As the new Chief Science Officer of the Lipedema Foundation, I am currently in the midst of a deep dive into the state of the art in Lipedema research. My review of the literature has shown me that the field, while still in its early stages, is full of promise and possibility, with efforts underway that are leveraging the latest advances in precision molecular medicine in the service of Lipedema patients.
Lipedema is diagnosed clinically by an experienced physician with specialist expertise. Despite its prevalence, it is not yet a routine part of the medical curriculum – medical students do not receive training in diagnosing and treating Lipedema. As a result, many doctors are unfamiliar with it. There are no biomarkers that can unambiguously identify Lipedema. In other words, we do not yet have a lab test (like a blood test or a scan) that can reliably identify the disease. Such tests would make diagnosis much more straightforward; more importantly, lab tests would help avoid delayed diagnoses and allow early intervention.
Apart from diagnosis, we must first understand the biology of a disease to develop effective treatments. We must discover answers to questions such as: What triggers Lipedema? Why do some people get it and not others? Why does Lipedema fat accumulate in some parts of the body and not others? In what ways is Lipedema fat different from the 'regular' fat seen in obesity? What causes these differences? Where does Lipedema pain come from?
Both clinical investigation and laboratory methods are required to advance understanding of any disease. Of course, for a patient, it is clinical understanding that is vital - how does the disease affect the patient? What are the common aspects of the disease, and what is the range of variability between different people? What is the nature of disease progression?
Lipedema research is still in its infancy. While we do not yet have definitive answers to many of the questions posed above, a handful of studies published in 2023 provide promising beginnings for future investigation. The studies featured here highlight the steady advancement of a nascent field. The past twelve months saw the publication of 100 papers on Lipedema, with close to 50 primary data papers, and some significant reports funded by the Lipedema Foundation (LF). We hope that this forward momentum will serve to inspire our community and ignite new research questions in 2024 and beyond.
- Ashok Srinivasan, PhD, Chief Science Officer
Tissue culture & molecular pathways
2023 was a productive year for tissue culture studies of Lipedema. Three groups of scientists funded by LF published reports of in vitro studies that set a baseline for future investigations.
In the LF-funded Ernst 2023 paper, scientists isolated adipose tissue-derived stromal/stem cells (ASCs) from Lipedema and non-Lipedema patients [1]. Such stem cells have the potential to produce fat cells in the body. This work revealed that Lipedema and non-Lipedema cells differ in their expression of genes involved in adipocyte (fat cell) formation. Interestingly, this study found increased myofibroblast-like (muscle-fibroblast-like) cells in "obese" Lipedema. Although this preliminary finding must be replicated, myofibroblasts are known to be involved in fibrosis, a characteristic of Lipedema fat. Future studies may clarify the role of these cells in Lipedema fibrosis and pain.
About a third of Lipedema patients have increased blood vessels in their thigh adipose tissue. The growth of blood vessels under healthy conditions is tightly regulated in a process called "angiogenesis". These Lipedema vessels, on the other hand, are often dysfunctional and leaky, leading to fluid accumulation. The process by which this increase in dysfunctional blood vessels occurs in women with Lipedema is not known. In a paper by Al-Ghadban and others, LF-funded scientists showed that stage-2 Lipedema cells produce signals that promote the growth of blood vessels [2]. Although healthy cells also make such signals, Lipedema cells showed a more significant effect in promoting blood vessel growth. This study also showed lower expression of genes controlling cell-cell attachment in Lipedema, potentially accounting for blood vessel leakiness. Although Lipedema stages other than stage 2 were not examined, this study establishes a system for investigating the signals influencing blood vessel growth and dysfunction in Lipedema.
Lipedema is often accompanied by inflammation in affected tissues. The triggers for this inflammation and the downstream consequences are not clear. In a study published in 2023, LF-funded researchers in Dr. Gouspoulos’s group (Von Atzigen, et al.) showed that Lipedema tissues often have increased numbers of a type of immune cell known as macrophages [3]. These macrophage cells were shown to communicate with the adipose cells (fat cells) in Lipedema tissue, affecting their function, including fat accumulation.
In follow-up work published in 2023, scientists from the Kim lab, in collaboration with the Gousopoulos group (Vasella, et al.), showed that the expression of a gene called MIF-1 was significantly higher in Lipedema patients compared to BMI, age, and anatomically matched non-Lipedema patients [4]. In parallel, the expression of CD74, a receptor for MIF-1, was also increased. MIF-1 and CD74 have been previously implicated in inflammatory processes. It is conceivable that this pathway may be involved in macrophage migration and signaling in adipose tissue. The consequences of these cell signaling interactions for disease remain to be demonstrated in future work.
Clinical Characterization and Profiling Studies
Stage-dependent changes in Lipedema adipose tissue are not well understood. Correlating disease severity and progression with tissue-level morphological and molecular changes may lead to early diagnosis, improved care, and more standardized criteria for diagnosis, staging, and intervention.
In a study published in 2023, LF-funded investigators reported a morphological assessment of adipose tissue and a molecular analysis of fibrosis and inflammation correlated with disease stage and severity.
