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Background Lipedema is a chronic condition characterized by abnormal fat accumulation, primarily in the lower extremities, affecting mostly women. Despite improvements in diagnosis and treatment, lipedema is often misdiagnosed as obesity or lymphedema. Patients with obesity and lipedema propose a distinct clinical challenge in treating both diseases. Improved recognition and understanding are necessary to enhance diagnosis and treatment outcomes. Purpose of this Review Lipedema is thought to be hormonally driven, often manifesting during puberty, pregnancy, or menopause. It presents as disproportionate fat accumulation in the lower body, often with microvascular changes. Misdiagnosis as obesity or lymphedema leads to ineffective treatments like weight loss programs and bariatric surgery. Effective management involves both conservative and surgical approaches, as well as a tailored strategy for patients with both lipedema and obesity. The focus of this review is to summarize the current literature addressing adequate treatment regimens for patients with both diseases and based on the literature we propose a treatment protocol. Conclusion Patients with concurrent lipedema and obesity propose a distinct clinical challenge, in which early recognition can benefit adequate treatment. A combination of conservative measures and surgical options, particularly liposuction and / or bariatric and metabolic surgery, can be beneficial in treating patients with both diseases. However future research is needed to assess the effect of different treat regimens.

Lipedema is a chronic disease characterized by the symmetrical accumulation of adipose tissue in the lower body, primarily affecting women. Despite being recognized for over 85 years, the pathophysiology, diagnosis, and treatment of lipedema remain complex and not fully understood. This review consolidates current knowledge, emphasizing histological, genetic, and hormonal factors, alongside diagnostic and therapeutic approaches. Histological studies highlight changes such as adipocyte hypertrophy, increased fibrosis, and vascular alterations like angiogenesis. Genetic studies suggest a strong familial component, with multiple loci potentially influencing disease onset, yet the condition remains polygenic and influenced by environmental factors. Hormonal influences, particularly estrogen, play a significant role in disease pathogenesis. Diagnostic imaging techniques like dual-energy X-ray absorptiometry (DXA), ultrasound (US), and magnetic resonance imaging (MRI) provide valuable insights but are not definitive. Therapeutic strategies, including diet, weight loss, and Complex Decongestive Therapy, offer symptom management but are not curative, with liposuction considered for severe cases where conservative methods fail. The condition's complexity stems from genetic, hormonal, and environmental influences, necessitating further research to improve diagnostic and treatment strategies. Integrating genetic and hormonal insights into clinical practice could enhance patient outcomes and quality of life, highlighting the need for continued exploration and understanding of lipedema.

Background. Lipedema is a chronic and progressive fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. Symptoms include pain, bruising, swelling, and subcutaneous nodules that are resistant to traditional interventions such as diet and exercise. Aim. The objective of this review is to summarize recent evidence on the characteristics, pathophysiology, diagnosis and treatment of lipedema. Matherial and Methods. A literature search was conducted using the PubMed database. The inclusion criteria were “full free text” and English scientific articles, published between 2015 and 2025. A total of 74 records were found, of which    publications were ultimately included in the review. Results. Awareness of lipedema in the medical field is increasing, but its differential diagnosis still remains a challenge. Lipedema is often unrecognized or misdiagnosed as obesity or lymphedema. Conclusion. This narrative review provides a deeper understanding of lipedema as a serious condition, discusses its pathophysiology and treatment options. The data reveal advances in knowledge, particularly in conservative and surgical treatment with a focus on improving quality of life. However, there is a lack of scientific evidence confirming the safety and efficacy of various treatment methods. Further research is required to ensure the safety and increase the efficacy of treatment for this complex condition known as lipedema.

