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BACKGROUND: Lipedema is a progressive disease, diagnosed most often in women, which is characterized by the unproportionate and symmetrical distribution of adipose tissue primarily in the extremities. Despite numerous results from in vitro and in vivo studies, many questions regarding the pathology and genetic background of lipedema have remained unanswered. METHODS: Adipose tissue-derived stromal/stem cells (ASCs) were isolated from lipoaspirates derived from non-obese and obese lipedema and non-lipedema donors. Growth/morphology, metabolic activity, differentiation potential and gene expression were evaluated using quantification of lipid accumulation, metabolic activity assay, live-cell imaging, RT-PCR, quantitative PCR and immunocytochemical staining. RESULTS: The adipogenic potential of lipedema and non-lipedema ASCs did not rise in parallel with the donors' BMI and did not differ significantly between groups. However, in vitro differentiated adipocytes from non-obese lipedema donors showed significant upregulation of adipogenic gene expression compared to non-obese controls. All other genes tested were equally expressed in lipedema and non-lipedema adipocytes. The ADIPOQ/LEP ratio (ALR) was significantly reduced in adipocytes from obese lipedema donors compared to their non-obese lipedema counterparts. Increased stress fiber-integrated SMA was visible in lipedema adipocytes compared to non-lipedema controls and appeared enhanced in adipocytes from obese lipedema donors. CONCLUSIONS: Not only lipedema per se but also BMI of donors impact adipogenic gene expression substantially in vitro. The significantly reduced ALR and the increased occurrence of myofibroblast-like cells in "obese" lipedema adipocyte cultures underlines the importance of attention towards the co-occurrence of lipedema and obesity. These are important findings towards accurate diagnosis of lipedema.

Expert representatives from 11 professional societies, as part of an autonomous work group, researched and developed appropriate use criteria (AUC) for lymphoscintigraphy in sentinel lymph node mapping and lymphedema. The complete findings and discussions of the work group, including example clinical scenarios, were published on October 8, 2022, and are available at https://www.snmmi.org/ClinicalPractice/ content.aspx?ItemNumber=42021. The complete AUC document includes clinical scenarios for scintigraphy in patients with breast, cutaneous, and other cancers, as well as for mapping lymphatic flow in lymphedema. Pediatric considerations are addressed. These AUC are intended to assist health care practitioners considering lymphoscintigraphy. Presented here is a brief overview of the AUC, including the rationale and methodology behind development of the document. For detailed findings of the work group, the reader should refer to the complete AUC document online.

Dysfunction of collecting lymphatic vessel pumping is associated with an array of pathologies. S-(-)-Bay K8644 (BayK), a small-molecule agonist of L-type calcium channels, improves vessel contractility ex vivo but has been left unexplored in vivo because of poor lymphatic access and risk of deleterious off-target effects. When formulated within lymph-draining nanoparticles (NPs), BayK acutely improved lymphatic vessel function, effects not seen from treatment with BayK in its free form. By preventing rapid drug access to the circulation, NP formulation also reduced BayK's dose-limiting side effects. When applied to a mouse model of lymphedema, treatment with BayK formulated in lymph-draining NPs, but not free BayK, improved pumping pressure generated by intact lymphatic vessels and tissue remodeling associated with the pathology. This work reveals the utility of a lymph-targeting NP platform to pharmacologically enhance lymphatic pumping in vivo and highlights a promising approach to treating lymphatic dysfunction.

Lipoedema is characterized by disproportionate painful fat accumulation mostly in the lower limbs. The presence of lymphoedema in lipoedema remains controversial. This study aimed to assess the presence or absence of lymphoedema in the lower limbs of women with lipoedema using indocyanine green (ICG) lymphography. A cross-sectional retrospective study was undertaken in women with a clinical diagnosis of lipoedema whose lower limbs were examined with ICG lymphography. MD Anderson Cancer Center (MDACC) ICG staging was used to determine lymphoedema presence and severity. Patient characteristics, ICG lymphography findings, Stemmer sign, body mass index, waist-to-hip ratio, limb volume and bioimpedance spectroscopy measures were recorded. Forty women with lipoedema underwent ICG lymphography for the lower limbs from January 2018 to July 2022. Thirty-four women (85.0%) were determined by ICG lymphography as MDACC ICG Stage 0 representing normal lymphatics. Of the six women who demonstrated dermal backflow on ICG lymphography, all were determined as ICG Stage 1, four had localized traumatic dermal backflow area at their ankles, one had previously diagnosed with primary lymphoedema and one was classified as lipoedema stage 4. ICG lymphography findings suggested the absence of lymphoedema in a clear majority of women with lower limb lipoedema.

