Hormonal Effects; Lipedema is strongly associated with periods of hormonal fluctuation in women, notably during puberty, pregnancy, and menopause, thereby suggesting a critical role for estrogen in its pathogenesis. Estrogen is known to modulate adipose tissue metabolism and distribution, potentially through altered estrogen receptor expression and enhanced paracrine estrogen release from adipocytes. Dysregulation of estrogen signaling pathways may promote adipogenesis and lipid accumulation within adipocytes, contributing to the distinctive adipose tissue expansion observed in lipedema [26].

Genetic and Molecular Factors; A genetic predisposition to lipedema has been proposed, although specific genetic markers have yet to be conclusively identified. Altered gene expression patterns associated with lipid metabolism and cellular proliferation have been documented in lipedema tissues. Disruptions within key signaling networks, particularly the Bub1 signaling pathway, have been implicated in the hyperproliferation of adipose-derived stem cells, suggesting a molecular mechanism underlying increased adipogenesis in lipedema [40].

Metabolic and Inflammatory Mechanisms; Different metabolic profiles have been identified in lipedema patients, including altered levels of metabolites such as pyruvic acid, histidine, and phenylalanine, which may serve as potential biomarkers of the disease [41]. Inflammatory processes are also involved, with increased macrophage accumulation and altered macrophage polarization observed in lipedema tissues. The MIF family, particularly the MIF-1-CD74 axis, is involved in these inflammatory changes [33].

Extracellular Matrix and Lymphatic Dysfunction; Lipedema is associated with extracellular matrix remodeling and lymphatic dysfunction and contributes to characteristic swelling and pain. Dysregulation of proteins such as CAV1 and matrix metalloproteinase MMP14 can disrupt feedback mechanisms, leading to fat hypertrophy and vascular dysfunction [42]. In lipedema, lymphatic changes are noted, such as increased vascular area and regional lymphostasis, which can exacerbate fluid retention and inflammation [18]. Ongoing research into the hormonal, genetic, and metabolic basis of lipedema is important to develop targeted therapies and improve patient outcomes.

Platelet Transcriptome and Thrombosis; Emerging evidence indicates that lipedema is associated with a prothrombotic phenotype, potentially linked to alterations in the platelet transcriptome. Patients with lipedema demonstrate distinct biological pathway profiles related to protein synthesis, degradation, and metabolism compared to individuals with lymphedema or obesity. These transcriptomic differences may underlie the elevated risk of venous thromboembolism observed in lipedema and underscore the necessity for further exploration of platelet activation mechanisms [43].

Immune Cell Infiltration and Adipocyte Differentiation; An increased infiltration of M2-polarized macrophages has been observed in lipedema tissues, significantly impacting adipocyte differentiation. Elevated numbers of CD163 + macrophages, involved in cytokine-mediated signaling and extracellular matrix organization, have been identified. Notably, pharmacological polarization of macrophages from the M2 to the M1 phenotype via PI3 Kγ inhibition has shown promise in restoring normal adipose-derived stem cell differentiation, presenting a potential therapeutic target [34].

MicroRNA and Gene Expression; Differential expression of specific microRNAs (miRNAs) in lipedema tissue has been implicated in the regulation of pathways involved in cell cycle control, insulin resistance, and inflammation. Upregulation of hsa-let-7 g-5p and downregulation of hsa-miR-205-5p have been documented, affecting the expression of target genes critical for cellular homeostasis [44]. These findings provide novel insights into the molecular underpinnings of lipedema.

Adipocyte Heterogeneity and Signaling Network; Single-cell RNA sequencing has revealed three distinct adipocyte populations in lipedema, each with unique gene signatures. These include lipid-producing, disease-catalyzing, and lipedemic adipocytes [45]. Dysregulated signaling networks, such as those involving the cell cycle regulator Bub1, drive the increased proliferation of adipose-derived stem cells in lipedema. Targeting these pathways may offer new therapeutic strategies [40].

Hormonal and Metabolic Factors: Estrogen plays an important role in the pathogenesis of lipedema and affects fat distribution and inflammation through its receptors. Hormonal changes during puberty, pregnancy, or menopause can trigger or worsen the condition [26]. Despite better regulation of glucose metabolism, lipedema patients have higher levels of cholesterol and inflammatory markers, indicating a complex interplay between metabolic and inflammatory pathways [46].

