This study provides preliminary insights into the vascular-lymphatic and immunometabolic changes accompanying clinical improvement during long-term calorie-restricted LCHF dietary intervention in women with lipedema. Importantly, because of the single-arm exploratory design, the findings should be interpreted as associations observed over time during the LCHF intervention rather than as evidence of causality or of specific mechanistic effects of the diet.

We observed a significant increase in circulating vascular factors, specifically VEGF-A, VEGF-D, and angiopoietin-2, while VEGF-C levels remained unchanged. VEGF-A and VEGF-D are key mediators of angiogenesis and lymphangiogenesis, respectively [21,22,23,24,25]. In the context of concomitant clinical improvement, these changes may be consistent with altered vascular and lymphatic signaling during the intervention. However, circulating factors alone do not allow us to determine whether they reflect adaptive remodeling, compensation, or other systemic processes. Accordingly, interpretations referring to improved tissue perfusion, microvascular function, endothelial plasticity, or lymphatic responsiveness remain hypothetical and were not directly examined in this study. Additionally, the elevated levels of angiopoietin-2 suggest that vascular signaling changed over the course of the LCHF intervention [26], but the biological meaning of this increase cannot be established on the basis of serum measurements alone. Overall, these findings suggest that clinical improvement was accompanied by changes in circulating markers related to vascular and lymphatic biology.

The absence of change in VEGF-C, in contrast to the increase in VEGF-D, is consistent with differential regulation of circulating lymphangiogenic markers during the LCHF dietary intervention. However, this interpretation should be made cautiously. Although VEGF-C and VEGF-D share overlapping functions [22,23,24,25], our data do not provide mechanistic evidence that one pathway predominated over the other, nor do they allow conclusions regarding the source, tissue specificity, or functional consequences of these circulating changes. Therefore, the observed pattern is better described as differential changes in circulating lymphangiogenic markers rather than proof of distinct pathway activation. The concurrent elevation of angiopoietin-2 may indicate additional changes in vascular-related signaling, although this likewise requires cautious interpretation.

Felmerer et al. reported altered vascular and lymphatic signaling and a pro-inflammatory adipose tissue environment in lipedema [6]. Our findings are compatible with the concept that circulating vascular and inflammatory mediators can change in parallel with clinical improvement in lipedema. However, we cannot conclude that these changes represent “normalization” of vascular homeostasis, because no healthy control group or tissue-level validation was included. Accordingly, terms such as “partial normalization” should be understood as descriptive and hypothesis-generating rather than definitive.

Moreover, while the rise in VEGF-D levels observed in our study may reflect structural remodelling secondary to adipose tissue loss, emerging evidence suggests that LCHF or ketogenic dietary approaches may also exert direct effects on lymphatic endothelial cell biology. This possibility is supported mainly by preclinical and limited clinical observations and should therefore be considered speculative in relation to our cohort. In preclinical models, ketone bodies have been shown to stimulate lymphatic vessel growth [27]. In a preclinical mouse model of tail lymphedema, which closely mimics features of human secondary lymphedema, ketogenic dietary intervention enhanced lymphatic vessel regeneration and function, reduced the infiltration of anti-lymphangiogenic immune cells, and led to a significant reduction in tissue oedema [27]. Clinical observations further support these findings. In patients with unilateral secondary lymphedema, adherence to a ketogenic diet was associated with measurable improvements in lymphatic function and reduction in limb oedema volume in a subset of individuals [28]. Nevertheless, extrapolation from secondary lymphedema models or other clinical populations to lipedema should be made with caution, and our data do not demonstrate direct lymphatic effects of the dietary intervention.

In our study, the LCHF diet was also associated with reductions in several circulating inflammatory and endothelial activation markers, evidenced by significant decreases in TNF-α, IL-1β, sVCAM-1, sICAM-1, and P-selectin. The reduction in circulating TNF-α and IL-1β is consistent with decreased systemic inflammatory activity [29,30], aligning with some previous findings on the possible anti-inflammatory effects of carbohydrate restriction and ketone body metabolism [31]. The marked reductions in soluble adhesion molecules (sVCAM-1, sICAM-1, and P-selectin) in our patients are consistent with reduced endothelial activation and leukocyte trafficking, which can be interpreted as improved vascular function and reduced endothelial inflammation during LCHF dietary intervention [32,33,34]. At the same time, because no control group was included, these changes cannot be attributed specifically to the LCHF diet itself and may also relate to weight loss, time-dependent variation, or other unmeasured factors.

