Lipedema: The Use of Cultured Adipocytes for Identification of Diagnostic Markers.

BACKGROUND: Lipedema, diagnosed most often in women, is a progressive disease characterized by the disproportionate and symmetrical distribution of adipose tissue, primarily in the extremities. Although numerous results from in vitro and in vivo studies have been published, many questions regarding the pathology and genetic background of lipedema remain unanswered. METHODS: In this study, adipose tissue-derived stromal/stem cells were isolated from lipoaspirates derived from nonobese and obese donors with or without lipedema. Growth and morphology, metabolic activity, differentiation potential, and gene expression were evaluated using quantification of lipid accumulation, metabolic activity assay, live-cell imaging, reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, and immunocytochemical staining. RESULTS: The adipogenic potential of lipedema and nonlipedema adipose tissue-derived stromal/stem cells did not rise in parallel with the donors' body mass index and did not differ significantly between groups. However, in vitro differentiated adipocytes from nonobese lipedema donors showed significant upregulation of adipogenic gene expression compared with nonobese controls. All other genes tested were expressed equally in lipedema and nonlipedema adipocytes. The adiponectin/leptin ratio was significantly reduced in adipocytes from obese lipedema donors compared with their nonobese lipedema counterparts. Increased stress fiber-integrated smooth muscle actin was visible in lipedema adipocytes compared with nonlipedema controls and appeared enhanced in adipocytes from obese lipedema donors. CONCLUSIONS: Not only lipedema per se but also body mass index of donors affect adipogenic gene expression substantially in vitro. The significantly reduced adiponectin/leptin ratio and the increased occurrence of myofibroblast-like cells in obese lipedema adipocyte cultures underscores the importance of attention to the co-occurrence of lipedema and obesity. These are important findings toward accurate diagnosis of lipedema. CLINICAL RELEVANCE STATEMENT: Our study highlights not only the difficulty in lipedema diagnostics but also the tremendous need for further studies on lipedema tissue. Although lipedema might seem to be an underestimated field in plastic and reconstructive surgery, the power it holds to provide better treatment to future patients can not be promoted enough.

Lipedema Research-Quo Vadis?

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.