Lymphangiogenesis is the mechanism by which the lymphatic system develops and expands new vessels facilitating fluid drainage and immune cell trafficking. Models to study lymphangiogenesis are necessary for a better understanding of the underlying mechanisms and to identify or test new therapeutic agents that target lymphangiogenesis. Across the lymphatic literature, multiple models have been developed to study lymphangiogenesis in vitro and in vivo. In vitro, lymphangiogenesis can be modeled with varying complexity, from monolayers to hydrogels to explants, with common metrics for characterizing proliferation, migration, and sprouting of lymphatic endothelial cells (LECs) and vessels. In comparison, in vivo models of lymphangiogenesis often use genetically modified zebrafish and mice, with in situ mouse models in the ear, cornea, hind leg, and tail. In vivo metrics, such as activation of LECs, number of new lymphatic vessels, and sprouting, mirror those most used in vitro, with the addition of lymphatic vessel hyperplasia and drainage. The impacts of lymphangiogenesis vary by context of tissue and pathology. Therapeutic targeting of lymphangiogenesis can have paradoxical effects depending on the pathology including lymphedema, cancer, organ transplant, and inflammation. In this review, we describe and compare lymphangiogenic outcomes and metrics between in vitro and in vivo studies, specifically reviewing only those publications in which both testing formats are used. We find that in vitro studies correlate well with in vivo in wound healing and development, but not in the reproductive tract or the complex tumor microenvironment. Considerations for improving in vitro models are to increase complexity with perfusable microfluidic devices, co-cultures with tissue-specific support cells, the inclusion of fluid flow, and pairing in vitro models of differing complexities. We believe that these changes would strengthen the correlation between in vitro and in vivo outcomes, giving more insight into lymphangiogenesis in healthy and pathological states.

The lymphatic circulation regulates transfer of tissue fluid and immune cells towards the venous circulation. While obesity impairs lymphatic vessel function, the contribution of lymphatic endothelial cells (LEC) to metabolic disease phenotypes is poorly understood. LEC of lymphatic microvessels are in direct contact with the interstitial fluid, whose composition changes during the development of obesity, markedly by increases in saturated fatty acids. Palmitate, the most prevalent saturated fatty acid in lymph and blood, is detrimental to metabolism and function of diverse tissues, but its impact on LEC function is relatively unknown. Here, palmitate (but not its unsaturated counterpart palmitoleate) destabilized adherens junctions in human microvascular LEC in culture, visualized as changes in VE-cadherin, ⍺-catenin, and β-catenin localization. Detachment of these proteins from cortical actin filaments was associated with abundant actomyosin stress fibers. The effects were Rho-associated protein kinase (ROCK)- and myosin-dependent, as inhibition with Y-27632 or blebbistatin, respectively, prevented stress fiber accumulation and preserved junctions. Without functional junctions, palmitate-treated LEC failed to directionally migrate to close wounds in 2-dimensions and failed to form endothelial tubes in 3-dimensions. A reorganization of the lymphatic endothelial actin cytoskeleton may contribute to lymphatic dysfunction in obesity and could be considered as a therapeutic target.

Liposuction plays an important role as a surgical treatment option for lipoedema. This document serves to critically review the evidence in the literature, as well as explain the differences between the lipoedema population compared to the aesthetic surgery population undergoing liposuction. It is not a comprehensive text on lipoedema management but serves to guide surgeons. This guidance was produced on behalf of the British Association of Aesthetic Plastic Surgeons (BAAPS) and British Association of Plastic Reconstructive and Aesthetic Surgeons (BAPRAS) by the expert liposuction group. The guidance is based on evidence available in the literature along with specialist expert opinion on liposuction for lipoedema to provide plastic surgeons with consensus recommendation for surgical treatment. The aim is to identify best practice to maximise the safety of patients. This article summarises current practises and safety considerations and outlines recommendations covering various aspects of patient care.

