Association of Epidermal Biophysical Properties with Obesity and Its Implications

Obesity is defined as a body mass index (BMI) of ≥30 in adults, and ≥95th percentile of body weight in children. Currently, the rates of obesity range from 2.1% to 61% of adults worldwide [1]. Individuals with obesity have a higher prevalence of comorbidities, including type 2 diabetes, insulin resistance, cardiovascular diseases, sleep apnea, osteoarthritis, respiratory disease, and dyslipidemia [2, 3]. For instance, over 85% of patients with diabetes are overweight or obese [4]. Studies showed that age-adjusted relative risk for new hypertension is associated with overweight (relative risk = 1.46 for men and 1.75 for women) [5]. Excessive increases in body weight during childhood are a risk factor for cardiovascular diseases in adulthood [6]. Every 5 kg/m² increase in BMI increases overall mortality by 30% (hazard ratio = 1.29, 95% CI: 1.27–1.32) [7]. Moreover, obesity is associated with some cutaneous conditions such as acanthosis nigricans, infections, hyperkeratosis, atopic dermatitis, and psoriasis [8]. These obesity-related conditions (as well as obesity alone) negatively impact the quality of patients’ lives. A recent study demonstrated that the severity of obesity is inversely correlated with an individual’s health-related quality of life [9]. In addition, being overweight/obese increases a person’s economic burden. For example, the direct medical cost for overweight and obesity was estimated to be $654 million in Brazil, with a population of 210 million [10], while the medical cost for obesity was thought to be $126 billion in the USA in 2016 [11]. In addition to adding medical costs, obesity reduces productivity [12]. Thus, it is associated with numerous comorbidities, and it negatively impacts a person’s overall health-related quality of life and economic status.

In addition, individuals with overweight or obesity can also exhibit multiple, epidermal functional abnormalities as described below, which have been largely underestimated by general population and healthcare professionals. This review summarizes the obesity-associated alterations in epidermal function, the possible underlying mechanisms, and their implications.

Alterations in epidermal function can be reflected by changes in epidermal biophysical properties such as transepidermal water loss rates (TEWL) (an indicator of epidermal permeability barrier function), skin capacitance (indicating stratum corneum hydration levels), and skin surface pH. A large body of evidence shows epidermal functional abnormalities in many individuals with obesity/overweight.

The epidermal permeability barrier resides primarily in the stratum corneum, the outermost layer of the skin. TEWL measurement is the most common approach used to assess epidermal permeability barrier function. The higher the TEWL is, the poorer the epidermal permeability barrier is. Several studies demonstrate a higher TEWL in both mice and humans with obesity than their normal controls. For example, TEWL rates were 33% higher in mice with obesity induced by a high-fat diet than in normal-weight mice [13]. In children aged 7–15 years, TEWL rates on the forearm were significantly higher in children with overweight/obesity than in normal-weight controls (65.1 ± 8.2 vs. 32.3 ± 7.8, p < 0.05). Particularly, children with abdominal obesity exhibited higher TEWL rates than those without abdominal obesity (p < 0.05) [14]. Similarly, adults with obesity also display significantly higher TEWL than normal controls (14.27 ± 4.4 vs. 11.3 ± 2.7, p < 0.05) [15]. The association of obesity with epidermal permeability barrier function is further demonstrated by the positive correlation of BMI with TEWL. Early studies by Löffler et al. [16] showed that basal TEWL rates on the forearm were the highest in individuals with obesity, followed by those with overweight and normal/underweight (11.5, 8.8, and 6.9 g/h/m², respectively). Positive correlation of BMI with TEWL has also been demonstrated in both Chinese and Indonesians (p < 0.001 and p < 0.05, respectively) [17, 18]. Moreover, a recent study in a large cohort of Chinese showed a positive correlation between BMI and TEWL on the shin in females (Pearson r = 0.07197, p < 0.05), but not in males (Pearson r = −0.02549). TEWL on the forearm did not correlate significantly with BMI in either males or females [19]. Likewise, TEWL rates on the breast, but not on the abdomen or the face, correlated positively with BMI [20], suggesting that correlation of TEWL with BMI varies with body site and gender. Collectively, this research indicates a defective epidermal permeability barrier in individuals with obesity.

