Lipedema is a chronic disorder characterized by the abnormal accumulation of adipose tissue, predominantly observed in women. It manifests as symmetrical fat deposition and tactile sensitivity in the extremities, affecting both sides of the body. While the etiology of the disease is not yet fully understood, genetic predisposition, hormonal fluctuations, a stressful lifestyle, as well as traumatic events are considered potential triggers. Lipedema remains a condition with low diagnostic awareness as well as is frequently misdiagnosed as obesity or lymphedema. While obesity is a risk factor for lipedema, the abnormal fat deposition characteristic of the disease can occur across a wide spectrum of body weights, from underweight to overweight individuals. Specific patterns of adipose tissue distribution may be associated with signs of inflammation as well as heightened pain perception, as well as individuals with eating disorders, such as anorexia, may additionally be affected.
Introduction
Lipedema, a chronic disease causing a painful bilateral disproportionate swelling of the legs and/or arms, mostly in female subjects, with an onset during or after puberty. It is a condition that is often overlooked and requires a multidisciplinary approach since it can lead to a significant reduction in subjects’ mobility. Lipedema has a highly variable progression over time through four stages, leading to disability for several decades if not treated. The fat tissue deposition occurs in arms and legs symmetrically, with a clear demarcation line between hands and feet (the cuff sign), and a clear disproportion between the upper and lower body, waist-to-hip ratio (WHR) and is characterized by heavy, dull pain, exacerbated trough pressure, touch, physical activity, or long periods of sitting. Besides pain, bruising and orthostatic edema are also very common clinical features. Other features include stable limb circumference despite weight reduction and caloric restriction, worsening of symptoms during the course of a day, visible vascular markings around fat deposits, and skin hypothermia. Staging is based on structural skin changes and skin palpation.
Given that current lifestyle interventions are often unsuccessful in the management of lipedema, and there is no consensus on the most effective nutritional approach for managing lipedema, ketogenic diets have emerged as a promising therapeutic option for lipedema. Characterized by low carbohydrate as well as high fat content, ketogenic diets facilitate metabolic improvements by reducing insulin resistance as well as supporting weight loss. This review aims to investigate the potential mechanisms of action, beneficial properties, and clinical implications of KD in lipedema. By synthesizing findings from in vitro, animal, and human studies, the review critically examines both the advantages and limitations of ketogenic dietary therapy. Additionally, a daily ketogenic meal plan is presented based on a case study, with calculated energy and nutrient values tailored for lipedema management.
Methodology
In the pursuit of ameliorating lipedema and its associated symptoms, the ramifications of specific nutritional strategies, particularly those employing ketogenic dietary methodologies, on the quality of life and recuperation of affected individuals are garnering significant scholarly interest. Within this framework, a thorough literature review was executed to evaluate the influence of ketogenic diets on the therapeutic management of lipedema. The literature search was conducted utilizing the PubMed/Medline, PsycINFO, Web of Science, Scopus, ScienceDirect, and Google Scholar bibliographic databases. Investigations published in the English language from 2018 to 2025 were included in the assessment. The subsequent keywords were employed throughout the search process: "lipedema," "fat accumulation," "ketogenic diet," "ketosis," "obesity," "inflammation," "pain," "edema," "bruising," "hormone," "insulin," "fat metabolism," "leg," "cellulite," and "painful cellulite."
Authors performed searches and full texts were reviewed according to the following inclusion criteria: (1) publications dated from 2018 to 2025 (2) availability in full-text format in English, (3) classification as original research articles, reviews, systematic reviews, meta-analyses, letters to the editor, clinical human studies, animal studies, in vivo, in vitro research, cell-based animal and human studies. Studies published in non-English languages or those in preprint stages were excluded from the review. A total of 93 references were analyzed based on the specified inclusion criteria, and the findings from seven key studies were summarized in a tabular format. The studies were accessed using the databases and search strategies described above.