Notably, the proinflammatory cytokine IL-8 increased following the LCHF diet in our study. Although IL-8 is traditionally classified as a pro-inflammatory chemokine, it also exerts potent pro-angiogenic effects and contributes to vascular remodeling [35,36]. This result does not support a simple uniformly anti-inflammatory interpretation of the biomarker profile. Rather, it underscores that the observed systemic response was biologically mixed and may have involved parallel inflammatory, reparative, or angiogenic processes that cannot be disentangled in this study. Therefore, this finding is difficult to interpret unambiguously and may reflect complex, context-dependent changes in inflammatory and angiogenic signaling rather than a purely beneficial or detrimental effect. Given this ambiguity, IL-8 should be regarded as one of the more difficult-to-interpret findings rather than as evidence of beneficial remodeling.

No significant changes were observed in IL-6, IL-13, or IL-28α, suggesting that the intervention was not associated with major alterations in selected Th2-related or interferon-mediated pathways. However, this interpretation should be considered with caution given the limited sample size and variability of cytokine responses [37,38,39,40]. IL-6 is a pleiotropic cytokine involved in inflammation, metabolism, and tissue stress responses; the absence of a significant change in IL-6 may therefore indicate either biological stability or insufficient power to detect modest effects [37,38]. IL-13, often linked to type 2 immune signaling and tissue remodeling, also remained unchanged at the group level, despite appearing in exploratory models of pain improvement [39]. IL-28α, a type III interferon, has less clearly defined relevance in lipedema, and its stability may simply indicate that this pathway was not prominently affected or that any effect was below the resolution of this small exploratory study.

From the perspective of lipid mediators, we documented a significant decline in several anti-inflammatory and endocannabinoid-related molecules, including AEA, OEA, PEA, 13,14-dihydro PGE1, 15-deoxy-Δ12,14-PGJ2, and both 1- and 2-arachidonoylglycerol (1-AG and 2-AG). These compounds typically exert immunomodulatory and homeostatic roles, particularly within inflamed adipose tissue [41,42]. At first glance, the decrease in several mediators with generally anti-inflammatory or homeostatic properties may appear counterintuitive. One possible explanation is that lower circulating concentrations reflect altered endocannabinoid-related signaling in the setting of changing metabolic and inflammatory status, although this remains tentative [43]. However, this interpretation remains tentative, because circulating concentrations do not directly capture tissue-specific production, receptor activation, or net biological effect. Therefore, our data support the presence of altered endocannabinoid-related and pro-resolving lipid signaling during the intervention, but not a definitive conclusion regarding whether these changes were beneficial, compensatory, or secondary to weight loss and altered nutrient intake. Notably, 15d-PGJ2, a potent PPAR-γ ligand, is involved in negative regulation of NF-κB and macrophage activity [44]. Its reduction may be compatible with reduced need for counter-regulatory signaling, but alternative explanations are also plausible. Conversely, we found no significant changes in several classical pro-inflammatory prostanoids and leukotrienes (PGE2, PGD2, PGF2α, TXB2, LTB4, and 6-keto-PGF1α). This stability may suggest that the LCHF diet primarily modulates resolution pathways and chronic inflammatory tone, rather than acute eicosanoid-mediated inflammation. Given the exploratory design and multiple comparisons, however, this pattern should be interpreted cautiously.

Our findings also identified exploratory associations between endocannabinoid-related lipid mediators and diet-induced body composition changes in women with lipedema. Baseline OEA levels and longitudinal decreases in OEA emerged as potential predictors of BMI reduction during the LCHF dietary intervention. Similarly, baseline AEA levels were also associated with BMI reduction over time. Because these analyses were exploratory and based on a small sample, these mediators should currently be viewed as candidate correlates of response rather than validated predictors. These findings are consistent with previous reports linking the endocannabinoid system to energy balance and adiposity regulation [41,42].

In exploratory modeling, change in IL-8 showed a nominal association with leg volume reduction, with greater increases in IL-8 associated with smaller reduction in leg volume. Given the small sample size, exploratory design, and biologically complex role of IL-8 [35,36], this finding should be interpreted with caution.

