How Radiofrequency Affects Fat Cells: Mechanisms of EBD Stimulation
This is the full text of my column in the May 2025 issue of D&PS.
The conventional treatment model for energy-based devices is to bring a target tissue to a target temperature and trigger wound healing. Other mechanisms have also been proposed. With a moderate temperature rise, the skin responds nonspecifically by immediately producing its own hyaluronic acid. This expression of hyaluronic acid and local edema can already occur above 42°C, helping explain why wrinkles improve immediately after treatment. Effects may therefore occur at much lower temperatures than those assumed in the “immediate collagen shrinkage” mechanism originally proposed for RF devices.
The longer-term effects of RF point to another mechanism as well: changes in volume through increased adipocyte number, enlargement, or conversion into other cell types, rather than through fibroblasts alone. Findings that hyaluronic acid is expressed during adipocyte differentiation are also relevant.
In a mouse study, depletion of hyaluronic acid reduced the differentiation of preadipocytes into adipocytes. This points to a relationship between increased adipocyte differentiation and greater hyaluronic acid availability. Prolonged UV exposure also downregulates hyaluronic acid synthase, reducing dermal hyaluronic acid. Conversely, activating dermal adipocytes may offer a way to regulate the skin's hyaluronic acid content.
Stimulating dermal adipocytes with energy-based devices induces expression of C/EBPα (CCAAT/enhancer-binding protein alpha) and PPARγ (peroxisome proliferator-activated receptor gamma), promoting adipogenesis. Inflammation may also be modulated, with effects on collagen synthesis, differentiation, and proliferation. The effects of EBDs therefore extend beyond collagen regeneration. By restoring visible volume while increasing collagen and hyaluronic acid content, they can address both aging changes and tissue tightening.
Figure 1. C/EBPα and PPARγ in adipogenesis. Schematic of molecular pathways involving genes implicated in Köbberling-Dunnigan syndrome and their roles in adipose-tissue differentiation, apoptosis, and tissue development. The Study of Genetic Mutations in Genes AGPAT2, LMNA, PPARG, PLIN1, AKT2, CIDEC in Köbberling-Dunnigan Syndrome, Shahin Asadi et al., March 2019, Journal of Diabetes & Metabolic Disorders 4(1):1–5.
Where does RF current concentrate in subcutaneous fat?
Electrical current never flows uniformly through subcutaneous adipose tissue. In particular, triglycerides conduct far less readily than the pericellular and intercellular fibrous structures in its extracellular matrix. RF current therefore concentrates mainly in collagen structures rather than spreading evenly through the tissue. Its distribution depends on how much fibrosis the adipose tissue contains.
This concentration greatly increases current density within fibrous structures, heating them above the average temperature of the surrounding fat. Pericellular and intercellular structures, along with adipocyte surfaces, are selectively heated. This can be described as a channeling effect.
Facial fat depots differ anatomically by region. Labial fat, for example, consists of small adipocyte clusters embedded in a dense collagen matrix, termed fibrotic fat. Malar fat contains larger clusters of mature adipocytes enclosed by thin collagen structures, known anatomically as structured fat. Buccal fat is quite different: its collagen network is much less extensive, and its structure resembles visceral fat. It is classified as depot fat. Fibrosis within these depots also changes with age and shows sexual dimorphism, helping explain why patients respond differently to the same RF treatment.
Figure 2. Adipocytes and their surrounding extracellular matrix. Sources: Scheme of adipose tissue components (left); adipocyte aggregates held within an extracellular collagen matrix (right). Obesity, Metabolic Dysfunction, and Inflammation in Polycystic Ovary Syndrome, Mira Aubuchon et al., DOI:10.1007/978-1-4614-8394-6_8, Polycystic Ovary Syndrome, pp.117–144.
The walls between adipose cells form closed boundaries, so each fat depot can be regarded micromechanically as a closed-cell foam. Although triglycerides occupy most of the tissue's volume, its mechanical properties are determined chiefly by pericellular fibrosis; triglycerides play a secondary role.
Skin is neither a perfect conductor nor a perfect dielectric. In physics, it is described as a lossy dielectric. It both dissipates electrical energy as Joule heat and stores energy like a capacitor. The distribution of current and the degree of heating depend on the balance between conductive and dielectric behavior. Dielectric properties vary with frequency, a phenomenon called dispersion. When conduction predominates, RF current mainly heats the tissue. When dielectric behavior predominates, displacement currents mainly redistribute charge, or polarize the tissue, without requiring strong heating. Generally, lower frequencies favor conductive behavior and higher frequencies favor dielectric behavior. At sufficiently high RF frequencies, all materials behave as dielectrics. The conductivity of subcutaneous adipose tissue remains almost constant at approximately σ ≅ 0.02 S/m over the broad frequency range of 100 kHz to 10 MHz. Its dielectric constant, however, is strongly frequency-dependent: approximately ε ≅ 40 at f = 100 kHz, ε ≅ 15 at f = 1 MHz, and ε ≅ 11 at f = 10 MHz. The ratio of the heat-producing to non-heat-producing current component in subcutaneous tissue is therefore about 90 at 100 kHz, 24 at 1 MHz, and 3 at 10 MHz. Conductivity of the whole skin (stratum corneum, epidermis, and dermis together) rises sharply with RF frequency: approximately σ ≅ 0.07 S/m at f = 100 MHz, σ ≅ 0.3 S/m at 1 MHz, and σ ≅ 0.4 S/m at 10 MHz. The corresponding ratios of heat-producing to non-heat-producing current in skin are approximately 0.6 at 100 kHz, 2.7 at 1 MHz, and 3.6 at 10 MHz.
| Tissue | Conductivity (S/m) |
|---|---|
| Blood | 0.7 |
| Bone | 0.02 |
| Fat | 0.03 |
| Dry skin | 0.03 |
| Wet skin | 0.25 |
Figure 3. Conductivity of different biological tissues at 1 MHz.