Background:  Lipedema is a progressive subcutaneous adipose tissue disorder predominantly affecting women. Characterized by painful nodules and inflammation, it impairs mobility and quality of life. Traditional nonsurgical treatments currently offer limited relief and necessitate additional interventions. This study aimed to evaluate the efficacy of SMiLE (Softening, Mobilization, Liposuction, Extraction), a lipedema reduction surgery (LRS) technique. This technique combines lymphatic-sparing liposuction with manual lipedema extraction to comprehensively remove lipedema nodules. Methods:  Sixty-two women who underwent LRS with the SMiLE technique by the primary author participated in the study and completed an online survey. Data were collected on prior medical history related to lipedema development and comorbidities and outcome measures such as pain, activities of daily living, and quality of life before and after surgery. Results:  The findings demonstrate significant improvements in patients’ daily lives following surgery. Pain levels decreased by an average of 73.9%, with the most notable reduction in the buttock shelf (81.3%). Mobility improved for 93% of participants who had faced challenges before LRS, and quality-of-life assessments indicated a 47.5% reduction in the negative impact of lipedema postsurgery. Conclusions:  The SMiLE technique offers an advancement in the surgical management of lipedema by enabling the effective removal of lipedema tissue. Alongside a reduction in pain and improvement in mobility, this method addresses physical and psychological burdens. This study suggested that the SMiLE technique could be considered an option as part of a comprehensive approach to treating patients with lipedema.

Background: Emerging evidence suggests that lipedema may share hormonal, inflammatory, and genetic mechanisms with gynecologic diseases, particularly endometriosis. However, the extent and nature of these interrelationships remain poorly characterized, supporting the need for this scoping review. Objectives: To map and synthesize the available evidence on the clinical, pathophysiological, and epidemiological interrelationships between lipedema in women, endometriosis, and other gynecologic diseases. Methods: Searches were conducted in international and regional health databases, including MEDLINE (PubMed), CINAHL, Scopus, Embase, Web of Science, the Cochrane Library, LILACS/VHL, APA PsycInfo, SciELO, Epistemonikos, and La Referencia, as well as grey literature sources and relevant institutional websites. There were no language restrictions. The search period began in 1940, the year in which lipedema was first described by Allen and Hines. Study selection followed a two-stage process conducted independently by two reviewers, consisting of title and abstract screening followed by full-text review. Data extraction was performed using a pre-developed and peer-reviewed instrument covering participants, concept, context, study methods, and main findings. The review protocol was registered in the Open Science Framework. Results: Twenty-five studies from ten countries were included. Synthesized evidence supports the characterization of lipedema as a systemic condition with metabolic and hormonal dimensions. Key findings include symptom onset linked to reproductive milestones, a high frequency of gynecologic and endocrine comorbidities, and molecular features overlapping with steroid-dependent pathologies. These patterns reflect a recent shift from a predominantly lymphovascular paradigm toward a more integrated endocrinometabolic framework. Conclusions: The findings indicate that lipedema clusters with hormone-sensitive gynecologic and endocrine features across reproductive life stages.

Background/Objectives: Lipedema is a chronic, progressive adipo-fascial disorder characterized by connective tissue dysfunction, fibrosis, microangiopathy, and adipose tissue proliferation. Although lipedema has traditionally been described as a regionally confined disorder, emerging evidence suggests that it may reflect a broader stromal and connective tissue dysfunction. It is therefore plausible that anatomical regions not historically associated with lipedema may also exhibit alterations consistent with this dysfunctional stromal pattern. From this perspective, breast tissue-rich in fibro-glandular and stromal components-represents a compelling model in which to investigate whether such features are present. The breast, with its complex fibro-glandular and stromal architecture, represents a physiologically plausible site of involvement; however, its structural features in lipedema have never been systematically examined. The primary aim of this study was therefore to determine whether breast tissue-rich in fibro-glandular and stromal components-shows recurrent imaging or histopathological features suggestive of lipedema-related involvement. A secondary aim was to compare the frequency of these findings with patterns typically reported in healthy screening populations. Methods: This retrospective cross-sectional study analyzed 62 women (mean age: 44 ± 8 years), obtained between September and November 2025, with a clinical diagnosis of lipedema who voluntarily provided breast imaging reports (ultrasound, mammography, or magnetic resonance imaging, MRI). Results: The findings revealed a remarkably high prevalence of fibro-glandular parenchyma (45%), multiple diffuse cysts (42%), microcalcifications (21%), and fibroadenomas (43.5%), with frequencies substantially exceeding those documented in healthy screening populations. Additional features included significant breast asymmetry or tuberous morphology (6%), reactive or sclero-lipomatous lymph nodes (19%), and recurrent stromal hyperplasia on biopsy. Histological evaluations (n = 9) consistently showed fibroproliferative alterations, including stromal hypercellularity, adenosis, fibroepithelial lesions, apocrine metaplasia, and pseudoangiomatous stromal hyperplasia, suggesting a shared extracellular matrix-related dysplastic phenotype between lipedema-affected breast tissue and peripheral adipose tissue. Conclusions: These findings support the hypothesis that lipedema may express a characteristic breast phenotype driven by stromal and extracellular matrix dysregulation. If confirmed in larger controlled studies, these recurrent alterations could contribute to improved diagnostic frameworks and raise awareness of lipedema as a systemic connective tissue disorder with underrecognized breast manifestations.