Lipedema is a chronic condition characterized by the abnormal accumulation of subcutaneous adipose tissue, primarily affecting women. Despite its frequent misdiagnosis as obesity, emerging research highlights distinct metabolic profiles in individuals with lipedema. Studies indicate that women with lipedema often exhibit better lipid profiles and reduced markers of insulin resistance compared to those with obesity, even when matched for BMI. This suggests that lipedema may not carry the same metabolic risks typically associated with obesity, such as type 2 diabetes and metabolic syndrome.

Research indicates that women with lipedema have better glucose metabolism regulation, as evidenced by lower HbA1c levels compared to BMI-matched controls [46]. Additionally, studies have shown that lipedema patients often have lower levels of total cholesterol, triglycerides, and glucose, despite having a high BMI [41]. Although lipedema is associated with increased levels of circulating inflammatory and oxidative stress markers, these do not seem to impair glucose metabolism, suggesting a unique metabolic adaptation in lipedema [46]. Lipedema is characterized by a distinct cytokine profile, with increased levels of certain interleukins, which may influence metabolic activity and contribute to the condition's unique metabolic phenotype [47]. Lipedema is often misdiagnosed as obesity or lymphedema due to overlapping symptoms, such as disproportionate fat distribution and swelling [31]. The lack of specific biomarkers further complicates accurate diagnosis [5, 47].

While the understanding of lipedema pathways is advancing, challenges remain in distinguishing it from similar conditions such as obesity and lymphedema. The lack of specific biomarkers makes it difficult to diagnose, often relying on clinical assessment [24]. Further research into molecular mechanisms and potential therapeutic targets, such as those identified in recent studies, is important to improve patient outcomes.

Lipedema may be complicated by lymphedema later in life. It is classified as primary or secondary. Primary lymphedema is caused by intrinsic abnormalities such as hypoplasia or dysfunction of the lymph vessels, while secondary lymphedema usually develops due to extrinsic factors such as surgical lymphadenectomy. It is characterized by bilateral and asymmetric swelling of both lower extremities with interstitial fluid accumulation due to inadequate drainage of fluid, cells, and proteins."Stemmer's sign,"a pathognomonic sign for lymphedema, is defined by the inability to lift the skin fold at the base of the second toe [48]. Additionally, the identification of platelet factor-4 as a potentially useful biological marker for lymphedema and lipedema suggests that there may be overlapping mechanisms underlying the pathophysiology of these two conditions [49].

Given that poorly managed lipedema can progress to the development of lipo-lymphedema, proper disease management is of paramount importance. This management includes two main objectives: first, to relieve subjective discomfort such as pain; and second, to prevent complications such as lipo-lymphedema, skin infections, psychological morbidities, gait disturbances, and joint deformities [50]. Common comorbidities of lipedema include cardiovascular diseases such as high blood pressure, disorders of the thyroid gland such as hypothyroidism, fibromyalgia, and type 2 DM [51]. In addition, Seefeldt et al. reported that menstrual irregularities, insomnia, and migraine are common in patients with lipedema [52]. In another study, disproportionate accumulation of lipedema tissue in the inner leg was shown to increase the risk of meniscal damage and osteoarthritis by causing valgus stresses, restricting knee flexion, and increasing the risk of falls by altering gait mechanics [53]. Considering the edema, gait changes, and symptoms of chronic venous disease associated with obesity, it is difficult to determine precisely to what extent lipedema and obesity contribute to clinical manifestations [38]. Lipedema cannot be effectively treated with bariatric surgery. In one study, no significant improvement was achieved in the characteristic pain symptoms of lipedema, despite patients losing an average of more than 50 kg [54]. Increased pain perception in lipedema has been associated with irregularities in local sensory nerve fibers through inflammatory processes. This cannot be explained by the mechanical compression of nerve fibers by expanding adipose tissue, as pain is not observed in other types of lipohypertrophy or lymphedema [24].