Figure 4. Tissue conductivity at different RF frequencies.
Figure 5. Changes in conductivity and free dipoles with RF frequency.
Can RF heating regulate caveolin-1?
Cells do not function in isolation. Each constantly exchanges signals with neighboring cells and the surrounding extracellular matrix. Cytokines, proteins, and growth factors circulate in this environment and bind to their corresponding cell-membrane receptors. Membrane structures called caveolae may be treatment targets across a range of skin conditions and aesthetic concerns, from aging and inflammation to scarring and melanin production.
Figure 6. Signaling molecules in cell-membrane caveolae: examples of signaling proteins localized in endothelial caveolae. Source: Caveolae, Caveolins, Cavins, and Endothelial Cell Function: New Insights, Grzegorz Sowa, Front. Physiol., 6 January 2012, Vascular Physiology, Volume 2, 2011 | https://doi.org/10.3389/fphys.2011.00120.
Figure 7. Model of caveolae and Cav-1 domains. CSD, caveolin scaffolding domain; EHD2, Eps15 homology domain 2; OD, oligomerization domain; S80, phosphorylation at serine 80; Y14, phosphorylation at tyrosine 14. Created with BioRender.com. Source: Caveolae: Metabolic Platforms at the Crossroads of Health and Disease, Dante Maria Stea, Int. J. Mol. Sci. 2025, 26(7), 2918. https://doi.org/10.3390/ijms26072918.
Caveolae are inward-folding pockets in the cell membrane. Their components include cavins and caveolins, notably caveolin-1. Just as wrinkles develop on the face with age, caveolae become more numerous on cell membranes. Their number also increases or decreases in response to many factors other than aging. Endothelial caveolae contain signaling molecules that interact with caveolin-1, including eNOS; receptor tyrosine kinases, such as VEGF receptor 2; G-protein-coupled receptors, such as bradykinin receptor 2, endothelin receptors, and muscarinic receptors; heterotrimeric G-protein subunits, such as Gq; TGF-β receptors I and II; and calcium channels, including TRPC1, TRPC4, and TRPV4.
Caveolin-1 is involved not only in heat shock proteins associated with skin aging and in collagen synthesis mediated by increased TGF-β, but also in the aging of facial fat. Studies report that increased caveolin-1 expression is associated with reductions in collagen and TGF-β. Other research finds lower caveolin-1 expression in people with atopic dermatitis than in healthy individuals. This is consistent with the greater prevalence of atopic dermatitis in children, who have fewer caveolae, than in adults, whose caveolae increase. Psoriasis, another major inflammatory skin disease, also appears to be associated with caveolin. Reduced caveolin-1 expression increases inflammation-related matrix metalloproteinases (MMPs). Regulating caveolin-1 may therefore be a therapeutic target in MMP-related inflammatory skin conditions, including atopic dermatitis, psoriasis, acne, and scars.
Extensive skin damage, such as severe infection, trauma, dehisced surgical wounds, or pressure ulcers, often involves impaired healing capacity and elevated caveolin-1. Caveolae also become more numerous in skin-cell membranes with age. Older people with increased caveolin-1 often have reduced wound-healing capacity, making early, careful wound management advisable. Conversely, excessively low caveolin-1 after injury can produce an exaggerated healing response and keloidal scarring. Children have fewer caveolae than adults and may therefore develop an excessive healing response that progresses to keloidal scars. This is one reason scar-forming surgery is generally avoided at a very young age. The proposed approach is to increase caveolin-1 in conditions associated with insufficient levels, such as atopic dermatitis, psoriasis, acne, and keloidal scars, and reduce it in chronic wounds such as pressure ulcers where levels are excessive.
Caveolae regulation also relates to melanin production. During pigmentation, caveolae increase at the interface between melanocytes and epidermal keratinocytes, and caveolin-1 correlates with increased cAMP in melanocytes. This association makes melanocyte caveolae a potential target for pigmentation treatment. In skin aging, where caveolae increase, reducing caveolin-1 is the relevant approach. Increased caveolin-1 expression is associated with reduced activity of EGF, an important factor in skin repair, and with less collagen regeneration. Higher caveolin-1 reduces expression of TGF-β, directly involved in collagen synthesis, thereby reducing collagen production. Lower HSP levels are also associated with increased caveolin-1.
Caveolin-1 can be regulated to some extent by inducing HSPs with ultrasound or other energy-based devices. MMPs, HSPs, and caveolin-1 are closely interconnected, and PPARγ is also strongly associated with caveolin-1. Through these pathways, EBDs promote differentiation and proliferation of adipose-derived stem cells.
(To be continued in the next issue)
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