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Background: An adequate dietary energy supply is particularly important in patients with lipedema as it promotes weight and fat loss. Accurate estimation of resting metabolic rate (RMR) allows implementing a proper calorie restriction diet in patients with lipedema. Therefore, an accurate assessment of energy demand in patients with lipedema is crucial in clinical practice. Our study aimed to compare actual resting metabolic rate (aRMR) with predicted resting metabolic rate (pRMR) in women with lipedema and to determine the association between individual anthropometric measurements and aRMR.Methods: A total of 108 women diagnosed with lipedema were enrolled in the study. aRMR was measured by indirect calorimetry (IC) using FitMate WM metabolic system (Cosmed, Rome, Italy). pRMR was estimated with predictive equations and BIA. All anthropometric measurements were based on BIA (bioelectric impedance analysis).Results: The mean aRMR in the study group was 1705.2 ± 320.7 kcal/day. Most methods of predicted RMR measurement used in our study significantly underpredicted aRMR in patients with lipedema. We reported statistically significant high correlations between all anthropometric measurements and aRMR/pRMR and a moderate correlation between visceral fat level (VFL) and aRMR. Conclusions: aRMR in patients with lipedema calculated with predictive equations was significantly lower than aRMR measured with other methods. This study found the agreement of predictive equations compared to IC is low (<60%). Fat-free mass (FFM) is a stronger determinant of RMR in patients with lipedema than fat mass.

Attention has been drawn to the role of changes in visceral adipose tissue rather than subcutaneous adipose tissue in the relationship between adipokines and dysfunctional adipose tissue. Especially in lipedema in which subcutaneous adipose tissue is affected, information about adipokines is insufficient. In this study, it was aimed to investigate adiponectin, ghrelin, resistin and visfatin levels and their relationship with adipose tissue thickness in patients with lipedema. For this purpose, subcutaneous adipose tissue thickness was evaluated objectively by ultrasonography. A total of 19 female patients diagnosed with lipedema and 15 healthy women with no age difference were included in the study. Skin and subcutaneous adipose tissue thickness were measured ultrasonographically. Serum levels of adiponectin, ghrein, resistin and visfatin of all subjects were measured using sandwich ELISA protocol. In patients with lipedema, subcutaneous subcutaneous tissue thickness and total skin-subcutaneous thickness were significantly increased in the thigh and calf, excluding skin thickness in the thigh, compared to controls (P0.05). No significant correlation was found between adiponectin, ghrelin, resistin and visfatin and skin, subcutaneous and total thickness measurements by ultrasound in patients with lipedema and controls (P>0.05). Although not statistically significant, when examined in detail, positive or negative correlations were observed between the groups in the relationship between adipokines and ultrasound measurements. According to our findings, although no significant relationship was found between serum levels of adipokines and subcutaneous adipose tissue thickness, it is controversial that they are completely unrelated. Further studies in larger series will shed light on the relationship between adipokines and subcutaneous tissue thickness and the importance of ultrasonography. , Adipokinler ve disfonksiyonel yağ dokusu arasındaki ilişkide subkutan yağ dokusundan ziyade viseral yağ dokusundaki değişikliklerin rolüne dikkat çekilmiştir. Özellikle cilt altı yağ dokusunun etkilendiği lipödemde adipokinler hakkında bilgi yetersizdir. Bu çalışmada lipödemli hastalarda adiponektin, ghrelin, resistin ve visfatin düzeylerinin ve bunların yağ doku kalınlığı ile ilişkisinin araştırılması amaçlandı. Bu amaçla cilt altı yağ dokusu kalınlığı ultrasonografi ile objektif olarak değerlendirildi. Lipödem tanısı almış toplam 19 kadın hasta ve yaş farkı olmayan 15 sağlıklı kadın çalışmaya dahil edildi. Deri ve deri altı yağ dokusu kalınlıkları ultrasonografik olarak ölçüldü. Tüm deneklerin serum adiponektin, ghrein, resistin ve visfatin seviyeleri sandviç ELISA protokolü kullanılarak ölçüldü. Lipödemli hastalarda, uyluk ve baldırda subkutan subkutan doku kalınlığı ve toplam deri-subkutan kalınlığı kontrollere kıyasla, uyluktaki deri kalınlığı dışında önemli ölçüde arttı (P0.05). Lipödemli hastalarda ve kontrollerde ultrason ile adiponektin, ghrelin, resistin ve visfatin ile deri, deri altı ve toplam kalınlık ölçümleri arasında anlamlı bir ilişki bulunmadı (P>0.05). İstatistiksel olarak anlamlı olmasa da detaylı incelendiğinde adipokinler ve ultrason ölçümleri arasındaki ilişkide gruplar arasında pozitif veya negatif korelasyonlar gözlendi. Bulgularımıza göre, serum adipokin düzeyleri ile deri altı yağ dokusu kalınlığı arasında anlamlı bir ilişki bulunmamakla birlikte, tamamen ilgisiz oldukları tartışmalıdır. Daha geniş serilerde yapılacak çalışmalar adipokinlerin cilt altı doku kalınlığı ile ilişkisine ve ultrasonografinin önemine ışık tutacaktır.