A study by Kruppa, et al. showed that progressive fibrosis accompanies the progression of Lipedema [5]. The researchers also confirmed observations reported in other LF-funded studies on the presence of M2 macrophages in early-stage Lipedema tissues. M2 macrophages are classified as anti-inflammatory. However, this research also suggests that elevated M2 macrophage infiltration is lower in advanced stages of Lipedema; in later stages, accumulated tissue damage perhaps leads to greater inflammation. These observations related to M2 macrophages, now confirmed in independent studies, present a point of entry for therapeutic intervention in the future.An independent study (with no external funding noted) published by Kempa, et al. examined the metabolic and lipidomic profiles of Lipedema patients [6]. 'Omic' studies often examine thousands of molecules simultaneously. This study examined a restricted subset of molecules important in general and fat metabolism. These authors used a different profiling technology (1H-NMR spectroscopy) from the one used in previous studies (liquid chromatography-mass spectrometry or LC-MS). The authors show that 9 out of 39 molecules examined differed in Lipedema patients compared to lean and obese controls. The results suggest that amino acid metabolism and energy metabolism may be affected in Lipedema. One metabolite in particular (pyruvic acid – involved in energy metabolism) could distinguish Lipedema with high confidence. If other laboratories can replicate this result, this metabolite could someday be developed as a biomarker for a blood test to diagnose Lipedema – a promising possibility.
Lipedema Symptomatology and Clinical Care
Basic research as described above is not an end in itself but a prelude to increasing the reliability of diagnosis, improving care and the quality of life for patients, and developing effective therapeutic interventions. Thus, research into the underlying biology of disease must go hand in hand with clinical investigation, especially when the standard of care affects access to treatment.
Accurate characterization of symptoms reported by patients is essential to understanding the nature of Lipedema, the commonalities and differences between patients at various stages of the disease, and common comorbidities. A reliable survey of symptoms can also aid the development of treatment plans and therapeutics for Lipedema. LF-funded researchers Aaron Aday, et al. studied Lipedema symptomatology in 707 women with Lipedema in the United States, publishing a report in 2023 [7]. One important finding is that Lipedema patients often report symptoms outside the lower body, suggesting systemic consequences beyond visibly affected areas - corroborating findings from the Lipedema Foundation Registry: First Look Report and other sources. This study is the largest Lipedema symptomatology survey cohort reported to date. It is foundational, allowing comparison of symptoms in cohorts from other countries to establish the range of variation.
In Germany, patients with a BMI greater than 40 kg/m2 are excluded from insurance coverage for Lipedema liposuction. Those with a BMI between 35 - 40 kg/m2 are required to first undergo conservative obesity therapy before being considered for liposuction. This emphasis on BMI raises the question of whether BMI assessment is an accurate criterion for Lipedema-related clinical decision-making. A study published by Brenner, et al., in 2023, which included patients from Germany, Spain, and the UK, suggests that obesity is often overestimated if Waist-to-Height-Ratio (WHtR) is not factored in [8]. The authors conclude that the exclusive use of BMI in Lipedema diagnosis is often unreliable.
Nutrition
Sleep, exercise, and nutrition are all critical components of general health. The way we eat is known to influence general inflammation, although its role in Lipedema-related inflammation remains to be analyzed. While current research suggests that Lipedema does not respond to caloric restriction, a healthy way of eating, informed by rigorous research and specifically tuned to the needs of Lipedema patients, could be beneficial. Two 2023 studies are relevant in this regard:
A 2023 study by Jeziorek, et al. of 24 women with Lipedema and 24 with obesity reported that a low-carbohydrate, high-fat diet (LCHF diet) maintained over seven months, may benefit Lipedema patients. [9] Since this study only examined laboratory parameters and not Lipedema symptomatology, it is best viewed as a supplemental nutrition strategy for general health with beneficial effects on weight, liver function, glucose profile, triglyceride, and HDL-C levels.
A parallel study by Jeziorek, et al. published in 2023 examined Lipedema-related parameters in response to an LCHF diet (n=56 Lipedema, 57 control) [10]. The authors reported a significant reduction in patient-reported pain levels. Significant reductions in body fat mass and leg adiposity were also reported, and ankle circumference decreased more in the Lipedema group. These preliminary observations suggest that an LCHF diet may be beneficial for managing Lipedema, especially disease-associated pain.
Future directions
When trying to unravel the biology of any disease, scientists usually use “model systems”. These may be animal models of disease or cell culture (in vitro) models. Such laboratory animals and cells capture some aspects of the disease (not all), which can then be conveniently studied in the laboratory. Well-validated findings from models can then be tested with human samples.
Model systems are a great unmet need in Lipedema research. Although obese mouse models exist, there are currently no animal models specifically for Lipedema, and tractable cell culture models are still being developed. Some of the studies described above and other ongoing, as-yet-unpublished research funded by LF are aimed at developing such systems, which might greatly speed up Lipedema research.
In vitro models remain an important priority. LF has funded multiple projects to develop cell culture models of Lipedema, in which various tissue types are isolated from patient biopsies and examined in the laboratory. Such studies can identify pathological and molecular characteristics of Lipedema and the biochemical pathways underlying the initiation and progression of the disease; and in the future, such cell culture models could be used to discover effective drug therapies. While the development of animal models is a more complex task, a deeper understanding of disease biology and the molecular signaling pathways involved may make such models feasible in the future.
LF has established a patient registry to drive clinical research in parallel with a focus on model systems. The Lipedema Foundation Registry now includes more than 3,500 patients, with almost a thousand patients registering in 2023 alone! The LF vision is to evolve the registry into a resource that benefits patients and clinical researchers, and in the not-too-distant future might help drive clinical trials for therapeutic agents.
Recent progress in adjacent fields is opening up new possibilities to advance our understanding of Lipedema. As we venture into a new year of progress in our field, we hope researchers, clinicians, and those living with Lipedema will continue to use the Lipedema Research Roadmap as a guide to putting some of the Lipedema puzzle pieces together. Stay tuned for announcements of future funding opportunities.
Cheers to an exciting new year of opportunity and innovation!
CITED REFERENCES