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Lipedema and obesity are often misdiagnosed or clinically confused yet arise via distinct mechanisms, complicating diagnosis and treatment. This review synthesizes evidence differentiating these conditions across genetic, hormonal, inflammatory and mechanical pathways to identify therapeutic targets. Lipedema may involve genetic predisposition (forkhead box C2 [FOXC2], prospero homeobox 1 [PROX1]), hormonal dysregulation with aberrant aromatase activity, and altered adipogenesis (peroxisome proliferator-activated receptor gamma [PPARγ], CCAAT/enhancer-binding protein [C/EBP]). A proinflammatory microenvironment with macrophage M1/M2 imbalance, elevated interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and extracellular matrix remodeling is hypothesized to drive fibrosis. Emerging evidence implicates gut-derived endotoxemia (lipopolysaccharide [LPS]-toll-like receptor 4 [TLR4]-nuclear factor kappa-B [NF-κB]) and mechanotransduction (Yes-associated protein [YAP]/transcriptional coactivator with PDZ-binding motif [TAZ]) in adipocyte hypertrophy and treatment resistance. Obesity involves systemic metabolic dysfunction with visceral adiposity and cardiometabolic comorbidities. Lipedema patients maintain metabolic health, exhibit gluteofemoral fat distribution and experience neuropathic pain via nociceptor sensitization (transient receptor potential vanilloid 1 [TRPV1] and ankyrin 1 [TRPA1]) with central amplification. Weight-loss interventions are ineffective, necessitating targeted strategies. Promising targets include TLR4 antagonism, vascular endothelial growth factor C/vascular endothelial growth factor receptor-3 (VEGF-C/VEGFR3) modulation for lymphatic enhancement, YAP/TAZ inhibition and neuromodulators for pain. Physical therapy functions as a biological modifier targeting inflammation, lymphatic drainage and mechanotransduction. This review highlights promising but largely hypothesis-generating molecular insights and calls for validated biomarkers, rigorous clinical trials, and mechanism-based therapies. Many of the pathways discussed require further confirmation in human studies.
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ObjectivesThis study aimed to analyze the complex components of pain in lipedema and to evaluate correlations among key pain-related parameters, including intensity, hypersensitivity, catastrophizing, central sensitization, and neuropathic pain.MethodsThis prospective study was conducted between June 2025 and September 2025. Patients aged 18 or older with a diagnosis of lipedema were included. Demographic/clinical characteristics were recorded. Pain intensity, hypersensitivity, pain catastrophizing, central sensitization, and neuropathic pain were assessed using the Numeric Rating Scale (NRS), a 0-3 verbal rating scale, the Pain Catastrophizing Scale, the Central Sensitization Inventory, and the painDETECT questionnaire, respectively.ResultsA total of 85 patients were included in the study. Patients had a median age of 44 years, a median Body Mass Index of 29.24 kg/m2, and most were classified as stage 2 lipedema (50.6%). Pain intensity was moderate, with a median NRS score of 5, while hypersensitivity levels were moderate (41.2%) to high (34.1%) in most patients. Pain catastrophizing, central sensitization, and neuropathic pain were present in 35.1%, 83.5%, and 27.1% of the patients, respectively. Pain intensity was significantly positively correlated with hypersensitivity, pain catastrophizing, central sensitization, and neuropathic pain (p < 0.05). All parameters were significantly correlated with each other (p < 0.05).ConclusionCentral sensitization may be observed in patients with lipedema and is associated with other pain parameters. The findings highlight significant interrelationships among pain intensity, hypersensitivity, pain catastrophizing, and central sensitization. Pain needs to be assessed in detail in patients with lipedema.
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