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.

BACKGROUND: Lipedema often remains undiagnosed in patients with obesity, leading to mismanagement of treatment. Because of this, despite remarkable weight loss after bariatric surgery and decreases in hip and abdomen circumference, some patients show only small decreases in circumference of the extremities and report persistent limb pain. OBJECTIVE: The goal of this work is to raise awareness of lipedema coincident with obesity, mistakenly diagnosed as obesity alone, in order to ensure the correct diagnosis of the condition and to achieve better treatment outcomes for people with lipedema and coincident obesity. SETTING: CG Lympha Clinic, Cologne, and Ernst von Bergmann Clinic, Potsdam. METHODS: From clinical records, we identified 13 patients who were diagnosed with lipedema only after undergoing bariatric surgery. We describe the course of their pain before and after bariatric surgery, focusing on the long-term progression of symptoms accompanying the disease. RESULTS: Lipedema cannot be cured by bariatric surgery, and although the patients in this study lost an average of more than 50 kg of weight, they displayed no improvement in the pain symptoms typical of lipedema. CONCLUSIONS: Because of the different etiologies of lipedema and obesity, lipedema requires its own specific treatment. Patients suffering from obesity should always be assessed for pain and lipedema. If coincident lipedema is diagnosed, we suggest that bariatric surgery only be performed first if diet and exercise have failed, the patient's body mass index is >40 kg/m2, and the patient has been informed of the possible persistence of pain. Lipedema, like a coincident disease, must be additionally treated conservatively or preferably surgically. This optimized treatment may help to better manage patient expectations after weight loss.

Background: Lipedema is a chronic and progressive adipose tissue disorder that causes significant morbidity and negatively influences mental health and quality of life, and increases the risk of depression, anxiety, and eating disorders. One construct of relevance to better understanding psychological disorders is emotion regulation (ER). Therefore, the aim of this study is to investigate the difficulties in ER among lipedema patients compared to healthy people without lipedema. Methods: This cross-sectional study assessed differences in ER and anxiety between two groups: 26 female patients with lipedema and 26 sex- and age-matched healthy controls. The Difficulties in Emotion Regulation Scale (DERS) assessed emotional regulation across six dimensions: Impulse control, goal-directed behavior, awareness, clarity, non-acceptance, and strategies. Anxiety was assessed by the Hamilton Anxiety Scale (HAM-A). ANOVA assessed differences in measures between lipedema and healthy control groups. Results: Lipedema patients presented with significantly more difficulties in ER and a higher level of anxiety than those without lipedema. Specifically, the lipedema group showed higher and significant differences in total DERS and anxiety scores and all DERS subscales scores compared to those without lipedema. Conclusions: Lipedema patients showed significant difficulties with ER, and were associated with anxiety symptoms, indicating that ER difficulties may play a role in developing emotional disorders, such as anxiety, for patients with lipedema. The health care provider should pay more attention to ER difficulties and psychological status among lipedema patients.

