD1 inhibitor. The number of lamellar bodies was increased in topical 11β-HSD1 inhibitor applied mice compared to wild aged mice. The amounts of SC lipids including ceramides, cholesterol, and fatty acids were increased in topical 11β-HSD1 inhibitor applied mice compared to wild aged mice. Expressions of mRNA of lipid synthesis related enzymes were increased in aged 11β-HSD1 KO mice and topical 11β-HSD1 inhibitor applied wild mice. Conclusively, 11β-HSD1 expression is elevated in the aged skin, that increases active GC and then deteriorates skin barrier function.

Oxazolone (Ox)-induced atopic dermatitis (AD) murine model has been considered to have immunological and biochemical changes similar to those of AD including Th2 immune response. However, alteration in Th1/Th2 balance during repeated applications was poorly studied. We investigated the serial change in the Th1/Th2 profile exhibited in T-cell subsets (either Th1 and Th2 lymphocytes) and the Th1/ Th2-related cytokines during the repeated challenge of Ox. Ten female hairless mice were sensitized by 1% Ox. A week later, five of them were challenged by 0.1% Ox and sacrificed at 12 hours after first challenge. The other five were repeated the challenge every other day for 4 weeks and sacrificed in the same manner. The differences in Th1 (CD4+CXCR3+) subset and Th2 (CD4+CCR4+CCR6-) subset in skin, spleen and lymph nodes using flow cytometry and Th1-related (IL-2, IFN-γ and TNF-α) and Th2-related (IL-4, -5, -10, and -13) cytokines in serum and skin were investigated. The ratio in Th1/Th2 cell number was lower in first (1-week) challenge than 5-week challenge in the skin as well as lymph node and spleen. Likewise, the ratio in IL-2/IL-5, IL-2/IL-10 and IL-2/IL-13 was lower in 1-week than 5-week. Nevertheless, the ratio in IL-2/IL-4 was constantly low in 1-week and 5-week. Ox-induced AD murine model showed the greater Th2 proportion even in first challenge. Repeated challenges increased Th1 immune response relatively. This study indicates that Ox-induced AD murine model has typical immunologic response similar to acute AD even after first challenge and comparable change to chronic AD following repetition.

Subcutaneous fat is now regarded as the pivotal regulator of metabolic homeostasis. Previously we demonstrated that ultraviolet (UV) irradiation to the skin induces loss of underlying subcutaneous fat, and also reduces the expression of adiponectin and leptin, which mediate further deterioration of extracellular matrix impairment in human skin. Here we investigated whether chronic UV irradiation modulates energy metabolism in high fat diet-fed mice in vivo. High fat diet-fed mice irradiated with UV for 12 weeks showed a significantly less increase in their body weights despite higher intake of diet and calories. Consistently, the hypothalamus from UV-irradiated mice showed significantly increased expression of orexigenic (appetite-stimulating) factors, while the expression of anorexigenic (appetite-suppressing) factors was decreased upon UV irradiation. On the other hand, the circulating level of anorexigenic hormone leptin was significantly down-regulated in mice irradiated with UV. Moreover, the expression of leptin was also significantly decreased and suppressor of cytokine signaling-3, which is implicated in the regulation of leptin signaling and resistance, was significantly increased in skin from UV-irradiated mice. Interestingly, UV also induced the expression of thermogenesis-related genes such as uncoupling protein 1 (UCP-1), β3-adrenergic receptor as well as that of cyclic AMP in mice. Collectively, our findings indicate that chronic UV irradiation induced changes in thermogenesis, appetite-regulating pathways, and energy metabolism via neuroendocrine factors and hormones, suggesting that UV irradiation may modulate whole-body energy homeostasis as well as subcutaneous fat metabolism.

