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Lipedema in its various clinical stages is a condition that almost exclusively affects the female sex and appears at puberty. The oedema does not respond to common low-calorie diets, nor to exercise, nor to common anti-oedema medical therapies, nor to bariatric surgery. In the more advanced clinical stages, it can induce more or less important functional impairments that induce physical disability, as well as psychological, relational, and social discomfort: pain, functional walking impotence, easy muscular fatigability, sleep-wake rhythm disturbances also linked to the state of anxiety and depression that affects subjects in whom, often, the response to the treatments they are directed towards is practically nil. Many epidemiological, aetiopathogenetic, diagnostic, and clinical aspects still need to be studied in depth, considering, moreover, that the disease was only recognized with its own specific code by the World Health Organization in the 11th edition of the International Classification of Diseases on 1 January 2022.

Lipedema is a chronic disorder affecting women with a 10% incidence worldwide. It is often confused with obesity. This study was undertaken to study microRNAs in lipedema tissue assessed by direct hybridization using the robust n-counter flex DX CE-IVD platform. The mean age of the subjects participating in the study was 40.29 (±12.17). The mean body weight and BMI were 67.37 (±10.02) and 25.75 (±4.10), respectively. The lipedema stages included were I and II. The differential expressed human (hsa)-miRNAs were determined according to a log2 fold-change (LFC) of 0.5 and p value < 0.05. To these, increased expression of hsa-let-7g-5p was evident, as well as reduced levels of hsa-miR-371a-5p, -4454+7975, -365a+b-3p, -205-5p, -196a-5p, -4488, -2116-5p, -141-3p, -208a-3p, -302b-3p, 374a-5p, and -1297. Then, several bioinformatics tools were used to analyze microarray data focusing on validated target genes in silico. KEGG and Gene Ontology (GO) pathway enrichment analysis was conducted. Furthermore, the protein-protein interaction and co-expression network were analyzed using STRING and Cytoscape, respectively. The most upregulated miRNA mainly affected genes related to cell cycle, oocyte meiosis, and inflammatory bowel disease. The downregulated microRNAs were related to endocrine resistance, insulin resistance, hypersensitivity to AGE-RAGEs, and focal adhesion. Finally, we validated by RT-PCR the upregulated hsa-let-7g-5p and two down-regulated ones, hsa-miR-205-5p and hsa-miR-302b-3p, confirming microarray results. In addition, three mRNA target miRNAs were monitored, SMAD2, the target of the hsa-let-7g-5p, and ESR1 and VEGFA, the target of hsa-miR-205-5p and hsa-miR-302b-3p, respectively. Our results open a new direction for comprehending biochemical mechanisms related with the pathogenesis of lipedema, shedding light on this intricate pathophysiological condition that could bring to light possible biomarkers in the future.

Lipedema is a pathology of adipose tissue, still of unclear etiology and challenging to diagnose. For these reasons, a therapeutic approach is also complex and sometimes controversial. The inflammation state present in lipedema can be limited by controlling the glycemic peaks. Specifically, the ketogenic diet (KD) seems to have the right conditions to be effective. Herein, we reported a subject diagnosed with lipedema who, with only KD nutritional intervention, achieved a significant weight loss (&minus;41 Kg), with a net decrease in body circumferences, and also reporting an improvement in pain, and therefore in the overall quality of life. She refused other types of intervention and kept KD for two years. This case could represent the first step to organize a KD nutritional protocol specifically applied to lipedema.

Lipedema is a chronic disease that mostly manifests in females as the abnormal distribution of subcutaneous adipose connective tissue, usually coupled with bruising, pain, and edema. Lipedema molecular pathophysiology is currently not clear, but several studies suggest that genetics and hormonal imbalance participate in lipedema pathogenesis. Women with lipedema present in some cases with elevated body mass index, and the appearance of obesity in addition to lipedema, where the obesity can cause serious health issues as in lipedema-free individuals with obesity, such as diabetes and cardiovascular disorders. Unlike obesity, lipedema tissue does not respond well to diet or physical exercise alone. Therefore, in this review we discuss the effect of various dietary supplements that, along with diet and physical exercise, cause fat burning and weight loss, and which could potentially be important in the treatment of lipedema. Indeed, an effective fat burner should convert stored fats into energy, mobilize and break down triglycerides in adipocytes, boost metabolism and inhibit lipogenesis. Common ingredients of fat burning supplements are green tea, caffeine, chromium, carnitine, and conjugated linoleic acid. The use of fat burners could act synergistically with a healthy diet and physical exercise for decreasing adipose tissue deposition in patients with lipedema and resolve related health issues. The effects of fat burners in human studies are sometimes contradictory, and further studies should test their effectiveness in treating lipedema.

Our data support the idea that cell alterations happen in the early stages of adipocyte development (endothelium/pericyte) in the adipose organ of women affected by lipedema.