Lipedema patients suffer not only from visual stigma but also reduction in their quality of life through pain and performance loss in daily life. In clinical practice, it is still difficult to reliably diagnose the disease. This study aims to provide further insights into the characteristics of lipedema patients of all stages and provide a baseline prior to surgery for a surgical treatment evaluation by means of patient-reported outcome measures. Methods: Patients completed a lipedema-specific questionnaire containing 50 items, the World Health Organization Quality of Life BREF (WHOQOL-BREF) and the Patient Health Questionnaire 9 (PHQ-9). The data were analyzed using SPSS statistics 27. Patients who had already received liposuction were excluded. Results: Five hundred and eleven patients were included, of whom 337 completed the PHQ9 and 333 completed the WHOQOL-BREF questionnaires. The general characteristics of lipedema patients, especially the daily symptoms, are described. Previous observations, such as the frequent occurrence of hypothyroidism and the low rate of type 2 diabetes, were confirmed. Over 49% suffer from severe impairments in their jobs, whereby the disease shows a familial accumulation. The results of the WHOQOL-BREF and the PHQ-9 suggest a high level of mental stress. Discussion: As surgical intervention in lipedema patients is gaining traction, its effects should be well-documented. Therefore, a comprehensive baseline needs to be established prior to surgical treatment. The psychological components are just as important as the inclusion of daily impairments.

Abstract Background Lipedema is characterized as an abnormal deposition of fat in the buttocks and legs bilaterally that may be accompanied by swelling, pain, and tenderness. It is still often confused with more frequent conditions such as obesity and lymphedema. The estimated prevalence in Europe varies between 0.06% and 39%. Objectives To evaluate the prevalence of lipedema and identify health factors related to it in the Brazilian population. Methods Administration of a previously validated online screening questionnaire to a representative sample of the general population. The questionnaire was distributed and administered to anonymous volunteers representing the general Brazilian population using software designed for population analyses. Results 253 women answered the questionnaire, 12.3 ± 4% (Confidence Interval [CI] 95%) of whom presented symptoms compatible with a high probability of being diagnosed with lipedema. Furthermore, anxiety, depression, hypertension, and anemia were also correlated with a high probability of the diagnosis. Conclusions The estimated prevalence of lipedema in the population of Brazilian women is 12.3%. , Resumo Contexto O lipedema é caracterizado por deposição anormal de gordura em glúteos e pernas bilateralmente, que pode ser acompanhada por edema, dor e sensibilidade ao toque. Ainda é frequentemente confundido com condições mais frequentes, como obesidade e linfedema. A prevalência estimada na Europa varia entre 0,06% e 39%. Objetivos Avaliar a prevalência do lipedema na população brasileira e identificar fatores de saúde relacionados a essa doença. Métodos Foi aplicado um questionário de rastreamento on-line, previamente validado em amostra representativa da população geral. O questionário de rastreamento foi distribuído e aplicado em voluntárias anônimas representativas da população geral brasileira por software dedicado a análises populacionais. Resultados Um total de 253 mulheres respondeu ao questionário, e 12,3 ± 4% (intervalo de confiança de 95%) apresentaram sintomatologia compatível com alta probabilidade de diagnóstico de lipedema. Ansiedade, depressão, hipertensão e anemia foram correlacionadas com a alta probabilidade diagnóstica da doença. Conclusões A prevalência estimada do lipedema na população de mulheres brasileiras é de 12,3%.

Objective Lipedema is an inflammatory subcutaneous adipose tissue disease that develops in women and may progress to lipolymphedema, a condition similar to lymphedema, in which lymphatic dysfunction results in irresolvable edema. Because it has been shown that dilated lymphatic vessels, impaired pumping, and dermal backflow are associated with presymptomatic, cancer-acquired lymphedema, this study sought to understand whether these abnormal lymphatic characteristics also characterize early stages of lipedema prior to lipolymphedema development. Methods In a pilot study of 20 individuals with Stage I or II lipedema who had not progressed to lipolymphedema, lymphatic vessel anatomy and function in upper and lower extremities were assessed by near-infrared fluorescence lymphatic imaging and compared with that of a control population of similar age and BMI. Results These studies showed that, although lower extremity lymphatic vessels were dilated and showed intravascular pooling, the propulsion rates significantly exceeded those of control individuals. Upper extremity lymphatics of individuals with lipedema were unremarkable. In contrast to individuals with lymphedema, individuals with Stage I and II lipedema did not exhibit dermal backflow. Conclusions These results suggest that, despite the confusion in the diagnoses between lymphedema and lipedema, their etiologies differ, with lipedema associated with lymphatic vessel dilation but not lymphatic dysfunction.