Background: Lipedema is a progressive disorder of subcutaneous connective tissue, predominantly affecting women, and characterized by an increase in subcutaneous adipose tissue, particularly in the lower body. This study aims to explore the gut microbiota (GM) profile in lipedema patients to characterize the associated GM and compare it with the control group. Methods: A prospective randomized case-control pilot study was conducted from September 2023 to May 2024, involving 55 Caucasian women, aged 20-60. The participants were divided into two groups: 35 with lipedema (LIPPY) and 20 controls (CTRL). Body composition was assessed using Dual X-ray Absorbimetry (DXA), and GM analysis was performed through 16S rRNA gene sequencing. Results: LIPPY subjects showed increased Intramuscular Adipose Tissue (IMAT) and reduced Lean Mass (LM)/Fat Mass (FM) ratios. While alpha and beta diversity metrics did not differ significantly between groups, differential abundance analysis identified a significant reduction in Eggerthellaceae (Log Fold Change (LFC) = -0.19, p = 0.04) and enrichment of Propionibacteriaceae (LFC = +0.18, p = 0.009) and Acidaminococcaceae (LFC = +0.32, p = 0.013) in the LIPPY group. Genus-level analysis showed a significant reduction in Blautia and Ruminiclostridium (LFC = -0.32 and -0.02; p = 0.02 and 0.04) and enrichment of Anaerostipes, Propionibacterium, and Phascolarctobacterium (LFC = +0.07, +0.17, and +0.34; p = 0.02, 0.005, 0.005, respectively). In correlation analyses, within LIPPY, Eggerthellaceae correlated negatively with Body Mass Index (BMI) (ρ = -0.61, p < 0.05) and positively with Appenicular (Appen) LM/Weight and AppenLM/BMI (ρ = +0.43 and +0.41, p < 0.05), while Anaerostipes correlated positively with these lean mass indices (ρ = +0.40, p < 0.05). In CTRL, only Anaerostipes showed a significant negative correlation with BMI (ρ = -0.64, p < 0.05). Conclusions: This study provides the first evidence of a distinct GM profile in LIPPY, with notable links to adverse body composition markers such as IMAT. Trial Registration: Trial registered on 24 June 2013 with ClinicalTrial.gov (NCT01890070).

Background/Objectives: Lipedema is a chronic disorder that affects almost exclusively women and is characterized by bilateral, symmetrical accumulation of subcutaneous fat, typically in the buttocks, hips, and lower limbs, and in some cases the arms. The primary objective of this study was to describe the clinical and anatomical manifestations of lipedema, together with the associated physical and psychological comorbidities, in a large Spanish cohort. Methods: Descriptive study of 1803 patients aged ≥ 17 years who attended two clinics in Spain between January 2022 and November 2024. Results: The mean age was 42.9 years (SD: 11.3), and 60.6% of patients were diagnosed during their reproductive years. The mean body mass index was 28.6 (SD: 6.2), and 87.6% presented a gynoid fat distribution. A total of 46.6% were classified as Schingale stage IV or V. The most frequent comorbidities were chronic low-grade inflammatory alterations and connective tissue damage. Particularly suspected high intestinal permeability (99%), bilateral trochanteric pain region (97.4%), iliotibial band involvement, and ligamentous hyperlaxity (95.8%). Thyroid disorders, inflammatory ovarian dysfunction, and psychological impairment were also common. Conclusions: Lipedema is a complex condition that extends beyond lower-limb adipose tissue and is associated with multiple comorbidities. This study also presents a novel approach to clinical assessment that may help physicians gain a deeper understanding of this pathology and formulate etiological hypotheses that will need to be tested.