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Etiology and Epidemiology of Lipedema
Lipedema is characterized by the abnormal proliferation of adipose tissue, primarily triggered by hormonal changes, leading to fat accumulation predominantly in the lower body. It is estimated that approximately 10% of women are affected by lipedema, although it is rarely observed in men. Globally, lipedema is believed to impact approximately one in nine adult women. Common clinical features include easy bruising, pain, impaired mobility, and hypersensitivity to touch, all of which contribute to significant functional limitations and reduced quality of life. In approximately 80% of cases, the upper extremities are also affected, although the hands and feet typically remain uninvolved.
Pain is considered the primary symptom and is associated with allodynia, heightened sympathetic nerve signaling, and estrogen-mediated mechanisms. Although the precise mechanisms underlying pain are not fully elucidated, effective treatment can provide significant symptom relief. The most minimally invasive and currently effective treatment for lipedema is microcannulated tumescent liposuction, which has been shown to substantially reduce pain in affected patients. While weight gain can exacerbate the symptoms of lipedema, there is no evidence suggesting that weight gain alone causes the disease. Rather, weight gain may serve as a trigger in genetically predisposed individuals. Traditional weight loss strategies, including intense physical activity and caloric restriction, are often ineffective at reducing lipedema-associated fat, sometimes exacerbating the disproportion between the upper and lower body.
Diagnosis of lipedema remains challenging due to the heterogeneity of its clinical presentation and the lack of objective diagnostic tools. Notably, significant differences have been documented in leg fat mass between women with lipedema and obese women without the condition. Revised diagnostic criteria for lipedema emphasize features such as gynoid fat deposition resistant to weight loss, bilateral lower limb swelling that persists despite elevation, and the presence of palpable nodules under the skin. Lipedema is classified into three progressive stages: Stage I: Small nodules and reversible edema, Stage II: Larger, nut-sized nodules with reversible or irreversible edema, Stage III: Severe fatty deposits, macro-nodular changes, associated lymphedema, and a possible positive Stemmer sign. Differentiating lipedema from non-lipedema obesity is crucial. In typical obesity, fat is distributed in an android pattern, responds to conventional weight loss methods, and does not exhibit pain or edema. Early and accurate diagnosis is vital, as misinterpreting lipedema as obesity may lead patients to harmful restrictive dieting practices, resulting in energy or protein-energy malnutrition. Various mechanisms and pathways and genes that increase and decrease lipedema are presented in Fig. 1.
Pathophysiology of Lipedema
Despite the recent publication of extensive histologic and molecular genetic studies, the basic etiology and pathology of lipedema remain largely unclear. Several hypotheses have been proposed regarding its pathophysiology, and it is thought that gene mutations associated with three main biological pathways may play a role in its somatic development. These are genes of leukocyte clones, genes related to mitochondrial activity, and genes related to localized disorders of subcutaneous adipose tissue. It is also thought that steroid hormones may play a role in the pathogenesis of lipedema. Indeed, AKR1 C1, a gene encoding a protein involved in steroid hormone metabolism, was identified as the first suggestion to be associated with lipedema. The study by Kaftalli et al. provides evidence that AKR1 C1 may be a key gene in the pathogenesis of lipedema and that common polymorphisms may predispose to the development of lipedema.
It is emphasized that lipedema should be considered as an endocrinological pathology. In addition to genetic predisposition, lipedema has been reported to be associated with significant hormonal changes, particularly abnormal expression of ERs in adipose tissue. In particular, downregulation of ER-α and upregulation of ER-β in affected areas have been identified as characteristic features. Despite the proposed autosomal dominant mode of inheritance based on family tree analyses, it has been proposed that this disorder is caused by a polygenic-mediated change in the alpha and ER distribution pattern in white adipose tissue in the affected areas (ER-α expression ↓, ER-ß expression ↑).