OBJECTIVE: This study examines the role of MTHFR gene polymorphism (rs1801133) in women with lipedema (LIPPY) body composition parameters compared to a control group (CTRL). SUBJECTS AND METHODS: We carried out a study on a sample of 45 LIPPY and 50 women as a CTRL. Body composition parameters were examined by Dual-energy X-ray Absorptiometry (DXA). A genetic test was performed for the MTHFR polymorphism (rs1801133, 677C>T) using a saliva sample for LIPPY and CTRL groups. Mann-Whitney tests evaluated statistically significant differences between four groups (carriers and non-carriers of the MTHFR polymorphism for LIPPY and CTRL groups) on anthropometric/body composition parameters to identify patterns. RESULTS: LIPPY showed significantly higher (p<0.05) anthropometric parameters (weight, BMI, waist, abdominal, hip circumferences) and lower waist/hip ratio (p<0.05) compared to the CTRL group. The association between the polymorphism alleles related to the rs1801133 MTHFR gene and the body composition values LIPPY carriers (+) showed an increase in fat tissue of legs and fat region of legs percentage, arm’s fat mass (g), leg’s fat mass (g), and leg’s lean mass (g) (p<0.05) compared to CTRL (+). Lean/fat arms and lean/fat legs were lower (p<0.05) in LIPPY (+) than in CTRL (+). In the LIPPY (+), the risk of developing the lipedema disease was 2.85 times higher (OR=2.85; p<0.05; 95% confidence interval = 0.842-8.625) with respect to LIPPY (-) and CTRL. CONCLUSIONS: The presence or absence of MTHFR polymorphism offers predictive parameters that could better characterize women with lipedema based on the association between body composition and MTHFR presence.

The disease "Lipedema", which has been known since 1940, is increasingly better understood. Dimpled edema in particular is not significant in women with fat distribution disorders on the arms and legs. These and other scientific findings are "work in progress" with the aim of renaming the disease. A "proper name" is "Lipohyperplasia dolorosa" (LiDo). With LiDo, the increase in volume is genetically fixed, but the pain is dynamically progressive. A LiDo must be distinguished from other symmetrical, painless fat distribution disorders on the arms and legs at first sight and after palpatory examination, especially from the occasionally coincident obesity. Obesity is never comorbid, but often coincident with LiDo. Although physical activity and a change in diet can reduce obesity, they cannot eliminate the disproportionate increase in fat tissue on the extremities that is exclusively caused by LiDo. In LiDo patients coincident with obesity, gastric surgery has no effect on the obligatory pain. There are both conservative and surgical treatment options for LiDo. A procedure that has been established since 1997 is surgical treatment using lymphological liposculpture. As part of this operation, large wounds are created under the skin, which, according to the "Rules of Nine" when treating both arms in one session and the suction of the legs in 2 sessions per operation, correspond to an area of ​​18% of the body surface. However, with adequate postoperative management and the administration of antibiotics and antithrombotics, local complications associated with the operation are rare. The most important result of consistent surgical treatment of lipohyperplasia dolorosa is the impact on quality of life: "It ruined her life" becomes "It improves her life".

As overweight and obesity rates have increased worldwide, the prevalence of metabolic disorders has also grown. Due to the lack of physiologically relevant adipose tissue platforms, research in adipose tissue biology has relied on animal models, leading to false conclusions on pathophysiological mechanisms and therapeutic efficacy. Despite the urgent need for an adipose tissue model, it is still extremely difficult to cultivate mature adipocytes and recapitulate multi-cellular interactions in adipose tissue in vitro. For this reason, adipose tissue modeling requires new technologies that allow better culture conditions for adipocytes and contain a complex network of microenvironments. Herein, we discuss recent technologies, including 3-dimensional (3D) adipocyte spheroids, biomaterial-based 3D culture, 3D bioprinting, and microphysiological systems, which may offer new opportunities to discover drugs targeting adipose tissue.