Atopic dermatitis (AD) and psoriasis are the most common chronic inflammatory dermatitis treated with topical glucocorticoids (GC). Although long-term use of topical GC may induce skin atrophy including striae distensa (SD), AD patients appear to cause less skin atrophy compared to psoriasis. Chronic AD lesions are characterized by eosinophil infiltration and dermal fibrosis. Periostin, encoded by POSTN gene, augments TGF-β production in eosinophils and inversely activated eosinophils can induce periostin production in fibroblasts. Periostin involves in tissue remodeling such as fibrosis and lichenification of chronic AD lesion. This study was designed to reveal that AD patients have less skin atrophy due to skin fibrosis related with eosinophils and periostin compared to psoriasis. For the skin atrophy including SD, we enrolled AD and psoriasis patients with similar ages and treatment durations. For the skin fibrosis and eosinophils, we compared lesional and non-lesional skin from the patients with AD, psoriasis, and allergic contact dermatitis (ACD). Also, we compared mRNA expression in the dermis from the mouse model of AD or psoriasis. AD patients have less SD than psoriasis. In AD patients, the ratio of the dermal fibrous tissues was significantly higher than psoriasis. Tissue and blood eosinophils were significantly higher in AD patients than ACD as well as psoriasis. Dermal thickness and fibrosis were significantly higher in AD mice than psoriasis even after the treatment with topical GC. There was a significant positive correlation between dermal fibrosis and tissue eosinophils counts. The mRNAs of POSTN, TGFB1, COL11A1, MMP1, and IL1R2 were significantly up-regulated in AD mice than psoriasis. We found that AD patients had less skin atrophy than psoriasis after the long-term use of topical GC. It might be resulted from the skin fibrosis caused by upregulation of tissue eosinophils and periostin.

Exogenous or endogenous glucocorticoids (GC) have negative effects on skin barrier function as well as wound healing. In skin where 11β-hydroxysteroid dehydrogenase 2 which prevents GC from binding to mineralocorticoid receptor (MR) is deficient, GC can bind to MR as well as GC receptor (GR). MR has been known to be implicated in GC-induced delayed wound healing and epidermal atrophy. We performed this study whether GC binds to MR and contributes to skin barrier dysfunction and thus MR antagonism can prevent GC-induced skin barrier dysfunction. In healthy young adults, after application of topical GC either with spironolactone (MR antagonist) cream or vehicle on each forearm, skin barrier function was measured. After treating cortisol and mifepristone (GR antagonist) or eplerenone (MR antagonist) to normal human epidermal keratinocytes (NHEKs) and 3D human skin models, the expression of GR, MR and keratinocyte differentiation markers was assessed. In the GC applied skin, co-application of MR antagonist improved stratum corneum integrity and barrier recovery rate compared to vehicle. In NHEKs, protein expression of GR but not MR was decreased by cortisol. In contrast, cortisol induced the nuclear translocation of both GR and MR, which were inhibited by mifepristone and eplerenone, respectively. In the 3D skin, mRNA expression of GR was not significantly changed by cortisol, mifepristone, or eplerenone treatment and that of MR was not detected due to low expression. Keratinocyte differentiation markers were decreased by cortisol treatment, then recovered by co-treatment of mifepristone and eplerenone in both NHEKs and 3D skin. GC activates MR as well as GR and contributes to skin barrier dysfunction. Therefore, MR antagonist as well as GR antagonist might prevent GC-induced skin barrier dysfunction.

Ultraviolet light (UV) radiation to the skin causes dose- and wavelength- dependent reactions, including skin barrier dysfunction. Long-term exposure to even low dose UV induces the alteration of skin barrier presenting prominent ceramide decrease in the stratum corneum (SC) intercellular lipids. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol in peripheral tissues and inhibits keratinocytes and fibroblasts proliferation, is known to be induced by UVB. We performed in vitro, in vivo, ex-vivo studies to elucidate whether skin barrier dysfunction induced by UV could be resulted from 11β-HSD1 activation after UV irradiation. We observed that 11β-HSD1 expression was increased by cortisol treatment itself and UV irradiation, thereby rapidly converting cortisone into cortisol. UVB irradiation increases 11β-HSD1 expression as well as inflammatory cytokines using HSD11B1 siRNA transfected normal human epidermal keratinocytes. 11β-HSD1 mRNA was prominently higher in UVB irradiated primary human keratinocytes compared with control. Keratinocytes transfected with HSD11B1 siRNA decreased the expression of 11β-HSD1 mRNA and did not increase cortisol even when the keratinocytes were irradiated by UVB. In vitro, increased cortisol converted by 11β-HSD1 inhibits keratinocyte differentiation. Cortisone decreased the mRNA and protein expression of keratinocyte differentiation markers in UVB-exposed keratinocytes. 11β-HSD1 expression remarkably increased in UV exposed skin and intrinsic aged skin. Skin barrier function presented by transpidermal water loss, SC hydration and SC integrity was impaired in long term UV exposed skin and intrinsic aged skin. Therefore, 11β-HSD1 activation by UVB might suggest another possible mechanism on skin barrier dysfunction due to UV exposure.