However, one study showed that TEWL rates on either the forehead or the abdomen did not differ between females who were normal weight and overweight (BMI 25–29.9 kg/m²) [21]. Likewise, TEWL on the cheek of females did not differ significantly between individuals with obesity and normal weight (19.4 ± 0.8 vs. 17.6 ± 0.7) [22]. In contrast, Guida et al. [23] reported that TEWL rates on the forearm were significantly lower in females with obesity than in normal controls, and that higher waist circumference also displayed lower TEWL rates than normal waist circumference. Another interesting study showed that individuals with overweight and class I and II (BMI = 30–39.9) obesity had lower TEWL on the face and the abdomen than normal-weight controls, while highest TEWL rates were observed in individuals with class III obesity (BMI >40) [20]. These discrepant results are likely due to the differences in body sites where TEWL was measured and the severity of subjects’ obesity. Most studies showed a positive correlation of BMI with TEWL on the forearm or the shin, but either no correlation or negative correlation of BMI with TEWL on the face or the abdomen. Also, if a majority of subjects are mildly obese (class I) and the number of subjects is small, significant differences in TEWL may not be observed between individuals with overweight/obesity and those with normal weight.

Stratum corneum hydration levels are usually determined by measurement of the stratum corneum capacitance. A higher capacitance indicates a higher hydration level. Skin with lower stratum corneum hydration levels often appears dry. In females, the stratum corneum hydration levels on the cheek are lower in individuals with obesity versus normal controls (26.6 ± 1.3 vs. 30.1 ± 1.2, p < 0.05) [22]. A study also demonstrated that the stratum corneum hydration levels on the forearm were significantly lower in individuals with obesity than in normal controls (37.86 ± 9.9 vs. 46.77 ± 11.5, p = 0.05) [15], and severity of obesity correlates negatively with the stratum corneum hydration levels. The highest stratum corneum hydration levels were observed in individuals with normal weight (31.86 ± 11.80), followed by those with overweight (30.36 ± 11.4), with the lowest hydration levels in individuals with obesity (28.06 ± 15.5) [17]. Similarly, the stratum corneum hydration levels on both the forearm and the shin of females correlated negatively with BMI (Pearson r = −0.1362 and −0.1636 for the forearm and the shin, respectively, p < 0.0001 for both). But in males, significant negative correlation between stratum corneum hydration levels and BMI was only observed on the forearm (Pearson r = −0.08298, p < 0.05), not on the shin [19]. Interestingly, one study showed that stratum corneum hydration levels on the face and abdomen were higher in individuals with overweight and class I and II obesity than in normal-weight individuals, while individuals with class III obesity had lowest stratum corneum hydration levels. But on the breast, the stratum corneum hydration levels were higher in individuals with obesity than in individuals with normal body weight [20]. Again, these results suggest that the association of BMI with stratum corneum hydration levels varies with body sites. However, stratum corneum hydration levels on the forearm were comparable in individuals with overweight/obesity versus normal controls in the elderly (>65 years old) [24]. One study showed a weak negative association of BMI with the prevalence of dry skin (odds ratio [OR] = 0.96, 95% CI 0.94–0.98) [25]. These results are no surprise. Because the majority of aged humans already exhibit lower stratum corneum hydration levels (dry skin) [26, 27], stratum corneum hydration levels may not differ significantly between aged individuals with versus without obesity. Nonetheless, abundant evidence indicates reduced stratum corneum hydration levels in individuals with overweight and obesity.

The data of skin surface pH in subjects with obesity versus those with normal weight are extremely limited. One study showed that skin surface pH was comparable among individuals with normal weight, overweight, and obesity [17], while the other study showed that skin surface pH was slightly higher in individuals with obesity than in normal controls (5.16 ± 0.4 vs. 4.92 ± 0.6, p = 0.075) [15]. However, a recent study revealed a positive correlation of BMI with skin surface pH on both the forearm (Pearson r = 0.2968, p < 0.0001) and the shin (Pearson r = 0.3461, p < 0.0001) in females, but not in males [19]. Thus, further studies are needed to confirm if this association exists.