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Another hypothesis suggests that lipedema is associated with macrophage accumulation and changes in macrophage polarization. A well-known protein superfamily contributing to macrophage polarization and accumulation is the MIF family. MIF-1 and MIF-2 regulate inflammatory processes in adipose tissue. In another study, mRNA expressions of MIF-1 and CD74 were significantly increased in patients with lipedema, while MIF-2 expression was unaffected, suggesting a possible contribution of the MIF family via the MIF-1-CD74 axis in lipedema. Given that different populations of macrophages influence adipose tissue differentiation and metabolic processes, the use of the selective PI3 Kγ antagonist IPI-549 to induce macrophage polarization from M2 to M1 in lipedema, followed by the differentiation of adipose tissue-derived stem cells from IPI-549-treated SVF in conditioned medium, resulted in a significant reduction in lipid accumulation compared to control SVF in lipedema. The results suggest that CD163 + macrophages are a crucial factor in lipedema and that repolarization of lipedema macrophages may normally differentiate adipose tissue-derived stem cells in vitro when assessed by cell lipid accumulation.
The GH/IGF-1 pathway is known to have significant effects on adipocyte metabolism due to GH being a potent stimulator of lipolysis. However, these effects do not occur via IGF-1; IGF-1 plays a critical regulatory role in the terminal differentiation processes of adipocytes. There are no studies in the literature specifically examining the GH/IGF-1 pathway in patients with lipedema. However, in an in vitro study on fat stem cells, it was found that IGF-1 expression was significantly increased during the proliferation process in stem cell cultures obtained from patients with lipedema compared to the control group.
Another hypothesis regarding the pathophysiology of lipedema is the presence of primarily microvascular dysfunction in the blood capillaries and the lymphatic system. This is thought to lead to endothelial dysfunction and thus increased angiogenesis due to hypoxic stimuli resulting from excessive expansion of adipose tissue. An alternative view suggests that this disorder may result from a mechanical deficiency in lymph drainage. Increased capillary permeability causes proteins to escape into the extracellular compartment ("capillary leakage"), resulting in tissue edema. According to another hypothesis, one of the main triggers of lipedema is the accumulation of bacterial lipopolysaccharides (endotoxins) in lower extremity fat deposits (gluteofemoral white adipose tissue; gfWAT). In addition, it has been suggested that interstitial fluid accumulation due to microvascular dysfunction may also play a role in the pathogenesis of lipedema. Disruption of interstitial fluid and tissue volume homeostasis is associated with increased interstitial fluid, tissue sodium, and adipose tissue accumulation in lipedema. Further studies have shown that edema, bruising, joint hypermobility, spider veins, cold-like symptoms, and fatigue are more commonly observed in individuals with lipedema. These findings support the theory that lipedema is not merely a fat storage disorder but rather a tissue disorder associated with microvascular and neurological dysfunction.
Mast cells, immune cells that secrete histamine and other inflammatory molecules, mediate hypersensitivity and allergic reactions in the body. Based on the hypothesis that mast cells play a role in lipedema pathology, biopsies were taken from SAT in both lipedema and control groups and histologically analyzed for the presence of mast cells. Histological examination confirmed the presence of mast cells in lipedema tissue. Furthermore, metabolomic analysis revealed elevated histamine levels and its metabolites in lipedema samples compared to controls. After a two-week treatment, histamine levels in lipedema tissue were significantly reduced, suggesting decreased mast cell activity.
Moreover, it has been suggested that progesterone causes a slower and less efficient decrease in 20-α-hydroxyprogesterone, which may lead to increased subcutaneous fat accumulation. This opens up the potential for targeted pharmacological therapies for lipedema. Thus, understanding the underlying genetic factors in lipedema could be crucial for developing pharmacological treatments that directly affect the relevant or causal molecules.
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Mechanisms of Formation of Lipedema and Pathways
Hormonal Effects
Lipedema is strongly associated with periods of hormonal fluctuation in women, notably during puberty, pregnancy, and menopause, thereby suggesting a critical role of hormones in its development. Estrogens promote fat storage by enhancing insulin secretion, increasing sensitivity of target tissues to this hormone, and in part by inhibiting fatty acid oxidation. In women with excessive body weight, lipolysis in buttock regions is reduced compared to the area of adipose tissue located in the abdomen.
Genetic Predisposition
Lipedema is not edema but rather a genetic disorder affecting adipose tissue mass and distribution. It is typically inherited either through X-linked dominant or autosomal dominant patterns. In rare cases, gene mutations like POU1F1/PIT-1 have been observed in short mothers, but their offspring did not exhibit noticeable phenotypic features.