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is an enzyme that converts inactive cortisone into cortisol, an active form. Its expression level is reported to be elevated with aging. Also, increased expression of this enzyme is known to be implicated various diseases associated with senescence and glucocorticoid excess. Prevalence of atopic dermatitis (AD) is the highest in infants, and tends to decrease after puberty. As the prevalence is relatively very low in the elderly, we have come up with an idea that 11β-HSD1 expression in the skin has a role not only in skin aging but also in the occurrence of AD. First, we have compared three groups of mice; young (8 weeks old) mice irradiated with sham light for 8 weeks, young mice irradiated with ultraviolet (UV) light for 8 weeks, and old (56 weeks old) mice irradiated with sham light for 8 weeks. Young mice group irradiated with UV light showed impaired skin barrier function and increased 11β-HSD1 expression in the skin comparable with the old mice group. Second, cortisol level in the stratum corneum (SC) was compared among normal young, normal aged, diabetes mellitus (DM) patient group, and AD group. The SC cortisol level of normal young group was significantly lower than AD and DM group. Normal aged group showed higher SC cortisol level than normal young group, but there was no statistical significance. Lastly, we have performed an experiment comparing the old (62 weeks old) and young (8 weeks old) mice in the occurrence of AD following repeated oxazolone (Ox) challenges. We have also used topical 11β-HSD1 inhibitor and vehicle in each aged and young group. As a result, AD developed more rapidly and seriously in the young mice group, and 11β-HSD1 inhibitor applied group after multiple Ox challenges. Collectively, 11β-HSD1 expression in the skin is increased in aged skin and may be responsible for the lower prevalence of AD in the elderly. Novel agents modulating the 11β-HSD1 activity could be used for AD treatment.

Psychological stress (PS) increases endogenous glucocorticoids (GC) by the activation of hypothalamic-pituitary-adrenal axis. Negative effects of PS on skin barrier function have been well known. However, endogenous GC can exert its activity when cortisone is converted into cortisol by 11β-hydroxysteroid dehydrogenase type I (11ß-HSD1) in peripheral tissues. Therefore, we performed this study to elucidate the effect of 11ß-HSD1 on skin barrier function under PS. 25 students were enrolled. All measurements were repeated under PS and normal state. Salivary cortisol at 8AM and midnight, mRNA and protein expression of 11ß-HSD1 from oral mucosa cells, and skin barrier functions were assessed. In addition, using insomniac PS murine model, we compared the changes in skin barrier function and the expression of 11ß-HSD1 in the epidermis among the control group and PS group. In PS status, cortisol level in the saliva and corneocytes, as well as basal transepidermal water loss (TEWL), and 11ß-HSD1 of oral mucosa significantly increased, and SC integrity significantly decreased. In addition, cortisol level in the corneocytes was positively correlated with basal TEWL and 11ß-HSD1 in oral mucosa and negatively correlated with SC integrity. In animal studies, epidermal expression of 11ß-HSD1 was increased in the PS group compared to the control group. Furthermore, the expression of 11ß-HSD1 in the epidermis showed a positive correlation with basal TEWL and a negative correlation with SC integrity and barrier recovery. Collectively, PS deteriorates skin barrier function by the activation of 11ß-HSD1 as well as endogenous GC.