Obesity prevalence is rising globally, as are the number of chronic disorders connected with obesity, such as diabetes, non-alcoholic fatty liver disease, dyslipidemia, and hypertension. Bariatric surgery is also becoming more common, and it remains the most effective and long-term treatment for obesity. This study will assess the influence of Laparoscopic Sleeve Gastrectomy (LSG) on gut microbiota in people with obesity before and after surgery. The findings shed new light on the changes in gut microbiota in Saudi people with obesity following LSG. In conclusion, LSG may improve the metabolic profile, resulting in decreased fat mass and increased lean mass, as well as improving the microbial composition balance in the gastrointestinal tract, but this is still not equivalent to normal weight microbiology. A range of factors, including patient characteristics, geographic dispersion, type of operation, technique, and nutritional and caloric restriction, could explain differences in abundance between studies. This information could point to a novel and, most likely, tailored strategy in obesity therapy, which could eventually be incorporated into health evaluations and monitoring in preventive health care or clinical medicine.

(1) Background: Although lipedema has gained more interest among researchers, specific treatment methods are still unknown. This study aims to identify the effects of compression therapy combined with exercises compared to exercising only. Moreover, the aim is to assess the methodology and outcome measurements before conducting a larger study. (2) Methods: Six women with lipedema were enrolled in the study; three were undergoing exercise program and compression therapy using compression leggings, and the remaining three were undergoing exercises only. During the first 4 weeks, intervention was under the supervision of a physiotherapist, and in the remaining weeks, participants were exercising independently. Measurements of circumference, weight, thickness of the skin and adipose tissue, symptom severity, and quality of life were taken at baseline, after 4 weeks and after 6 weeks; (3) Results: There was a significant decrease in the subjectively reported tendency for bruising and pain at palpation among patients that received compression therapy. Additionally, there was a tendency to reduce or maintain the circumference of the legs in patients using compression, while it tended to increase in patients without compression. (4) Conclusions: Preliminary results indicate that compression therapy, combined with exercises, could improve the quality of life and decrease the severity of lipedema symptoms. Further studies on a large clinical group are advisable.

Lipedema is a chronic adipose tissue disorder affecting approximately 11% of women worldwide. The illness is often misdiagnosed as obesity, and because of this, women often struggle in meetings with healthcare providers. Few studies have assessed these encounters of younger women with lipedema. The aims of this qualitative study were to explore women’s experiences in meetings with healthcare providers and the importance of social support and belonging, with a focus on younger women. Fifteen women with lipedema between the ages of 21 and 47 years (mean age 36.2 years) were interviewed. The results indicated that women felt stigmatized by healthcare providers and that younger women in their 20s and early 30s struggled more often than women of higher age when receiving their diagnosis. The feeling of shame and stigma were also dependent on the woman’s resources in handling the illness. The younger women reported that their self-confidence and romantic relationships were challenging. Social support and the feeling of belonging through romantic relationships or support groups were important resources for managing the illness. Highlighting the experiences of women may aid in increasing recognition and knowledge of lipedema. This in turn may reduce the stigma and lead to equitable healthcare services.

Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in SRD5A2, HSD17B3, and HSD3B2 genes that lead to disordered sexual development, salt wasting, and other severe disorders provide a glimpse of the impacts of mutations in steroid hormone transforming enzymes. In a departure from these established examples, this review examines disease-associated germline coding mutations in steroid-transforming members of the human aldo-keto reductase (AKR) superfamily. We consider two main categories of missense mutations: those resulting from nonsynonymous single nucleotide polymorphisms (nsSNPs) and cases resulting from familial inherited base pair substitutions. We found mutations in human AKR1C genes that disrupt androgen metabolism, which can affect male sexual development and exacerbate prostate cancer and polycystic ovary syndrome (PCOS). Others may be disease causal in the AKR1D1 gene that is responsible for bile acid deficiency. However, given the extensive roles of AKRs in steroid metabolism, we predict that with expanding publicly available data and analysis tools, there is still much to be uncovered regarding germline AKR mutations in disease.