Although data show reductions in stratum corneum hydration levels and elevations in TEWL in individuals with obesity, the underlying mechanisms accounting for such changes are not well understood. However, evidence suggests obesity-associated changes in epidermal function can be attributable to several possible mechanisms. Epidermal permeability barrier function is mainly determined by intercellular lipids and differentiation marker-related proteins in the stratum corneum [28], while the content of natural moisturizers in the stratum corneum is the determinants of stratum corneum hydration levels [29, 30]. Among stratum corneum lipids, ceramide 3 is one of the key factors for a competent epidermal permeability barrier. The proportion of ceramide 3 in the stratum corneum was 7% lower in individuals with obesity than in normal controls [22]. Accordingly, topical applications of a ceramide 3-containing product lowered TEWL [31, 32]. Moreover, BMI correlated negatively with the content of epidermal fatty acids (Pearson r = −0.629, p < 0.01) and cholesterol (Pearson r = −0.607, p < 0.01) in individuals with BMI of 20–35 [33], and both compounds are crucial for epidermal permeability barrier function [34‒36]. Reduced fatty acid and cholesterol content in individuals with obesity are due to the decreased expression levels of genes related to epidermal lipid synthetic enzymes, such as acetyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase, in addition to reduced expression of peroxisome proliferator-activated receptor (PPAR) δ and α [33]. Both PPARs are nuclear hormone receptors, positively regulating keratinocyte differentiation and lipid synthesis [37, 38]. Thus, topical applications of PPAR δ ligands improve epidermal permeability barrier function [38, 39]. Furthermore, individuals with obesity display lower expression levels of gamma-aminobutyric acid receptor (2.9-fold reduction) compared to individuals who are not obese [40]. Because topical applications of a gamma-aminobutyric acid receptor agonist improve the epidermal permeability barrier [41], reduced expression of gamma-aminobutyric acid receptor could also contribute to the increased TEWL in individuals with obesity. Reduced amounts of adiponectin, an anti-inflammatory cytokine secreted by adipose tissues, can also cause a defective permeability barrier [42]. Adiponectin levels are decreased in individuals with obesity in comparison to those with normal body weight [43, 44]. Adiponectin can also increase expression of PPARs and liver X receptor α, resulting in stimulation of keratinocyte differentiation and lipid synthesis, leading to an enhanced epidermal permeability barrier function [45]. An in vitro study showed that adiponectin increased filaggrin mRNA expression [46], while filaggrin deficiency can induce epidermal permeability barrier dysfunction in both humans and mice [47, 48]. Hence, increased TEWL can result from reduced adiponectin. Another previous study showed that desmoglein-1 deficiency increased epidermal permeability [49]. In mice with obesity, expression levels of both desmoglein-1 protein and mRNA were markedly decreased in comparison to normal-weight mice, along with a remarkable reduction in aquaporin-3 expression [13], another crucial determinant for both epidermal permeability barrier and stratum corneum hydration [50]. Thus, reductions in desmoglein-1 and aquaporin-3 are other mechanisms contributing to compromised epidermal permeability in obesity. However, one study showed that individuals with obesity display higher expression levels of S100A [40], a gene associated with epidermal differentiation. This could be a compensatory response of the skin to a defective permeability barrier. Taken together, the increased TEWL in individuals with obesity can be ascribed, in part, to reduced epidermal lipid production, and decreased expression levels of gamma-aminobutyric acid receptor, filaggrin, aquaporin-3, and desmoglein-1.