OBJECTIVE: Lipedema is a chronic and progressive disease associated with lymphatic impairment at later stages. The aim of our study was to describe the functional status and anatomy of lower limb superficial lymphatic system using indocyanine green (ICG) lymphography in patients with lipedema. METHODS: Following ICG injection at the dorsum of the foot, distance (cm) covered by the dye at 10 (T10') and 25 min (T25') was measured and normalized for limb length. If the dye did not reach the groin within 25 min, patients were classified as "drainage-needing" group (DNG). Values of fat and lean distribution assessed by dual-energy X-ray absorptiometry were extracted, and correlation analysis was performed. Furthermore, anatomical patterns of superficial lymphatics were assessed. RESULTS: Overall, 45 women were included, 25 (56%) of whom were classified as DNG. Symptoms duration was significantly associated with DNG status at multivariate analysis (odds ratio 1.07; 95% CI 1.01-1.14; p = 0.047). Moreover, Spearman's analysis showed a negative correlation between symptoms duration and T25' dye migration (r = -0.469; p = 0.037). Overall, no major anatomical lymphatic changes were found. CONCLUSIONS: Present study suggests that lymphatic functioning in patients with lipedema correlates with symptoms duration. Further research on larger cohorts should verify our findings and clarify their potential therapeutic implications. Overall, ICG lymphography may be promising technique to assess both lymphatic anatomy and functioning in patients with lipedema.

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.

Background Lipedema is an underdiagnosed condition in women, characterized by a symmetrical increase in subcutaneous adipose tissue (SAT) in the lower extremities, sparing the trunk. The lipedema SAT has been found to be resistant to diet, exercise and bariatric surgery, in regard to both weight loss (WL) and symptom relief. Current experience indicates that a low carbohydrate and high fat (LCHF-diet) might have a beneficial effect on weight and symptom management in lipedema. Objective To assess the impact of an eucaloric low carbohydrate, high fat (LCHF)-diet on pain and quality of life (QoL) in patients with lipedema. Methods Women diagnosed with lipedema, including all types and stages affecting the legs, (age 18-75 years, BMI 30-45 kg/m2) underwent 7 weeks (wk) of LCHF-diet and, thereafter 6 wk of a diet following the Nordic nutrition recommendations. Pain (visual analog scale) and QoL (questionnaire for lymphedema of the limbs), weight and body composition were measured at baseline, wk 7 and 13. Results Nine women (BMI: 36.7±4.5kg/m2 and age: 46.9±7 years) were recruited. The LCHF diet induced a significant WL -4.6±0.7 kg (-4.5±2.4%), P<0.001 for both, and reduction in pain (-2.3±0.4 cm, P=0.020). No correlation was found between WL and changes in pain at wk 7 (r = 0.283, P = 0.460). WL was maintained between wk 7 and 13 (0.3±0.7 kg, P=0.430), but pain returned to baseline levels at wk 13 (4.2±0.7 cm ,P=0.690). A significant increase in general QoL was found between baseline and wk 7 (1.0 (95% CI (2.0, 0.001), P=0.050) and 13 (1.0 95% CI (2.0, 0.001) P=0.050), respectively. Conclusion A LCHF-diet is associated with reduction in perceived pain and improvement in QoL, in patients with lipedema. Larger randomized clinical trials are needed to confirm these findings. This article is protected by copyright. All rights reserved.

Lipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility and quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses of whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), and adipocytes from patients with or without lipedema.