When studying the current literature, one might get the impression that lipedema is a “modern” disease, with increasing incidence and augmenting prevalence throughout Western countries during the last decade. However, a quick look into older textbooks shows that disproportionate accumulation of fat in female bodies has long been known without being recognized as an independent disease. Nevertheless, it was not until 1940 that Allen and Hines described a “syndrome characterized by fat legs and orthostatic edema” in a seminal publication. The mere awareness that people who have lipedema are not just overweight but suffer from a yet poorly defined pathological condition, may be considered a decisive leap forward in the understanding of lipedema. A number of comprehensive publications have since dealt with the clinical presentation of lipedema and have provided the first clues towards the potential pathological mechanisms underlying its initiation and progression. Nevertheless, despite all effort that has been undertaken to unravel lipedema pathology, many questions have remained unanswered. What can be deduced with certainty from all experimental and medical evidence available so far is that lipedema is neither a cosmetic problem nor is it a problem of lifestyle but should be accepted as a serious disease with yet undetermined genetic background, which makes women’s lives unbearable from both a physical and psychological point of view. To date, results from clinical inspections have led to the categorization of various types and stages of lipedema, describing how the extremities are affected and evaluating its progression, as demonstrated by skin alterations, adipose tissue volume increase and physical and everyday-behavioral impediments. There is accumulating evidence showing that advanced stages of lipedema are usually accompanied by excessive weight or obesity. Thus, it is not unreasonable to assume that the progression of lipedema is largely driven by weight gain and the pathological alterations associated with it. Similarly, secondary lymphedema is frequently found in lipedema patients at advanced stages. Needless to say, both conditions considerably blur the clinical presentation of lipedema, making diagnosis difficult and scientific research challenging. The present literature review will focus on lipedema research, based on evidence fromex vivo and in vitro data, which has accumulated throughout the last few decades. We will also open the discussion as to whether the currently used categorization of lipedema stages is still sufficient and up-to-date for the accurate description of this enigmatic disease, whose name, strangely enough, does not match its pathologic correlate.

Lipoedema is a painful non-pitting diffuse “fatty” swelling, usually confined to the legs, that occurs mainly in women. This scoping review aimed to provide an overview of the available research on the functioning of people with lipoedema, according to the International Classification of Functioning, Disability and Health (ICF) framework. Relevant publications and gray literature were retrieved until October 2022. The results sections of each publication were organized using a thematic framework approach. All included studies reported at least one outcome fitting within the domains of body functions and body structures, with most studies focusing on the categories of “sensation of pain”, “immunological system functions”, and “weight maintenance functions”. The ICF domains of activities and participation and environmental factors were mentioned in a small number of the included studies (17 and 13%, respectively), while the domain of personal factors was studied in half of the included studies. In conclusion, the emphasis of lipoedema research is on its description from a disorder-oriented point of view in the form of body functions and body structures, with a lack of information about the other domains of functioning.

The aim was to analyze the effect of compression tights on skin temperature in women with lipedema and to assess the effect of different knitting on skin temperature. Twenty-four women with lipedema (Grade I = 25%; Grade II = 75%) were divided into three groups according to the compression tights prototype assigned: control (n = 9), Flat (n = 7) and circular (n = 8). The participants performed a gait test two times, separated by 15 days: before wearing the tights of the study and after the treatment (15 days employing compression tights). Skin temperature was measured using infrared thermography before and after the gait test on both days, and six regions of interest were determined in the anterior and posterior leg. The skin temperature decreased in the different regions of interest after exercise in all the groups (e.g., anterior thigh (IC95% (−1.1, −0.7 °C) p < 0.001), but no differences were observed in skin temperature between groups before and after walking (p > 0.05). The use of compressing tights for 15 days does not alter skin temperature in women with lipedema before and after walking. The absence of differences in skin temperature between tights in the different assessments allows for obtaining the benefits of wearing compression tights during exercise without negative thermal effects.

Lipedema is a pathologic accumulation of adipose tissue in the subcutaneous layer of the extremities. This connective tissue disorder, which predominately affects females, is often misdiagnosed despite an incidence of ∼11%. Misdiagnosis often leads to delays in appropriate treatment, further increasing the morbidity of the condition. The authors report their facilities' experience in treating a patient with lipedema, requiring multiple surgical interventions involving liposuction and skin debulking to achieve desired aesthetic outcomes. The patient presented to the plastic surgery clinic with severe lipedema of the bilateral lower extremities. She previously underwent a panniculectomy and bilateral lower extremity liposuction without achieving the desired aesthetic results. Prior conservative management and liposuction alone were both unsuccessful treatment options and she required debulking procedures, along with further liposuction, as definitive management. The patient underwent 2 procedures at the clinic, both consisting of liposuction and panniculectomy of the lower extremities and buttocks. The procedures were conducted 1 year apart but were able to achieve the patient's desired aesthetics goals. Management of lipedema can be challenging, but not impossible. This case report shows that local excision is a viable option for treatment if minimally invasive options yield limited results.