It has been reported that there is a significant relationship between the development of obesity and the emergence of lymphedema in individuals with lipedema [54]. It has been reported that the most common comorbidity in lipedema is obesity. In a study conducted on Swedish women diagnosed with lipedema, it was found that individuals were overweight and obese [55]. Women with lipedema are at high risk of becoming morbidly obese. Obesity itself is a risk factor for lymphedema and can trigger lipedema and accelerate its progression [1, 23]. Nemes et al. found that left atrial and left ventricular dimensions were larger, as well as ejection fraction, in patients with lipedema [56]. Melander et al. found that the persistent feelings of weight and pain in the legs experienced by women with lipedema lead to feelings of weakness and loss of control over the body [57]. Another study found that it is difficult to reduce excess fat in patients with lipedema using traditional weight loss techniques such as lifestyle changes, bariatric surgery, and pharmacological interventions [58]. The development of depression, appearance-related distress, self-hatred, low quality of life, and social isolation are quite common in patients with lipedema [48]. It is also reported that patients with lipedema have psychological difficulties, can become depressed, and are stressed by their appearance [8, 51, 59].

As general nutritional recommendations in lipedema, short-term diets should be strictly avoided, as they can often cause the yo-yo effect. The balance of energy intake and expenditure should be considered. Patients should be educated about adequate, balanced, and healthy nutrition and food diversity that they can follow sustainably for the rest of their lives. To reduce hyperinsulinemia, there should be no more than 4–6 h between meals, and attention should be paid to eating little and often. Sugar and sugar-containing foods and snacks and processed foods that increase blood glucose levels should be avoided [23, 60]. Consumption of healthy fats should be increased, trans fats should be avoided, and physical activity should be increased. Body weight should be monitored, controlled, managed, and tracked [1, 23]. In recent years, many dietary models and patterns have attracted attention in the medical nutrition treatment of lipedema. One of them is the ketogenic diet.

KD is defined as an extremely low-carb, high-fat, and adequate or low-protein diet that promotes the production of ketone bodies [61]. Glucose, initially stored in the form of glycogen, can be used as an energy source. However, after three to four days, this storage is depleted, and fats in the body can be broken down into free fatty acids, providing raw material for ketone production in the liver [62]. The adult brain uses glucose as its main energy source, which accounts for about 2% of body weight and meets about 20–23% of the body's total energy needs [63]. KD increases the production of ketone bodies in the body, leading to a state of nutritional ketosis. This causes the body to use ketone bodies instead of glucose as the main energy source for vital processes [64]. When carbohydrate intake is insufficient, the oxidation of fatty acids peaks in mitochondria in hepatocytes, and acetyl-CoA production increases. Acetyl-CoA is then combined with oxaloacetate and enters the citric acid cycle. When oxaloacetate is depleted and its amount does not reach equilibrium in the citric cycle, acetyl-CoA is converted to ketone bodies as an alternative energy source for tissues outside the liver. These ketone bodies are produced by the liver in two main forms, acetoacetate and βHB [65]. Acetoacetyl-CoA combines with the enzyme HMG-CoA synthase to form HMG-CoA. HMG-CoA is cleaved to acetyl-CoA and AcAc by the enzyme HMG-CoA lyase. Acetoacetate is reduced to BHB by the action of BHB dehydrogenase or converted to acetone and excreted in breath and urine [66]. These ketone bodies are known for their ability to control substrate utilization, inflammation, oxidative stress, catabolic processes, and gene expression [67]. Ketone bodies produce more ATP than an equivalent amount of glucose [68].

Current ketogenic diet treatment modalities fall into four main groups: classical ketogenic diet, modified Atkins diet, medium-chain triglyceride ketogenic diet, and low glycemic index therapy [69]. KDs are given in ratios such as 3:1, 2:1, or 1:1 and are called modified KDs, determined according to the patient's age, individual tolerance, target ketosis level, and protein requirements while preparing the nutrition plan [70]. The difference between these diets is that the type and amount of fat they contain are different, and it has been reported that there is no significant difference in terms of effectiveness between these diet types [71]. Many potential mechanisms reveal the anti-inflammatory potential of the ketogenic diet. Firstly, the KD puts the body into a state of dietary ketosis. The processes that occur during ketosis have a systemic anti-inflammatory effect that directly impacts CVD. The second most significant factor is the removal of pro-inflammatory sugars from the diet. This directly impacts CVD. Restricting the total amount of carbohydrates in the diet can provide specific anti-inflammatory benefits in the cardiovascular metabolic health context. A high-fat, well-composed ketogenic diet is also rich in omega-3 fatty acids, whose anti-inflammatory and cardioprotective effects are well known [72]. A traditional KD is a 4:1 formulation of carbohydrate plus protein to fat content. A classic 4:1 KD provides 90% of calories from fat, 8% from protein, and only 2% from carbohydrates [73]. To improve flexibility and palatability, less strict KD variants have been developed in recent years, including lower ratio KDs, modified Atkins diet (MAD), low glycemic index therapy (LGIT), and combining these diets with medium-chain triglyceride (MCT) fat [70]. Ketogenic diets are a type of diet rich in fat and low in carbohydrates and protein, and the contents of ketogenic diets in clinical use are given in Table 1. A comparison of 4 basic ketogenic diets used clinically (1000 kcal/day) is given in Table 2.

