The skin is not just a physical covering of the body, but a multilayered barrier that simultaneously protects against external factors and prevents water loss. Maintaining this function depends not only on the stratum corneum but also on the skin barrier’s immune function. Importantly, this immune component is not provided solely by immune cells. Skin-resident immune cells, such as Langerhans cells, dendritic cells, innate lymphoid cells (ILCs), and T cells, continuously interact with structural skin cells, including keratinocytes and fibroblasts.

In this context, increasing attention is being paid to skin-associated adipocytes located in the subcutaneous fat layer. These cells are no longer viewed as passive energy storage, but as active regulators of inflammation and host defense. They secrete cytokines, adipokines, and antimicrobial peptides (AMPs), influencing both immune cells and skin-resident cells. The mini-review by Guan et al. summarizes current knowledge and highlights the role of adipocytes within the skin barrier system [1].

The skin barrier can be described as a system of four interconnected levels: microbiome, chemical, physical, and immune. These levels are tightly linked, and dysfunction in one can amplify barrier damage and sustain inflammation. Within this framework, adipose tissue represents an additional regulatory layer. In animal models, dermal white adipose tissue (dWAT) is identified as a distinct compartment, whereas in human skin, the boundary between dermal and subcutaneous fat is less clearly defined [1].

How adipocytes contribute to skin immunity

Regulation of inflammation
Adipocytes respond to immune signals via receptors for interleukin (IL)-1β, tumor necrosis factor (TNF), and IL-17, and in turn produce pro-inflammatory mediators such as IL-6, IL-1β, TNF-α, and monocyte chemoattractant protein-1 (MCP-1) [1].

Adipokines play a central role in this process. Leptin enhances pro-inflammatory signaling pathways and promotes the production of inflammatory mediators in skin cells. Chemerin participates in immune cell recruitment, while visfatin stimulates keratinocyte chemokine production [1].

At the same time, adipocytes produce anti-inflammatory signals. Adiponectin suppresses TNF-dependent pathways, stimulates the production of anti-inflammatory cytokines, and contributes to skin repair processes, including cell proliferation and lipid synthesis [1]. Thus, adipocytes act as regulators of inflammatory balance rather than purely pro-inflammatory drivers.

Antimicrobial defense

Adipocytes also contribute to host defense. During inflammation or injury, reactive adipogenesis occurs, leading to increased adipocyte numbers and enhanced production of antimicrobial peptides [1].

Experimental studies demonstrate that preadipocytes can protect against Staphylococcus aureus infection by producing cathelicidin [2]. Dermal adipose tissue is therefore considered part of the skin’s innate defense system [3].

Barrier lipids

Lipids, including ceramides, cholesterol, and free fatty acids, are essential components of the physical barrier. Alterations in lipid composition are associated with conditions such as atopic dermatitis, psoriasis, and acne. While adipocytes may influence lipid homeostasis, the exact mechanisms remain insufficiently understood [1].

What happens when these mechanisms are disrupted

Imbalance in adipokines, cytokines, and antimicrobial peptides can sustain chronic inflammation and impair barrier recovery.

For example, altered chemerin distribution is observed in psoriasis. At the same time, reduced expression of zinc alpha(2)-glycoprotein (ZAG), a protein involved in keratinocyte differentiation and immune regulation, is reported in both atopic dermatitis and psoriasis. Restoration of ZAG has been associated with improved barrier function [1, 4].

Additionally, reduced leptin levels may impair antibacterial defense, highlighting the connection between metabolic status and skin immunity [1].

Practical implications for clinicians

Recognizing adipocytes as active participants in barrier immunity shifts the clinical perspective on chronic inflammatory skin conditions.

First, barrier dysfunction should not be viewed as limited to the epidermis. Even when the stratum corneum appears restored, inflammation may persist due to signals originating from deeper layers, including adipokines [1, 4].

Second, this helps explain why visible improvement does not always correspond to full clinical remission. Restoration of deeper skin homeostasis requires time.

Third, it supports a comprehensive approach targeting multiple barrier levels simultaneously: lipid barrier restoration, inflammation control, and microbiome balance [1, 5].

Importantly, metabolic and nutritional status should also be considered. Leptin levels are linked to antimicrobial defense, and significant caloric restriction may impair this function. Therefore, balanced nutrition without extreme deficiencies is relevant for maintaining skin immune competence [1].

Fourth, therapeutic strategies should address all barrier components: supporting endogenous AMP production, restoring lipid integrity, and modulating inflammatory signaling pathways involving both keratinocytes and adipocytes [1, 2, 5].

Overall, adipocytes should no longer be regarded as a passive background layer. Instead, they represent a meaningful component in strategies aimed at achieving stable remission in inflammatory skin conditions, where restoration of deep skin homeostasis is required [1, 3, 5].

References

1. Guan J., Wu C., He Y., Lu F. Skin-associated adipocytes in skin barrier immunity: A mini-review. Front Immunol. 2023; 14: 1116548. doi: 10.3389/fimmu.2023.1116548
2. Zhang L., Guerrero-Juarez C.F., Hata T. et al. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 2015; 347(6217): 67–71.
3. Chen S.X., Zhang L., Gallo R.L. Dermal white adipose tissue: A newly recognized layer of skin innate defense. J Invest Dermatol. 2019; 139(5): 1002–1009.
4. Noh J.Y., Shin J.U., Kim J.H. et al. ZAG regulates the skin barrier and immunity in atopic dermatitis. J Invest Dermatol 2019; 139(8): 1648–1657.
5. Guerrero-Juarez C.F., Pikus M.V. Emerging nonmetabolic functions of skin fat. Nat Rev Endocrinol 2018;1 4(3): 163–173.