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Background: Lipedema is a chronic, progressive adipose tissue disorder that almost exclusively affects women,characterized by bilateral, disproportionate subcutaneous fat accumulation in the limbs, pain, easy bruising, andresistance to conventional weight-loss interventions. Because its appearance is frequently mistaken for obesity,women with lipedema are exposed to prolonged misdiagnosis, weight stigma, and inadequate healthcareresponses. The psychological, psychosocial, and behavioral burden of the condition is increasingly recognized,but the evidence is fragmented across clinical, psychological, and eating-related research. Objective: To synthesize the available evidence on the psychological, psychosocial, and behavioralconsequences of lipedema in adult women — including psychological distress, anxiety and depression, pain andfunctional impact, delayed diagnosis, weight stigma, body image, shame, emotion regulation, quality of life, andeating-related outcomes — and to organize this evidence within an explicit biopsychosocial framework. Methods: A structured narrative review following SANRA principles and incorporating applicable PRISMA2020 elements was conducted. Databases targeted included PubMed/MEDLINE, Embase, Scopus, Web of Science, PsycINFO, and the Cochrane Library; a complete PubMed search strategy is reported. Observational,qualitative, mixed-methods, longitudinal, and relevant intervention studies and reviews of adult women withclinically diagnosed lipedema and separately identifiable lipedema data were eligible. Data were extracted intostandardized tables, appraised for methodological quality, and synthesized thematically by domain. Each findingwas classified as direct evidence (lipedema populations), indirect evidence (related populations such as obesity,chronic pain, lymphedema, or weight-stigma research), or hypothesis (theoretical mechanisms not directlydemonstrated). Results: Thirty-six sources formed the evidence base. Direct evidence documents substantially reducedhealth-related quality of life across physical, emotional, and social domains, elevated prevalence of depressivesymptoms, and frequent experiences of weight stigma, shame, and body-image disturbance. Pain and functionallimitations are nearly universal and are associated with disability, kinesiophobia, and reduced activity. Emotionregulation difficulties and coping styles characterized by depressive processing are reported. Eating-disorderscreening indicators are elevated in preliminary samples, and clinically diagnosed binge-eating disorder waspresent in 14.7% of patients in one specialist pilot cohort. Direct evidence for compensatory behaviors andcompulsive exercise in lipedema was not identified. Conclusions: Distress, stigma, body image concerns, and impaired quality of life are the relativelybetter-documented psychological consequences of lipedema. Emotion regulation, eating-disorder risk, anddysfunctional eating behaviors remain less studied and methodologically heterogeneous. A biopsychosocialmodel — in which pain, functional limitation, delayed diagnosis, and stigma converge on body image, emotionregulation, eating behavior, and quality of life — is supported by converging direct and indirect evidence,although most links remain associative rather than causal. Multidisciplinary, non-stigmatizing, individualizedcare is warranted.

Lipedema affects an estimated 11–12% of women worldwide and is characterized by bilateral, symmetric adipose deposition in the lower extremities, disproportionate pressure pain, spontaneous bruising, and resistance to conventional dietary interventions. Despite its prevalence, lipedema lacks a unifying mechanistic framework. Current descriptions treat it as a fat storage disorder with secondary vascular and inflammatory features, leaving critical observations mechanistically unexplained: a highly characteristic quantitative sensory testing (QST) pattern with no published alternative mechanistic explanation, a paradoxical immunological profile, a 35–40% comorbidity with fibromyalgia, a 1.42 relative risk for ADHD, estrogen-dependent onset, and asymmetric expression in the presence of local vascular triggers. We propose the gfWAT-IIT2 framework, which posits that lipedema is fundamentally a syndrome of polarization of the gluteofemoral white adipose tissue (gfWAT) microenvironment toward innate type 2 immunity (IIT2), amplified by estrogen via mast cell estrogen receptors, and generating neuropathic pain through selective histaminergic sensitization of Aδ/C fibers (H1/H4 receptors, PPT↓) and inhibition of Aβ fibers (H3 receptor, VDT↑), with thermal thresholds remaining normal: a triad that is mechanistically explained by histaminergic peripheral sensitization. The gfWAT-IIT2 framework integrates reported clinical, sensory, immunological, and depot-specific observations into a testable mechanistic cascade, generates fourteen falsifiable predictions, and repositions the therapeutic target from adipocyte to mast cell. The framework further proposes that asymmetric lipedema (where one limb expresses the disease more severely due to an identifiable local trigger) constitutes a natural controlled experiment suggesting that local trigger removal may be disease-modifying in selected patients with documented triggers.