In comparison to normal-weight individuals, individuals with overweight and obesity often experience psychological stress, manifested by depression and anxiety [51]. The prevalence of psychological disorders can be as high as 60% in subjects with obesity [51], whereas psychological stress can be a risk factor for obesity [52]. In murine models, psychological stress such as living in a crowded or lonely environment, or sleep deprivation, compromises epidermal permeability barrier, mainly via reductions in epidermal lipid production [53, 54]. In humans, having an important interview (a psychological stressor) alone delayed epidermal permeability barrier recovery on the forearm and increased TEWL on the cheek [55]. Likewise, barrier recovery in medical students is slower at final examination times than after a winter break, and the extent of barrier abnormality correlates with the severity of psychological stress (profile of mood states, Pearson r = −0.42, p < 0.05) [56]. Apparently, psychological stress-induced alterations in epidermal function are in part mediated by glucocorticoids. Psychological stress increases circulating levels of glucocorticoids by 4-fold [57], while keratinocytes express glucocorticoid receptor [58]. Moreover, psychological stress increases expression levels and activity of 11β-hydroxysteroid dehydrogenase type I, leading to an increase in cortisol, active form of glucocorticoids, in keratinocytes [59]. Production of cortisol by keratinocytes is also evidenced by the observation that cortisol content is increased by 3-fold following exposure of epidermis to low humidity [60]. Blockade of glucocorticoid receptor overcomes psychological stress-induced abnormalities in epidermal function [61]. Hence, prolonged, sustained psychological stress can compromise epidermal permeability barrier in individuals, including those with obesity.

Reduced stratum corneum hydration levels are possibly due to increased proinflammatory cytokines and decreased moisturizers in the stratum corneum. A feature of obesity is increased inflammation, including increased expression levels of proinflammatory cytokines, in both the circulation and the skin [62‒64]. Previous studies demonstrated that stratum corneum hydration levels correlated negatively with TNF-α levels in the stratum corneum, while TNF-α levels were higher in individuals with obesity than those without obesity [22]. Moreover, individuals with obesity had lower levels of ceramide 3 in the stratum corneum compared to the normal-weight controls [22], while topical treatments of the skin with ceramide 3-containing products increased stratum corneum hydration levels [31, 32], suggesting reduced ceramide 3 content could account for the low stratum corneum hydration in individuals with obesity. In addition, aquaporin-3, a glycerol transporter, regulates stratum corneum hydration. Aquaporin-3-deficient mice exhibit low levels of stratum corneum hydration [65, 66], and expression levels of aquaporin-3 were decreased in mice with obesity [13]. Thus, decreased expression levels of epidermal aquaporin-3 can also contribute to the reduced levels of stratum corneum hydration in individuals with obesity. Taken together, obesity-associated reductions in stratum corneum hydration levels can be attributable to increased cutaneous inflammation and decreased natural moisturizers in the stratum corneum. However, current existing evidence is insufficient to conclude whether and how skin surface pH is altered in subjects with obesity.

As mentioned above, individuals with obesity/overweight can suffer from epidermal functional abnormalities such as increased TEWL or decreased stratum corneum hydration levels, which can induce or worsen cutaneous and extracutaneous inflammation. Previous studies demonstrated that disruption of the epidermal permeability barrier increases expression levels of proinflammatory cytokines and the density of Langerhans cells in the epidermis and mast cells in the dermis, in addition to elevating circulating levels of proinflammatory cytokines [67‒71]. A defective permeability barrier increases skin sensitivity to irritant and allergen challenges due to enhanced penetration of these substances into the skin [72]. Reduced stratum corneum hydration can also provoke cutaneous inflammation [73]. For example, subjects with dry skin often experience pruritus, a symptom of cutaneous inflammation [74]. IL-1α levels are higher in the stratum corneum in winter months, when the skin is dry [75], and exposure of mice to low humidity increases mast cell density and histamine content in the dermis [76]. Conversely, improvements in epidermal functions with topical emollients or occlusion (artificial correction of permeability barrier function) alleviate cutaneous inflammation in both murine and humans. For instance, occlusion of essential fatty acid-deficient mice, which exhibit a defective epidermal permeability barrier and low stratum corneum hydration, with a latex glove lowers expression levels of TNF-α and IL-1α [77]. Topical applications of emollients to aged mouse skin decrease expression levels of cytokines in both the skin and circulation [69] and inhibit cutaneous inflammation in murine model of acute contact dermatitis [78]. Similarly, treatments of aged human skin with topical emollient lower circulating cytokine levels [79], and improvements in epidermal function can mitigate cutaneous inflammation in inflammatory dermatoses in humans. Our previous study showed that topical applications of emollients prevented the development of psoriasis [80], and the benefit of emollient application for eczematous dermatitis has also been demonstrated in a number of studies [81]. Taken together, the bulk of research indicates that obesity-associated epidermal dysfunction can induce or aggravate cutaneous and extracutaneous inflammation.