Objectives: This study aimed to evaluate the clinical efficacy of transfer energy capacitive and resistive (TECAR) therapy in females with Stage 2 lipedema, focusing on limb circumference, pain, functional status, and quality of life. Patients and methods: A prospective, randomized controlled trial was conducted with 30 female patients diagnosed with Stage 2 lipedema between September 2024 and May 2025. Participants were randomized to a TECAR group (n=15; mean age: 52.7±13.1 years; range 39 to 66 years) or a control group (n=15; mean age: 45.9±12.9 years; range, 37 to 59 years). Both groups received compression garments and a structured exercise program. The TECAR group additionally underwent six TECAR sessions over three weeks. Outcomes included lower limb circumference, Visual Analog Scale for pain, Lower Extremity Functional Scale, and Lymphedema Quality of Life Questionnaire-Leg, assessed at baseline and at one and three months after treatment. Results: The groups were comparable at baseline for age (p=0.163) and body mass index (31.85±4.08 kg/m² in the TECAR group and 30.02±4.08 kg/m² in the control group; p=0.112). The TECAR therapy resulted in greater reductions in lower limb circumference compared to standard care, with a statistically significant and sustained improvement observed only in the supramalleolar region at three months (p<0.05). A significant short-term reduction in pain was observed at one month (p=0.003) only in the TECAR group, but this effect was not maintained at three months (p>0.05). Functional scores showed a nonsignificant trend toward improvement (p=0.058). The overall quality of life score improved significantly in the TECAR group (p=0.002), although no individual Lymphedema Quality of Life Questionnaire subdomain reached statistical significance (p>0.05). Conclusion: As an adjunct to standard care, TECAR therapy appears to reduce pain and limb volume and enhance overall quality of life in Stage 2 lipedema. Further long-term studies are needed to confirm these findings.

BACKGROUND: Lipedema is a chronic, progressive adipose tissue disorder that predominantly affects women and is characterized by disproportionate fat accumulation, pain, and edema. Hormonal fluctuations are frequently reported as triggers or modulators of symptoms, but the impact of exogenous hormones, especially hormonal contraceptives, remains poorly defined. OBJECTIVE: This study aimed to investigate the association between hormonal contraceptive use and the presence, severity, and self-reported worsening of lipedema symptoms in Brazilian women. METHODS: This observational, cross-sectional study was conducted at Amato - Instituto de Medicina Avançada using a structured online questionnaire applied between August and November 2025. We included women aged 18 years or older, residing in Brazil, with suspected or confirmed lipedema who provided electronic consent and completed core sections on lipedema symptoms, hormonal history, and contraceptive use. Questionnaires with less than 50% of core items answered, duplicate entries, and biologically implausible values were excluded. Symptom (0-8) and quality of life (0-15) scores were calculated. Self-reported changes in symptoms after starting hormonal contraceptives were analyzed as a four-level variable and as a binary worsening variable. Free text on side effects and timing of onset was categorized with natural language processing. Statistical analyses included chi-squared tests, Spearman correlations, and logistic and linear regression. RESULTS: A total of 637 women were included (mean age 41.8±8.7 years; mean body mass index (BMI) 28.9±6.4 kg/m²); 77.1% had a confirmed diagnosis of lipedema and 92.3% were current or previous users of hormonal contraceptives. Among users, 58.8% reported symptom worsening after starting contraceptives (34.5% severe; 24.3% slight), 40.3% reported no change, and 0.9% reported improvement (p<0.001). Free text analysis showed that 15.1% reported onset of lipedema symptoms temporally coinciding with contraceptive initiation. In multivariable analysis, a higher baseline symptom score was the strongest independent predictor of worsening, while duration of contraceptive use was not associated with risk. Pain intensity and BMI were the main independent predictors of quality of life impact. CONCLUSIONS: In this large sample of Brazilian women with suspected or confirmed lipedema, hormonal contraceptive use was frequently associated with self-reported worsening of symptoms, and a substantial minority reported symptom onset around contraceptive initiation. Women with higher baseline symptom burden appeared particularly vulnerable. These findings support individualized contraceptive counseling for women with lipedema and highlight the need for prospective studies with objective measures to clarify causality and mechanisms.