Background: Our aim is to propose a framework for the development of a research case definition of lipedema, based on current available literature and those observations that can be applied to future lipedema research with the intent to standardize and strengthen the scientific evidence base. Methods and Results: We conducted a narrative review of the literature, and identified consensus characteristics and disputed characteristics that could be included in a research case definition of lipedema. After considering the strength of the evidence and how each characteristic might be measured in a research study, we recommended an approach for the development of a research case definition of lipedema that would be based on consideration of five agreed-upon characteristics, and five disputed, or less substantiated, characteristics as additional evidence to enhance specificity. Conclusions: We present a case definition framework for lipedema drawn from the scientific literature that can be applied to future studies on lipedema. Utilizing this framework should help to increase the sensitivity and specificity of case definition and provide an opportunity for meta-analysis of clinical studies and facilitate future research intercomparisons.

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.

Lipedema is an often underdiagnosed chronic disorder that affects subcutaneous adipose tissue almost exclusively in women, which leads to disproportionate fat accumulation in the lower and upper body extremities. Common comorbidities include anxiety, depression, and pain. The correlation between mood disorder and subcutaneous fat deposition suggests the involvement of steroids metabolism and neurohormones signaling, however no clear association has been established so far. In this study, we report on a family with three patients affected by sex-limited autosomal dominant nonsyndromic lipedema. They had been screened by whole exome sequencing (WES) which led to the discovery of a missense variant p.(Leu213Gln) in AKR1C1, the gene encoding for an aldo-keto reductase catalyzing the reduction of progesterone to its inactive form, 20-α-hydroxyprogesterone. Comparative molecular dynamics simulations of the wild-type vs. variant enzyme, corroborated by a thorough structural and functional bioinformatic analysis, suggest a partial loss-of-function of the variant. This would result in a slower and less efficient reduction of progesterone to hydroxyprogesterone and an increased subcutaneous fat deposition in variant carriers. Overall, our results suggest that AKR1C1 is the first candidate gene associated with nonsyndromic lipedema.

Lipedema predominantly affects women and is characterized by an abnormal distribution of adipose tissue, accompanied by pain or discomfort in affected areas. Despite growing awareness, inconsistent diagnostic criteria and treatment approaches hinder medical care and research. This multi-phase Delphi study was conducted to address the need for internationally accepted consensus on fundamental aspects of the disease. Through online surveys and an in-person discussions, experts representing 19 countries evaluated on 62 original statements regarding (1) clarity, (2) agreement, (3) recommendation for inclusion, (4) strength of evidence, and (5) whether additional evidence was needed. Ultimately, 59 statements reached consensus across eight domains encompassing the definition and management of lipedema. The findings provide a framework to guide internationally applicable recommendations for patients with lipedema that may improve outcomes globally. Limited evidence in several areas highlights the importance of further research, standardization of data reporting, and international collaboration among healthcare providers, researchers, and patient advocates to address this women's health disparity effectively.

Background: Expressed by endothelial cells, CDH5 is a cadherin involved in vascular morphogenesis and in the maintenance of vascular integrity and lymphatic function. The main purpose of our study was to identify distinct variants of the CDH5 gene that could be associated with lymphatic malformations and predisposition for lymphedema. Methods and Results: We performed Next Generation Sequencing of the CDH5 gene in 235 Italian patients diagnosed with lymphedema but who tested negative for variants in known lymphedema genes. We detected six different variants in CDH5 five missense and one nonsense. We also tested available family members of the probands. For family members who carried the same variant as the proband, we performed lymphoscintigraphy to detect any lymphatic system abnormalities. Variants were modeled in silico. The results showed that CDH5 variants may contribute to the onset of lymphedema, although further in vitro studies are needed to confirm this hypothesis. Conclusions: Based on our findings, we propose CDH5 as a new gene that could be screened in patients with lymphedema to gather additional evidence.

Lipedema is a disabling disease characterized by symmetric enlargement of the lower and/or upper limbs due to deposits of subcutaneous fat, that is easily misdiagnosed. Lipedema can be primary or syndromic, and can be the main feature of phenotypically overlapping disorders. The aim of this study was to design a next-generation sequencing (NGS) panel to help in the diagnosis of lipedema by identifying genes specific for lipedema but also genes for overlapping diseases, and targets for tailored treatments. We developed an NGS gene panel consisting of 305 genes potentially associated with lipedema and putative overlapping diseases relevant to lipedema. The genomes of 162 Italian and American patients with lipedema were sequenced. Twenty-one deleterious variants, according to 3 out of 5 predictors, were detected in PLIN1, LIPE, ALDH18A1, PPARG, GHR, INSR, RYR1, NPC1, POMC, NR0B2, GCKR, PPARA in 17 patients. This extended NGS-based approach has identified a number of gene variants that may be important in the diagnosis of lipedema, that may affect the phenotypic presentation of lipedema or that may cause disorders that could be confused with lipedema. This tool may be important for the diagnosis and treatment of people with pathologic subcutaneous fat tissue accumulation.