Obesity has been linked to inflammation [62, 82, 83], while individuals with obesity exhibiting chronic low-grade inflammation, manifested by increased expression levels of proinflammatory cytokines in adipose tissues and in circulation [82, 84]. Increased infiltration of macrophages and Th1 cells in adipose tissues is also attributed to the development of obesity [85, 86]. Proinflammatory cytokines such as TNF-α and IL-1β can downregulate expression of PPARγ, leading to inhibition of adipogenesis [87‒89]. Moreover, inflammation contributes to the development of leptin and insulin resistance [90, 91], both of which play a pivotal role in the pathogenesis of obesity [92, 93]. Furthermore, TNF-α and IL-6 can induce adipocyte hypertrophy and hyperplasia, as well as lipid accumulation [87, 94]. The link between inflammation and obesity is further supported by an increased prevalence of obesity in individuals with inflammatory dermatoses such as atopic dermatitis and psoriasis. For example, the prevalence of obesity is higher in individuals with atopic dermatitis than in those without atopic dermatitis (15.6% vs. 6.7%, OR = 3.2, 95% CI: 1.8, 5.7) [95]. Likewise, the prevalence of obesity in psoriatic patients is higher than that in normal controls (28% vs. 19%) [96]. The OR for obesity in psoriatic patients is 1.66 (95% CI 1.46–1.89), correlating the severity of obesity with the severity of psoriasis [97]. In murine model, anti-inflammation can mitigate the development of obesity induced by a high-fat diet [98], and obesity can increase the risk of atopic dermatitis and psoriasis [99, 100]. Nevertheless, a line of evidence indicates a pathogenic role of cutaneous inflammation in obesity. Therefore, alleviation of cutaneous inflammation can possibly mitigate obesity.

It is worth noting that keratinocytes express oxytocin, a neuropeptide [101]. Deficiencies in oxytocin signaling and oxytocin receptor expression result in the development of obesity, while individuals with obesity exhibit lower levels of plasma oxytocin [102]. Oxytocin deficiency can also induce oxidative stress and increases cytokine expression in keratinocytes [103]. Thus, oxytocin-mediated oxidative stress and inflammation can account for additional mechanism by which individuals with obesity display abnormal epidermal function and inflammation.

In conclusion, individuals with obesity often display epidermal dysfunction, which can provoke and/or worsen inflammation, while inflammation is linked to obesity. Thus, obesity and altered epidermal function can negatively impact each other. Correction of one condition can benefit the other one. Stratum corneum levels are negatively correlated with circulating levels of proinflammatory cytokines [104], while compromised epidermal permeability increases serum cytokines [69]. Because individuals with obesity display increased TEWL and decreased stratum corneum hydration levels, skin care products that can improve both epidermal permeability barrier and stratum corneum hydration could be beneficial to an individual’s obese condition (Fig. 1). However, this hypothesis remains to be validated in clinical settings.

Authors are grateful to Ms. Joan S. Wakefield for English editing.

All authors declare no conflicts of interest.

This work was supported, in part, by the Natural Science Foundation of China (NFC82103756) and the research foundation of Yunnan Education Department (2022J0718), with resources from the research and development service, Department of Veterans Affairs Medical Center, San Francisco. This content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.

T.Z. and S.Y., literature search and draft; M.M.Q., conceptualization and draft; and T.M., critical review. All authors approve the final version of the manuscript.

Tingting Zhu and Shuyun Yang contributed equally to this work.