In patients with atopic dermatitis (AD), the penetration of contact allergens is potentially increased through disrupted barrier, and hence the risk of sensitization is also increased. We performed this study to predict allergic contact dermatitis (ACD) accompanied in AD patients. 207 patients with AD who underwent patch test were included in the study. Subjects with any positive result were classified as “AD with ACD” (N=43, 20.8%), and negative result as “AD only” (N=164, 79.2%). Gender, age, past and family history, skin lesions, laboratory findings and gene variations including FLG 3321delA, FLG K4022X, KLK7, SPINK5, DEFB1, KDR, IL5RA, IL-5, IL-9 and IL12RB1,2 were compared between the two groups. “AD with ACD” was more common in female (p<0.001). Patients’ age and disease onset age were older in “AD with ACD” (p<0.001). “AD with ACD” patients had more personal and family histories about ACD (p<0.001). Nummular eczema was more common in “AD with ACD” (p=0.019). In multivariate logistic regression analysis, family history of ACD, female, older age had higher odds of ACD (9.82[3.38-30.26], 5.41[2.43-12.97], 1.07[1.05-1.10]). Receiver operating characteristics (ROC) curve analysis of age showed that optimal cutoff value was 7 years and the area under the ROC curve was 0.748 with the sensitivity of 95.3% and specificity of 43.9% (p<0.001). In multivariate logistic regression analysis with propensity score matching for age and gender, the heterozygous mutation in FLG 3321delA had higher odds of ACD (6.81 [1.09-131.79]). In conclusion, patients with AD who fall into one of the following cases, female over 7 years of aged, show nummular eczema, have heterozygous mutation in FLG 3321delA, should be suspected for accompanied ACD and patch test should be done.

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is an enzyme that converts cortisone into cortisol. Its expression level is reported to be elevated with aging. Also, increased expression of this enzyme is known to be implicated various diseases associated with senescence and glucocorticoid excess. Prevalence of atopic dermatitis (AD) is the highest in infants, and tends to decrease after puberty. As the prevalence is relatively low in the elderly, we have come up with an idea that 11β-HSD1 expression in the skin has a role not only in skin aging but also in the occurrence of AD. First, we have compared three groups of mice; young mice irradiated with sham light, young mice irradiated with ultraviolet (UV) light, and old mice irradiated with sham light. Young mice group irradiated with UV light showed impaired skin barrier function and increased 11β-HSD1 expression in the skin comparable with the old mice group. Second, cortisol level in the stratum corneum (SC) was compared among normal young (NY), normal aged (NA), diabetes mellitus (DM) patient group, and AD group. The SC cortisol level of NY group was significantly lower than AD and DM group. NA group showed higher SC cortisol level than NY group, but there was no statistical significance. Lastly, we have compared the old and young mice in the occurrence of AD following repeated oxazolone (Ox) challenges. We have also used topical 11β-HSD1 inhibitor and vehicle in each aged and young group. As a result, AD developed more rapidly and seriously in the young mice group, and 11β-HSD1 inhibitor applied group after Ox challenges. Collectively, 11β-HSD1 expression in the skin is increased in aged skin and may be responsible for the lower prevalence of AD in the elderly.

Atopic dermatitis (AD) and psoriasis (PSO) are the commonest chronic inflammatory dermatosis, which have been commonly treated with topical glucocorticoids (GCs). Although long-term use of topical GCs may induce striae distensae (SD), patients with AD have been felted to develop less SD than patients with PSO. AD is characterized by infiltration of eosinophils and fibrosis in chronic lesions. Therefore, this study was designed to elucidate whether patients with AD have less SD, and the development of more fibrosis of the skin, and tissue eosinophilia than patients with PSO. Using the Korea Health Claims Database (KHCD) from 2009 to 2013, we compared the proportion of patients who had SD among all patients diagnosed with AD or PSO, respectively. For skin fibrosis and tissue eosinophilia, we compared the histopathology of both lesional and non-lesional skin of patients. The degree of fibrosis of the skin was analyzed by the density of fibrous tissues of dermis (DD), and tissue eosinophils were counted. RNA-sequencing and microarrays were performed to identify differentially expressed genes in 6 AD patients versus 5 PSO patients. We confirmed that AD patients have significantly less SD than PSO patients from KHCD. Besides, the ratio of DD in the lesional to non-lesional skin was significantly higher in AD than PSO. Tissue eosinophils were also significantly higher in AD patients. Among the genes, periostin (a systemic biomarker of eosinophilic inflammation and airway fibrosis gene in asthma), MMP12, and MMP28 were increased while TGFA, IL1B, IL8, CXCL10 and HRH2 were decreased in the AD patients. Collectively, We found that patients with AD develop less SD compared to PSO despite topical GC treatments, which could be due to the formation of skin fibrosis from tissue eosinophilia.