In mice, embryonic dermal lymphatic development is well understood and used to study gene functions in lymphangiogenesis. Notch signaling is an evolutionarily conserved pathway that modulates cell fate decisions, which has been shown to both inhibit and promote dermal lymphangiogenesis. Here, we demonstrate distinct roles for Notch4 signaling versus canonical Notch signaling in embryonic dermal lymphangiogenesis. Actively growing embryonic dermal lymphatics expressed NOTCH1, NOTCH4, and DLL4 which correlated with Notch activity. In lymphatic endothelial cells (LECs), DLL4 activation of Notch induced a subset of Notch effectors and lymphatic genes, which were distinctly regulated by Notch1 and Notch4 activation. Treatment of LECs with VEGF-A or VEGF-C upregulated Dll4 transcripts and differentially and temporally regulated the expression of Notch1 and Hes/Hey genes. Mice nullizygous for Notch4 had an increase in the closure of the lymphangiogenic fronts which correlated with reduced vessel caliber in the maturing lymphatic plexus at E14.5 and reduced branching at E16.5. Activation of Notch4 suppressed LEC migration in a wounding assay significantly more than Notch1, suggesting a dominant role for Notch4 in regulating LEC migration. Unlike Notch4 nulls, inhibition of canonical Notch signaling by expressing a dominant negative form of MAML1 (DNMAML) in Prox1+ LECs led to increased lymphatic density consistent with an increase in LEC proliferation, described for the loss of LEC Notch1. Moreover, loss of Notch4 did not affect LEC canonical Notch signaling. Thus, we propose that Notch4 signaling and canonical Notch signaling have distinct functions in the coordination of embryonic dermal lymphangiogenesis.

Lipoedema UK welcomed our involvement with NICE and the opportunity to comment on noncosmetic liposuction (NCL) as a proposed interventional procedure for chronic lipoedema. In response, we have been proactive in capturing the views and experiences of individuals in the UK living with lipoedema and from those who have undergone non-cosmetic liposuction.

<p>Bei 640 Patientinnen einer Fachklinik für operative Lymphologie erfolgte mittels Fragebogen der Deutschen Schmerzgesellschaft e. V. eine Befragung. Neben Fragen zum Schmerz und zur Schmerzcharakteristik wurden gleichzeitig noch demografische Daten miterhoben. Es ergab sich, dass nur bei etwas über 50 % eine echte Adipositas nachgewiesen werden konnte. Lipödem und Adipositas müssen als unabhängige Krankheitsbilder gewertet werden. Der Schmerz wurde überwiegend als drückend und ziehend empfunden. Attribute wie klopfend oder pochend, passend zu einer akuten Entzündung, erfuhren die Wertung „nicht zutreffend“. Die Beschwerdesymptomatik war unabhängig vom BMI, der bei der Lipohyperplasie dolorosa nur bedingt verwertbar ist. Insgesamt ist das Leitsymptom „Schmerz“ sehr facettenreich, das angeborene, nicht erworbene Lipödemfett der Extremitäten führt zu einer deutlichen Beeinträchtigung der Aktivitäten sowohl allgemein als auch im Freizeitbereich. Die durch den G-BA initiierte Studie muss daher kritisch gesehen werden. Da bislang keine objektivierbaren Befunde beim Lipödem erhoben werden können, ist eine subtile Befragung betroffener Patientinnen zur Diagnosestellung notwendig.</p>

Whole-body three-dimensional surface imaging (3DSI) offers the ability to monitor morphologic changes in multiple areas without the need to individually scan every anatomical region of interest. One area of application is the digital quantification of leg volume. Certain types of morphology do not permit complete circumferential scan of the leg surface. A workflow capable of precisely estimating the missing data is therefore required. We thus aimed to describe and apply a novel workflow to collect bilateral leg volume measurements from whole-body 3D surface scans regardless of leg morphology and to assess workflow precision. For each study participant, whole-body 3DSI was conducted twice successively in a single session with subject repositioning between scans. Paired samples of bilateral leg volume were calculated from the 3D surface data, with workflow variations for complete and limited leg surface visibility. Workflow precision was assessed by calculating the relative percent differences between repeated leg volumes. A total of 82 subjects were included in this study. The mean relative differences between paired left and right leg volumes were 0.73 ± 0.62% and 0.82 ± 0.65%. The workflow variations for completely and partially visible leg surfaces yielded similarly low values. The workflow examined in this study provides a precise method to digitally monitor leg volume regardless of leg morphology. It could aid in objectively comparing medical treatment options of the leg in a clinical setting. Whole-body scans acquired using the described 3DSI routine may allow simultaneous assessment of other changes in body morphology after further validation.