Microvascular Dysfunction
Another hypothesis regarding the pathophysiology of lipedema is the presence of primarily microvascular dysfunction in the blood capillaries and the lymphatic system. This is thought to lead to endothelial dysfunction and thus increased angiogenesis due to hypoxic stimuli resulting from excessive expansion of adipose tissue. Increased capillary permeability causes proteins to escape into the extracellular compartment ("capillary leakage"), resulting in tissue edema.
Inflammation
Lipedema can coexist with a state of obesity, which in turn can promote a state of chronic low-grade inflammation. This state of chronic low-grade inflammation in turn can impair lymphatic function, exacerbating adipose tissue accumulation. The excessive IF surrounding adipocytes represents a source of nutrients, thus further promoting fat cell hypertrophy.
Ketogenic Diet for Lipedema Management
Ketogenic diets have emerged as a promising therapeutic option for lipedema. Characterized by low carbohydrate as well as high fat content, ketogenic diets facilitate metabolic improvements by reducing insulin resistance as well as supporting weight loss.
Principles of a Ketogenic Diet
A ketogenic diet is very low in carbohydrates and high in healthy fats. When carbohydrate intake is restricted, the body starts using dietary fat, as well as fat stored in adipose tissue, for fuel. A limitation on carbohydrates results in the production of ketones from fat, or ketogenesis. This shifts the body from a sugar-burning machine to a fat-burning machine. Because a ketogenic way of eating requires you to limit your daily carbohydrate intake to 20 grams/day or less, this means that foods like bread, rice, pasta, and starchy vegetables, such as potatoes, are eliminated from your diet. Foods that are high in carbohydrates (sugars), even if natural food like honey or fruit, must be severely limited or even avoided completely.
The ketogenic diet consists of:
- Very Low Carbohydrate: limit to 20 grams of carbohydrates per day or fewer.
- Moderate Protein: moderate protein intake is 1.5-1.75 g per kg of “ideal” body weight. For a 150 lb. person (68 kg), this would be 102-119 g of protein.
- High Healthy Fat: healthy fats include highly stable plant- or animal-sourced saturated and monounsaturated fats (olive oil, avocado oil, coconut oil, lard and butter) and omega-3 polyunsaturated fats from marine sources. Fill in with fat for satiation.
- Avoid Partially Hydrogenated Seed and Vegetable Oils: corn, safflower, sunflower, grapeseed, soy, and peanut oils are high in omega-6 polyunsaturated fats. Getting too much of this kind of fat can be unhealthy.
- Eliminate Artificial Sweeteners and Sugar Substitutes: artificial sweeteners can result in weight gain or, at the very least, a weight loss stall. Continued reliance on sweetened foods keeps your craving for sugar and carbohydrates alive, can cause an insulin response, and stimulate hunger.
Benefits of Ketogenic Diet for Lipedema
- Swelling/inflammation decrease: Carbohydrates are inflammatory which can create pain and swelling.
- Pain reduction: There can be a significant reduction in the levels and intensity of pain experienced in lipedema limbs.
- Fat Creates Satiety: The consumption of fat creates a feeling of satiety which lasts for long periods.
- Carbohydrate Addiction: Eating carbohydrates causes an insulin spike, which results in more hunger.
Clinical Evidence
Current evidence on the efficacy of VLCKD in the context of lipedema is scarce, with only two studies reporting clinical benefits of a ketogenic diet (KD) in subjects with lipedema. Sørlie et al. 9 women with lipedema (aged 46.9 ± 7 years). The low carbohydrate, high fat diet induced a significant weight loss (−4.5 ± 2.4%, p < 0.001) and reduction in pain (−2.3 ± 0.4 cm, p = 0.020). Weight loss was maintained between week 7 and 13, but pain returned to baseline levels at week 13. Studies on women with lipedema who underwent KD protocols reported significant reductions in upper limb, lower limb, waist, and hip circumferences.