Given the progressive characteristics of diseases such as lipedema. early diagnosis and treatment are of great importance. These diseases can lead to a significant decrease in quality of life and immobility [74]. Conventional weight loss treatments are often inadequate in patients with lipoedema due to inflammation and fibrosis of the affected adipose tissue [75]. Ketogenic diets induce a state of metabolic ketosis in which the body shifts from relying on glucose to using ketone bodies as the primary energy source. This shift is associated with increased fat oxidation and decreased fat storage, which may contribute to the reduction of subcutaneous adipose tissue in lipedema [15, 76]. A low-carbohydrate diet has been shown to specifically target SAT in the lower limbs, a key feature of lipedema. A randomized controlled trial found that a low-carbohydrate diet reduced calf SAT area and circumference compared to a low-fat diet [14].

Lipedema a is associated with chronic inflammation, which contributes to disease progression and symptom severity. Ketogenic diets have been shown to reduce systemic inflammation by lowering levels of proinflammatory cytokines such as TNF-α and IL-6 [15, 76]. A high-fat ketogenic diet was reported to be more effective in reducing anthropometric measurements and improving symptoms in lipedema patients [77]. Ketogenic diets may also contribute to increased pain sensitivity and reduced swelling in affected areas [2, 76, 78].

It has been suggested that very low-calorie ketogenic diets, particularly in the context of obesity, may be more effective than other dietary approaches such as the Mediterranean diet or intermittent fasting in the treatment of lipedema [79]. Ketogenic diets have found significant improvements in short-term body weight, glucose tolerance, liver function, and lipid profiles in patients with lipedema and no adverse effects on kidney or thyroid function [80]. In addition, it is known to improve insulin sensitivity by reducing carbohydrate intake. This leads to lower insulin levels and improved fat metabolism. Improved insulin sensitivity may play a role in reducing the abnormal fat accumulation seen in lipedema [44, 81].

Recent studies (2018–2025) (Table 3) consistently report that ketogenic diets, especially when combined with other interventions or nutraceuticals, can reduce body fat, improve pain, and enhance quality of life in patients with lipedema. Both pilot studies and systematic reviews highlight significant improvements in anthropometric and metabolic parameters, though larger and longer-term studies are still needed for confirmation. The mechanisms of action of the ketogenic diet on lipedema are presented in Fig. 2.

The mechanisms of action of the ketogenic diet on lipedema

Women with lipedema have demonstrated the negative impact of the disease on their mental health and quality of life, underlining the need for more individualized and empathetic therapeutic approaches [82]. It has been proven that weight loss does not affect the prognosis of lipedema caused by fat accumulation. Lipedema resistance to dietary treatment is high, with 95% of patients unable to lose weight in lipedema areas. In individuals with insulin resistance, increased lipolysis and impaired lipogenesis in adipose tissue lead to the release of cytokines and lipid metabolites, ultimately increasing insulin resistance. Therefore, since no specific diet has been developed for lipedema to date, an isoglycemic diet appears appropriate [25]. It has been hypothesized that the ketogenic diet may be effective in the treatment of lipedema in terms of weight loss, reduction of edema, modulation of the inflammasome, and subsequent improvement of the redox status [15]. The diet may partially affect systemic inflammation through its effect on weight. High BMI and obesity are associated with low-grade inflammatory status and elevated levels of circulating inflammatory markers. Therefore, weight loss leads to a reduction in inflammatory cytokines, including CRP, IL-6, and TNF-α. These cytokines and metabolic effects intersect with