Angiogenesis, the growth of blood vessels from pre-existing vasculature, is primarily regulated by vascular endothelial growth factor receptors (VEGFRs). Dysregulated angiogenesis is associated with cancers, obesity, and over 70 vascular diseases. Upregulated VEGFR protein expressions in diseased vasculature are promising biomarkers for predicting clinical outcomes, as indicated by non-quantitative immunohistochemical studies in patients with impaired vascularization or tumor angiogenesis. While the quantitative characterization of VEGFRs is critical in identifying biomarkers for anti-angiogenic therapies, VEGFR biomarker development presents two particular challenges: (1) The invasive tissue biopsy needed limits the amount of VEGFR data that can be collected from both normal and diseased vasculatures, and (2) we poorly understand the significance of endothelial and various non-endothelial VEGFR-expressing cells in angiogenic therapies. To address these challenges, here I pioneer a blood biopsy-based proteomic approach that allows non-invasive VEGFR quantification. More significantly, I identify and establish age- and sex-specific basal levels of VEGFRs on endothelial cells and bone marrow-derived progenitor cells (Chapter 2). In recent years, blood biopsies have expanded our knowledge of vascular pathology. In particular, circulating angiogenic cells, such as circulating endothelial cells (cECs) and circulating progenitor cells (cPCs), are isolated and counted, and their elevated abundances are often correlated with vascular disease progression and cancer prognosis. However, cECs and cPCs have been overlooked as accessible proxies for profiling vascular biomarker expressions by activated or damaged vasculatures. For the first time, I show that cPCs and cECs exhibit heterogeneous plasma membrane expression of VEGFRs, which are correlated with donor sexes and ages, particularly pre- vs. post-menopausal status. Menopause is known to reduce regenerative and angiogenic capacities, as manifested by decreased capillary growth in skeletal muscle and increased risks for cardiovascular diseases. Here I provide baseline VEGFR expression ranges for these cells, showing that ~50% of cECs in premenopausal females exhibit intermediate-to-high plasma membrane expression (138,000 VEGFR1 and 39,000-236,000 VEGFR2/cell) and ~25% of cECs in males exhibit high VEGFR plasma membrane expression (206,000 VEGFR1 and 155,000 VEGFR2/cell). In marked contrast, nearly all cECs in postmenopausal females are VEGFR-low (2,900 VEGFR1 and 3,400 VEGFR2/cell), agreeing with the reduced angiogenic capacities after menopause. Additionally, VEGFR1 signaling is critical for cPC localization to activated or damged blood vessels. My data show that VEGFR1 plasma membrane localization in cPCs occurs only in postmenopausal females, suggesting menopause activates VEGFR1 signaling pathways in cPCs. Therefore, my data offer quantitative insights into how VEGFR-regulated regenerative and angiogenic capacities are altered due to menopause. Overall, these findings provide the first insights into how sex and age interactions, particularly menopause, influence VEGFR plasma membrane localization in circulating angiogenic cells. More importantly, the findings help establish age- and sex-specific VEGFR baselines for predicting vascular disease progression and therapeutic outcomes. The second challenge is quantitatively characterize how endothelial and non-endothelial VEGFR-expressing cells contribute to angiogenic regulation. Here, I quantitatively elucidate the changes in VEGFR expressions by endothelial cells and non-enodthelial cells in adipose tissues, and identify biomarkable adipose tissue cells that show altered VEGFR membrane expressions in normal versus high-adiposity states (Chapter 3). Obesity is a major risk factor for vascular disorders, including peripheral artery disease, critical limb ischemia, and several cancers. I hypothesize that VEGFR membrane expression by adipose tissue cells is altered as body fat accumulates (increased adiposity). The VEGFR quantification data presented here indicate that ~ 20% of activated lymphocytes upregulate their membrane expressions of VEGFR1 and VEGFR3 by tenfold in response to increased subcutaneous adiposity induced by lipedema, which is very commonly accompanied by impaired vascularization and chronic inflammation. On the other hand, in murine visceral adipose tissue, myeloid progenitor cells exhibit the highest VEGFR membrane expressions (16,000 ± 4,700 VEGFR1, 50,000 ± 6,200 VEGFR2, and 2,100 ± 460 VEGFR3/cell). Compared to myeloid progenitor cells, visceral endothelial cells exhibit an order of magnitude lower VEGFR1 and VEGFR2 levels (2,400 ± 710 VEGFR1/cell, 1,100 ± 190 VEGFR2/cell, and 1,200 ± 220 VEGFR3/cell, respectively). My approach and findings are foundational to a systematic understanding of how VEGFR-expressing adipose cells regulate adipose angiogenesis and adipogenesis. Future studies are warranted to compare how VEGFR membrane expressions differ in chow-fed and high fat-fed mice, and the quantitative proteomic findings will guide therapies for visceral obesity-associated vascular disorders. Last but not least, unlike VEGFRs, many receptors of clinical interest, particularly the oxytocin receptor (OXTR) and its genetic variants, do not have specific antibodies that enable quantitative characterization. To overcome this issue, I have designed a transfected cell model that is engineered to express HA-OXTR-GFP protein complexes, in which an N-terminal HA acts as a proxy for membrane OXTR detection and a C-terminal GFP acts as an indicator in selecting transfected cells from untransfected cells (Chapter 4). This transfected cell model is applied to characterize the varied dose-response profiles of OXTR wild-type and variant cells to oxytocin, a common labor induction drug. My OXTR quantification data show clear correlations to oxytocin-induced functional outcomes, including calcium release and cell desensitization, suggesting that the quantities of different OXTR variants are predictive of cell responses to administered oxytocin and should be considered when making personalized oxytocin dosing decisions. Overall, my results demonstrate that membrane expression of VEGFRs is significantly associated with physiological factors such as sex, age, and menopause, and with pathological adipose tissue expansion. Although VEGFR protein expression is a promising biomarker for many vascular diseases and cancers, quantitative and baseline VEGFR data are still needed for VEGFR-driven pathology. My work on both VEGFRs and other biomarkable receptors, such as OXTR, provides much-needed standardized approaches and quantitative data, a first step towards proteomic biomarker-driven precision medicine.