Background: Lipedema is a progressive adipofascial disorder marked by painful nodular fat deposition that is often mistaken for obesity. While tumescent liposuction reduces limb volume with relative lymphatic safety, persistent large, painful lobules frequently remain, and excisional strategies risk iatrogenic lymphatic injury. We evaluated the application of intraoperative indocyanine green (ICG) lymphography to identify and preserve lymphatic channels during debulking surgery for symptomatic lipedema. Methods: We conducted a single-center case series (University of Pittsburgh Medical Center, July 2023–December 2024) of adults with lipedema refractory to conservative therapy who underwent a selective dermato-lipectomy (lobule/skin excision) with or without tumescent liposuction. Patients with clinical lymphedema or dermal backflow in ICG were excluded. Near-infrared ICG (SPY-PHI) was used for pre-incision mapping and real-time intraoperative guidance; lymphatic trajectories were marked and spared during lobule excision. Primary measures included dermal backflow patterns and lymph node transit time; secondary outcomes were complications and symptom burden (Lymphedema Life Impact Scale, LLIS) through ≥24 months. Results: Eight patients (five female/three male; mean age 49.5 ± 14.4 years; median BMI 52.65 kg/m2) underwent ICG-guided surgery. Preoperatively, linear lymphatic patterns were visualized up to the knee in all patients, but dermal backflow patterns could not be visualized in 83% from the level of the knee to the groin. Still, 67% demonstrated inguinal nodal uptake (mean transit 24 min), suggesting preserved lymphatic transport. All cases achieved intraoperative confirmation of intact lymphatic flow after debulking. The mean liposuction aspirate was 925 ± 250 mL per lower extremity; the mean excision mass was 2209 ± 757 g per lower extremity. Complications included two superficial cellulitis events (25%) and one wound dehiscence (12.5%); no hematomas or skin necrosis occurred. No patient developed clinical or imaging evidence of iatrogenic lymphedema during follow-up. Conclusions: Intraoperative ICG lymphography is a practical adjunct for lymphatic-sparing debulking of symptomatic lipedema, enabling real-time identification and preservation of superficial collectors while addressing focal lobules. This hybrid approach—targeted tumescent liposuction followed by ICG-guided superficial dermato-lipectomy—was associated with meaningful symptom improvement and a low morbidity in this early series.

INTRODUCTION: Lipedema is a chronic female disease, characterized by an excessive accumulation of subcutaneous adipose tissue in the limbs and is commonly mistaken for obesity, although the two conditions often coexist. Obesity is associated with increased hedonic hunger and dysfunctional eating behavior. However, these aspects have not been investigated in females with lipedema and obesity. OBJECTIVES: The objective of this secondary analysis from a randomized controlled trial was to compare changes in hedonic hunger and eating behavior following two different low-energy diets, low-carbohydrate (CHO) or low-fat, in females with lipedema and obesity. METHODS: Females with lipedema and obesity (body mass index (BMI) 30-45 kg/m2) were randomized to two different low-energy diets (1,200 kcal), low-CHO diet (LCD) (75 g CHO) or low-fat diet (180 g CHO) for 8 weeks. Hedonic hunger was assessed using the power of food scale (PFS) and eating behavior was assessed using the Dutch Eating Behavior Questionnaire (DEBQ) pre- and post-intervention. RESULTS: A total of 70 females were included with a mean age of 47 years, and a BMI of 37 kg/m2. The LCD group reported a reduction in Food Present (p < 0.001) and in Aggregated Score (p = 0.035) from the PFS, while no changes were seen in the low-fat diet group, with changes in Food Present over time being significantly different between groups (p = 0.050). The low-fat diet group reported increases in Restrained Eating from the DEBQ (p = 0.036) while only the LCD group reported decreases in Diffuse Emotions (p = 0.040), however, no differences between groups were found. CONCLUSION: A LCD may induce more favorable changes in hedonic hunger and eating behavior than an isocaloric low-fat diet in females with lipedema, which may be related to altered metabolic signaling pathways related to satiety and reward.