Lipedema is a chronic and progressive adipose tissue disorder characterized by disproportionate fat accumulation, microvascular dysfunction, chronic inflammation, and progressive fibrosis. Despite its prevalence and significant impact on quality of life, current therapeutic approaches remain largely symptomatic and fail to address the underlying biological mechanisms of the disease. Emerging evidence suggests that lipedema should be understood as a multifactorial condition involving genetic susceptibility, endothelial alterations, immune dysregulation, and extracellular matrix remodeling. In this context, pharmacological strategies targeting these pathways have gained increasing attention. Metformin, through activation of AMP-activated protein kinase (AMPK), exerts antifibrotic and immunometabolic effects, including inhibition of TGF-β signaling, reduction of extracellular matrix deposition, and modulation of adipose tissue inflammation. In parallel, incretin-based therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/GIP agonists such as tirzepatide, have demonstrated pleiotropic effects that extend beyond weight reduction, including improvements in metabolic homeostasis, reduction of systemic inflammation, and enhancement of endothelial function. These therapies appear to act through complementary mechanisms, with metformin primarily targeting tissue remodeling and fibrosis, and incretin-based therapies exerting broader systemic effects on metabolism, inflammation, and vascular integrity. This review proposes a hypothesis-generating mechanistic framework, supporting a shift from weight-centric and symptomatic approaches toward disease-modifying strategies. Although current evidence in lipedema is largely indirect, the convergence of experimental and clinical data provides a strong rationale for further investigation. Future studies should focus on evaluating combined therapeutic approaches and identifying biomarkers that reflect fibrosis, inflammation, and microvascular dysfunction, with the aim of developing targeted and personalized treatments for this complex disorder.

Background: The aim of the study was to verify the effectiveness of a 5-week intensive protocol of multilayer bandaging alone or in combination with diet, applied to the clinical practice of lipedema. Methods: 114 women with lipedema were studied, divided into three groups: 35 women were treated with multilayer bandaging in biweekly sessions for 5 weeks, 48 were treated with the same bandaging protocol combined with an anti-inflammatory diet, and 31 women received no treatment. The effect on anthropometry, lower limb volume, pain caused by the tissue fold, and subjective symptoms were evaluated. Results: Women who completed the 5-week intensive protocol of multilayer bandaging showed a statistically significant reduction in all observed parameters: body weight, waist and hip circumference, lower limb volume, pain, and subjective symptoms. The group of women treated with multilayer bandaging and diet showed a significantly greater reduction in lower limb volume and body weight. The treatments were effective regardless of age, BMI, clinical stage, and the presence of fovea in both groups. The wearing time with the multilayer bandage had a positive correlation in the group treated with bandage in combination with diet. Conclusion: A 5week intensive protocol of multilayer bandaging of the lower limbs is an effective treatment for reducing the symptoms and clinical signs of lipedema at all stages of the disease, even in the absence of edema. Adding nutritional therapy during the bandaging cycle increases the effectiveness of the treatment on the volume of the affected extremities and body weight.

Lipoedema is a chronic adipose tissue disorder mainly affecting women with excess subcutaneous fat deposition on the lower limbs, associated with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is not well studied. We conducted a genome-wide association study (GWAS) for this disorder in a clinically ascertained cohort from Spain and performed a meta-analysis with the UK lipoedema cohort GWAS. We then used the results of this study as a replication of the inferred UK Biobank “lipoedema phenotype” study. Whilst our meta-analysis alone did not identify any genome-wide significant associations, our clinical cohorts provide support for three loci identified through the UKBB study: the chr2q24.3 GRB14-COBLL1 locus (rs6753142, PMETA=1.64x10-6), chr6p21.1 VEGFA locus (rs4711750, PMETA=8.99x10-7) and the chr5q11.2 ANKRD55-MAP3K1 locus (rs3936510, PMETA=1.67x10-5). We identify numerous rare SNPs with strong association signals in our meta-analysis (P<1x10-6) with support in both UK and Spanish datasets, three of which also show nominal support in the UKBB (P<0.05). These findings provide a starting point towards understanding the genetic basis of clinical lipoedema and demonstrate the utility of the interplay of large-scale biobanks genetic data and clinically ascertained cohorts to elucidate the genetic architecture of lipoedema.