Both lipedema and juxta-articular adiposis dolorsa are painful disorders of subcutaneous adipose tissue. We investigated 297 female patients with lipedema treated at our department for the presence of juxta-articular adiposis dolorsa. Occurrence of both disorders was identified in 4.4% of lipedema patients. The common presence of both disorders was observed only in more advanced lipedema (grade II and III). Juxta-articular adiposis dolorosa of the knees is seen exclusively on the inner knees, and it presents neither bruising nor creases or hypothermia. Choices of surgical treatment are either microcannula liposuction or dermolipectomy. Recurrences have not been observed.

OBJECTIVES: The association between serum Vitamin D (Vit. D) and mood disorders in lipedema patients has not been investigated. Therefore, the main aim of this study is to investigate the correlation between serum Vit. D, depression and anxiety risk. METHODS: A cross-sectional cohort of lipedema patients were investigated by collecting the clinical and demographic data. The Hamilton Depression Scale (HAM-D) and the Hamilton of Anxiety Scale (HAM-A) were used to evaluating the risk of depression and anxiety. Serum concentrations of Vit. D were measured. The association between Vit. D levels and both HAM-A and HAM-D scores were statistically examined by bivariate and partial correlations. RESULTS: Forty lipedema patients were enrolled in this study. Around two-thirds of them had a higher depression or anxiety risk, and 77.5% were under the normal serum Vit. D levels. A significant and inverse correlation was observed between serum Vit. D levels and both HAM-D (r=-0.661, p<0.001), and HAM-A (r=-0.496, p=0.001) scores. This strong association was sustained after the statistical model adjusted for the main potential confounding factors (age, body mass index (BMI), disease duration, and lipedema stages). Additionally, serum Vit. D correlated significantly and inversely with BMI (r=-0.647, p<0.001). Moreover, BMI significantly correlated with HAM-D: r=0.560, p<0.001, and HAM-A: r=0.511, p=0.00. CONCLUSIONS: This study suggests a strong correlation between Vit. D levels, depression scores, and anxiety scores in lipedema patients. Our results also demonstrate a strong and direct relationship between BMI, Vit. D levels, depression, and anxiety.

Lipedema is a chronic, progressive disease that almost exclusively affects women and often misdiagnosed as obesity or primary lymphedema. Research concerning lipedema is sparse, and there is a lack of studies focusing on women's experiences of living with the illness. We interviewed fourteen women with lipedema with the aim of describing their experiences of living with lipedema. Our results show that women felt controlled by their body, and were fat-shamed and viewed by others as a person who lacked character. They received unsupportive advice on how to manage from healthcare, and blamed themselves while striving to take responsibility.