Lipedema, a chronic condition primarily affecting women, is characterized by abnormal subcutaneous fat accumulation and swelling in the extremities (while sparing the hands, feet, and trunk). This disease is associated with genetic predisposition, hormonal imbalances, impaired lymphatic function, and vascular dysfunction. Lipedema does not directly cause weight gain, but excess weight can worsen symptoms and accelerate disease progression. Bariatric surgery is considered a treatment option for body weight management and reduction of subcutaneous fat; however, reported studies have indicated that this treatment cannot reduce localized fat accumulation or fat cell hypertrophy or alleviate pain symptoms. Although no proven dietary treatment currently exists, nutrition plays a key role in managing lipedema. Certain dietary approaches such as ketogenic, low-carbohydrate, and modified Mediterranean diets have been explored for weight management and inflammation reduction in lipedema, with studies showing positive effects on body composition and pain. However, according to the current literature no evidence-based nutritional treatments or nutritional supplements are effective in this patient group. Nutritional therapy in lipedema is complicated by frequent comorbidities; therefore, precision nutritional therapy should be planned by evaluating the causes and consequences of the disease. In this review, we evaluated reported studies of current evidence-based clinical nutritional approaches to lipedema treatment.

Obesity is increasingly recognized not only as a metabolic disorder, but also as a state of chronic low-grade inflammation that predisposes to systemic complications. Within this context, Dercum's disease (DD), or adiposis dolorosa, emerges as a rare yet debilitating disorder characterized by painful subcutaneous lipomas, most commonly affecting middle-aged women. Despite its clinical impact, DD remains underdiagnosed and is often misclassified as lipedema, fibromyalgia, or lipomatosis, complicating prevalence estimates and hindering the development of targeted interventions. Current evidence suggests that DD represents a distinctive model of inflammatory obesity, where adipose tissue actively contributes to pain generation rather than serving as a passive fat reservoir. Histological and molecular findings point to adipose tissue dysfunction, immune cell infiltration, and elevated secretion of pro-inflammatory adipokines, signals which appear to fuel systemic low-grade inflammation, perineural immune interactions, and nociceptor sensitization. Peripheral mechanisms further shape the clinical phenotype. While familial clustering suggests possible genetic contributions, no definitive markers have been identified, and the role of obesity-induced epigenetic modifications remains unexplored. Therapeutic strategies remain largely symptomatic, including analgesics, antidepressants, physical rehabilitation, and surgical excision of lipomas, whereas molecularly targeted and diet-based interventions are still experimental. This article discusses the pathophysiology of DD, current treatments, and future perspectives, emphasizing that advancing patient registries, omics-based analyses, and interdisciplinary clinical trials will be crucial to elucidate disease mechanisms and guide novel therapies. Improved understanding of DD may not only enhance patient care, but also provide broader insights into the interplay between obesity, inflammation, and chronic pain.

Summary: Lipedema is a chronic disease characterized by the disproportionate and symptomatic accumulation of fat in the lower limbs and arms. Women with lipedema experience heaviness, fatigue and p...