Beyond volumetric and metabolic improvements, reductions in adipose tissue pain were associated with changes in markers of endothelial activation and vascular-immune signaling. In exploratory analyses, greater pain improvement was linked to decreases in P-selectin and VEGF-A and to increases in IL-13, suggesting that symptom relief may be related to reduced endothelial activation and a shift toward a more anti-inflammatory tissue environment rather than to adipose tissue loss alone. Such interpretation is biologically plausible in light of previous work linking selectins, VEGF-A, and IL-13-related pathways to pain modulation [45,46,47]. These associations are intriguing, but they should not be interpreted as evidence that changes in these biomarkers mediated pain reduction. Rather, they indicate that symptom improvement and selected circulating markers changed in parallel within this cohort. Given the small sample size and exploratory design, these findings should be interpreted cautiously and considered hypothesis-generating.

Collectively, these observations do not establish a mechanistic model, but they do suggest that clinical improvement during the intervention coincided with changes in endothelial, inflammatory, angiogenic, and lipid-related circulating mediators. Any mechanistic interpretation, such as reduced endothelial activation, modulation of angiogenic signaling, altered immune-stromal interactions, improved microvascular stability, or changes in tissue fluid regulation, remains hypothetical and requires confirmation in controlled studies with functional and tissue-level endpoints. Although these associations were identified in exploratory analyses and require confirmation in larger cohorts, they suggest a biologically plausible association between metabolic intervention, vascular-lymphatic function, and nociceptive symptom burden in lipedema.

This study has several strengths. It is one of the few prospective interventional studies evaluating the clinical and biochemical effects of a long-term LCHF dietary intervention in women with lipedema. The individualized, medically supervised 7-month intervention enabled assessment of sustained changes, while the combined evaluation of clinical outcomes and a broad panel of circulating angiogenic, inflammatory, and lipid mediators provided an integrated characterization of systemic responses accompanying the intervention. The use of Luminex multiplex assays and LC-MS/MS further strengthened the analytical approach. These strengths should, however, be interpreted in the context of the exploratory design.

However, several limitations should be acknowledged. This study was designed as an exploratory, hypothesis-generating pilot investigation and no formal a priori sample size calculation was performed. The relatively small sample size and multiple exploratory comparisons limit statistical power and generalizability, and the observed associations should be interpreted with caution and confirmed in larger cohorts. Because multiple biomarkers were analyzed, the risk of false-positive findings should also be considered, particularly for secondary and exploratory associations. In addition, the absence of a control group (either women with lipedema not following a LCHF diet or individuals with obesity without lipedema) limits the ability to distinguish diet-specific effects from disease-related or time-dependent changes. Furthermore, all analyses were based on circulating biomarkers, which may not fully reflect local processes within adipose tissue; tissue-level investigations would provide more direct insight into local inflammatory, angiogenic, and lipid-signaling mechanisms. Finally, although the dietary intervention was medically supervised, adherence was not objectively verified using standardized dietary records or biochemical markers such as circulating ketone bodies, which may have introduced inter-individual variability in metabolic response. This point is particularly important when interpreting the findings as LCHF-specific or related to carbohydrate restriction, because the degree of carbohydrate restriction and ketosis achieved over time was not objectively documented. An additional limitation is that the intervention combined carbohydrate restriction with caloric restriction; therefore, the respective contributions of macronutrient composition and energy deficit could not be distinguished. Despite these limitations, the prospective design and integrated clinical and biomarker evaluation provide meaningful descriptive insight into the biological adaptations accompanying a long-term LCHF dietary intervention in lipedema.

Overall, the clinical improvement observed in this cohort was accompanied by changes in circulating metabolic, vascular-related, inflammatory, and lipid mediators. However, because the intervention combined LCHF dietary composition with a moderate energy deficit, the present study does not allow separation of the effects of macronutrient composition from those of caloric restriction, weight loss, or reduced adiposity. Caloric restriction itself is known to improve metabolic parameters and reduce systemic inflammation. Therefore, our findings should be interpreted as reflecting systemic changes accompanying a calorie-restricted LCHF intervention rather than effects attributable specifically to carbohydrate restriction or ketosis. Future controlled, ideally isocaloric, comparative studies are needed to distinguish between the effects of energy deficit and dietary composition in lipedema.

Moreover, future studies should validate our findings in larger cohorts and investigate whether baseline or dynamic profiles of angiogenic, inflammatory, and lipid mediators can be used to stratify patients, guide personalized nutritional strategies, and better understand the biological pathways associated with dietary intervention in lipedema. Such studies should ideally include appropriate control groups, objective adherence measures, and tissue- or function-based assessments to better define the biological relevance of circulating biomarker changes.