A systematic review reported that women following KD protocols for approximately 15.85 weeks exhibited a mean BMI reduction of 4.23 kg/m2, an average weight loss of 7.94 kg, and decreased waist and hip circumferences, alongside improvements in body composition. In a controlled study, a low-carbohydrate diet significantly reduced calf subcutaneous adipose tissue area and pain, highlighting its potential therapeutic benefits. The anti-inflammatory effects of ketogenic diets are also considered beneficial in alleviating symptoms of lipedema. Further studies have reported improvements in pain reduction, body weight loss, and quality of life following ketogenic interventions. Personalized approaches, such as combining KD with carboxytherapy, have shown even greater efficacy in improving body composition and reducing pain.
Study on Low-Carbohydrate-High-Fat Diet (LCHF) vs. Low Glycemic Index Medium-Fat-Medium-Carbohydrate (MFMC)
A total of 108 women diagnosed with lipedema based on typical clinical signs were enrolled in the study between January 2020 and June 2021. Clinical evaluation and diagnosis of lipedema was confirmed by a physician specialized in angiology. The age of the participants ranged from 18 to 76 years (mean 43.2 ± 12.8 years; median = 40.0). A total of 91 female participants completed the study (n = 91). The participants were subsequently divided into 2 groups. The participants enrolled between January and October 2020 were enrolled to the MFMC group, and the participants enrolled from November to June 2021 were enrolled to the LCHF group. One group received a low-carbohydrate-high-fat diet (LCHF; n = 46) and the other group a low glycemic index medium-fat-medium-carbohydrate (MFMC; n = 45). Patients were measured for resting metabolic rate (RMR) assessment to determine energy requirements at baseline. Both diets were applied for 16 weeks in each group. The individualization of the dietary plans contributed to increased adherence to the diet by the study patients.
The mean total energy value of two diets was significantly different (1677.0 kcal for LCHF vs 1724.3 kcal for MFMC; p = 0.001) due to individual estimation of energy requirements. The total energy value of the LCHF diet ranged from 1390 to 2022 kcal/day, compared to 1480 to 2088 kcal/day in the MFMC diet. The total carbohydrate content of the LCHF diet was 29.8 g/day, which accounted for 6.1% of the energy value, and that of the MFMC diet was 189.4 g/day, which equaled 39.1% of the energy value (p < 0.001). The proportion of fat in the diet was 134.6 g/day (72.3% of energy value) for LCHF and 78.0 g/day (39.1% of energy value) for MFMC; p < 0.001. Both diets did not differ significantly in protein content (p = 0.076). Protein supply in both groups was not less than 0.8-1.0g/kg of body weight.
- 0% of all the patients were in stage 1 of lipedema (47.8% in LCHF group; 40.0% in MFMC group), 41.8% of them were in stage 2 (43.5% in LCHF group; 40.0% in MFMC group), 13.2% of them were in stage 3 (8.7% in LCHF group; 13.2% in MFMC group) and 1.1% was in stage 4 (2.2% in MFMC group). Based on mean BMI, 78.0% of all the patients were characterized as being overweight (BMI ≥ 25.0 kg/m2)30-78.3% in MCMF group and 77.8% in LCHF group. The most participants in both groups had obesity class I (BMI 30.0-34.9 kg/m2) - 34.8% in MCMF group and 26.7% in LCHF group. 10.9% and 22.2% of patients in MCMF and LCHF group had obesity class II (BMI 35.0-39.9 kg/m2), respectively. 13.0% of participants in MCMF group and 17.8% in LCHF group were characterized by obesity class III (BMI ≥40.0 kg/m2). The percentage of patients with body fat greater than or equal to 30.0% of body weight accounted for 84.6% of all patients, with the largest proportion of patients with body fat greater than 40.0% of body weight (58.0% of all obese patients).
Additional Conservative Treatments
We should note that the ketogenic diet can give great results for people with lipedema, but other conservative treatments are required for truly remarkable results. Work with a trained therapist well-versed in lipedema to develop your personal protocol for management. Your protocol may include: compression therapy with a pneumatic compression pump and/or compression stockings, manual lymph drainage, skin care, and exercise.