Objectives This double-blind, randomized clinical trial sought to demonstrate the effectiveness of Pycnogenol® in the symptomatic control and body composition management of patients with lipedema. Methods This was a double-blind, randomized clinical trial with 60 days of follow-up involving one hundred patients. The study utilized a quality-of-life questionnaire (QuASiL), bioimpedance analysis, and clinical monitoring. Results Of the one hundred patients initially included, seven were lost to follow-up; however, monotonic multiple imputation was applied for data analysis. The two groups were similar in all aspects except for initial weight. The placebo group showed an increase in mean QuASiL scores after 30 and 60 days from the first assessment, representing a worsening of symptoms over time. In contrast, the intervention group demonstrated a progressive and significant reduction in scores, with means of 69.5 ± 28 at 30 days and 63.2 ± 27 at 60 days (p < 0.001). This group also showed a statistically significant reduction in weight, BMI, and body fat percentage. Conclusions Pycnogenol® appears to be a promising therapeutic option to support the clinical management of lipedema, a condition that exerts numerous negative physical and emotional impacts throughout the lives of affected patients.

Lipedema is a chronic disorder characterized by the symmetrical accumulation of subcutaneous adipose tissue, predominantly affecting women. Despite increasing recognition, the pathophysiological mechanisms underlying adipose tissue dysfunction in lipedema remain incompletely understood. This mini review combines current knowledge about adipose tissue biology in lipedema, highlighting recent discoveries, ongoing controversies, and future research directions. A comprehensive literature review was conducted focusing on adipose tissue-related research in lipedema with emphasis on pathophysiological mechanisms, cellular composition, and therapeutic implications. Recent studies reveal that lipedema adipose tissue exhibits distinct characteristics, including M2 macrophage predominance, stage-dependent adipocyte hypertrophy, progressive fibrosis, and altered lymphatic/vascular function. The inflammatory profile differs markedly from obesity, with an anti-inflammatory M2-like macrophage phenotype rather than the pro-inflammatory M1 response seen in classic obesity. Emerging evidence suggests lipedema may represent a model of “healthy” subcutaneous adipose tissue expansion with preserved metabolic function despite increased adiposity. Current research proposes menopause as a critical turning point, driven by estrogen receptor imbalance and intracrine estrogen excess. Lipedema represents a unique adipose tissue disorder distinct from obesity, characterized by specific cellular and molecular signatures. Current research gaps include the need for validated biomarkers, standardized diagnostic criteria, and targeted therapeutics. Future research should focus on elucidating the molecular mechanisms driving adipose tissue dysfunction and developing precision medicine approaches.

Lipedema is a chronic, progressive adipose tissue disorder that affects up to 10% of women and is characterized by disproportionate lower-limb fat accumulation, pain, edema, and resistance to conventional weight-loss approaches. Its pathophysiology involves a complex interplay of adipocyte hypertrophy, chronic inflammation, extracellular matrix fibrosis, mitochondrial dysfunction, and sex steroid imbalance, highlighting the need for disease-modifying therapies. This narrative review synthesizes mechanistic, translational, and clinical evidence linking metabolic, inflammatory, and fibrotic pathways to lipedema and tirzepatide's potential therapeutic relevance. Tirzepatide, a dual GLP-1 (Glucagon-Like Peptide-1)/GIP (Glucose-Dependent Insulinotropic Polypeptide) receptor agonist, has demonstrated unprecedented efficacy in obesity and diabetes, alongside pleiotropic actions on inflammation, fibrosis, and adipose remodeling. Mechanistic studies reveal favorable effects on macrophage polarization, cytokine signaling, extracellular matrix turnover, and thermogenesis, suggesting potential relevance to lipedema biology. Translational evidence from related fibro-inflammatory conditions such as steatohepatitis and heart failure further supports its antifibrotic and immunomodulatory plausibility. Although direct clinical evidence in lipedema is lacking, the convergence of mechanistic pathways provides a strong rationale to investigate tirzepatide as a disease-modifying candidate. If future clinical studies confirm these mechanisms, tirzepatide could represent a novel metabolic-hormonal therapy capable of modifying the natural course of lipedema.