Obesity Reviews

REVIEW OPEN ACCESS

Lipedema: Progress, Challenges, and the Road Ahead

Vincenza Cifarelli

Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA

Correspondence: Vincenza Cifarelli ([email protected])

Received: 31 January 2025 | Revised: 11 April 2025 | Accepted: 30 April 2025

Funding: This study was supported by the Lipedema Foundation and Saint Louis University startup fund.

Keywords: adipose tissue | inflammation | lipedema | lymphatics | VEGF-­C

ABSTRACT
Introduction: Lipedema is a chronic and progressive disease that predominantly affects women, characterized by a dispropor-
tionate increase in subcutaneous adipose tissue (AT), particularly in the lower limbs. It is associated with significant physical
disability, chronic pain, thromboembolism, and psychosocial distress. Despite its profound impact on women's health and quality
of life, lipedema remains underrecognized and insufficiently studied, with an estimated prevalence of approximately 10% among
women worldwide. Although the exact etiology of lipedema remains unclear, emerging evidence suggests a multifactorial origin
involving genetic predisposition, hormonal influences, and vascular dysfunction—all contributing to its development and pro-
gression. Current therapeutic options provide only partial symptom relief and remain noncurative, highlighting the urgent need
for expanded research and improved management strategies.
Methods: A systematic review was conducted to assess the current understanding of lipedema pathophysiology and current
treatment options. Research articles were sourced from PubMed, Web of Science, ScienceDirect, and Scopus databases. Over 100
studies were incorporated.
Results: This review provides a comprehensive overview of lipedema, encompassing its clinical features, pathophysiological
mechanisms, diagnostic challenges, and current treatment modalities. Additionally, the review discusses whether the molecular
and metabolic differences between abdominal and femoral AT depots mirror those observed in classical obesity.
Conclusions: Multidisciplinary, research-­informed care is essential for managing lipedema, combining conservative therapies,
tailored exercise, and liposuction for advanced cases. More research to better understand the underlying pathophysiology is crit-
ical to developing targeted treatments, improving diagnostic accuracy, and informing standardized, evidence-­based care.

1   |   Introduction pain [7]. Despite the clinical impact on women's health and qual-
ity of life, lipedema is largely understudied and misdiagnosed as
Lipedema is a chronic and progressive disease characterized by classical obesity, delaying appropriate treatment and worsening
the disproportionate painful accumulation of subcutaneous adi- disease morbidity.
pose tissue (AT) in the hips, buttocks, and legs [1]. Lipedema oc-
curs almost exclusively in women and usually develops during Indirect estimates suggest that lipedema may be more common
early adulthood due to stress, surgery, and/or hormonal changes than previously recognized. Epidemiological data, derived from
[2]. Lipedema in males is rare, and it is usually associated with the misdiagnosis of lipedema as lymphedema, indicate that the
higher estrogen and lower testosterone levels [3] and severe liver condition could affect 6%–11% of women in the general popula-
disease [4]. Lipedema is associated with impaired mobility, ve- tion [8, 9]. However, the true prevalence of lipedema remains
nous thromboembolism (VTE) [5, 6], osteoarthritis, and chronic unknown reflecting several barriers to accurate estimates.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2025 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.

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These include the following: (i) Although the World Health cases. Vascular endothelial growth factor (VEGF)–A is an estab-
Organization classified lipedema as a distinct disease in the lished regulator of angiogenesis and vessel remodeling. VEGF-­
International Classification of Diseases (ICD-­11), the United A-­mediated vascularization of AT is essential for maintaining
States still uses ICD-­10 and cannot yet adopt the new code, with metabolic homeostasis by ensuring proper oxygenation, nutrient
no clear timeline for transition. (ii) Awareness is lacking among supply, and waste removal [18]. A well-­developed and functional
healthcare providers who are unfamiliar with the condition and vascular network supports healthy AT expansion, preventing
fail to identify cases in the clinical practice resulting in misdi- the development of hypoxia—a condition characterized by low
agnosis with obesity or lymphedema, because of its association oxygen levels—which can trigger inflammation, fibrosis, and
with increased AT deposition, or swelling. (iii) A definitive di- metabolic dysfunction [19]. VEGF genetic variants, along with
agnostic test or biomarker for lipedema is absent, making the other 62 different loci, were recently reported to be significantly
diagnosis reliant on clinical evaluation and patient history. This associated with both higher adiposity and lower cardiomet-
subjectivity contributes to the variability in the recognition and abolic risk [20], in line with key clinical features of lipedema
report of lipedema, further complicating efforts to measure its [21]. The growth factor receptor-­ bound protein 14 (GRB14)/
prevalence. cordon-­bleu WH2 repeat protein-­like 1 (COBLL1) locus has been
linked to body fat distribution [15, 22]. Although the precise
molecular mechanisms are not completely understood, GRB14
1.1   |   Lipedema Etiology and COBLL1 play distinct roles in adipocyte biology and insu-
lin signaling. GRB14 inhibits insulin receptor signaling [23] by
The etiology of lipedema remains unclear, though evidence preventing the phosphorylation of downstream signaling mol-
points to a combination of genetic, hormonal, and vascular ecules such as protein kinase B (PKB/AKT) and extracellular
factors that contribute to its development and progression [10]. signal-­regulated kinase (ERK) [24, 25]. In murine primary he-
Although no single causative gene has been confirmed, familial patocytes, knockdown of Grb14 leads to a significant decrease in
clustering and inheritance patterns support a hereditary compo- insulin-­induced processing and expression of sterol regulatory
nent, with variations in gene expression potentially influencing element-­binding protein 1c, highlighting its role in lipid metab-
disease severity and progression. Family history is frequently olism [26]. In human preadipocytes, GRB14 knockout results in
reported, with many cases showing inheritance patterns that decreased differentiation efficiency, proliferation rate, and lipid
suggest a possible autosomal dominant mode with incomplete storage. Conversely, COBLL1 knockout leads to excessive lipid
penetrance [11]. A familial case of lipedema has been linked to a storage and lipolysis without affecting adipogenesis or insulin-­
mutation in the AKR1C1 gene, encoding for an aldo-­keto reduc- stimulated AKT2 phosphorylation [27]. Despite these efforts,
tase that catalyzes the reduction of progesterone to its inactive the genetic driver(s) of lipedema remains elusive, highlighting
form, 20-­alpha-­hydroxyprogesterone [12]. In a different study, the need for follow-­up studies using larger and more diverse
a mutation in the PIT1 gene [3] (POU class 1 homeobox 1) was populations to further investigate the identified loci and asso-
identified. This gene encodes for a transcription factor that reg- ciated genes, validate findings, and uncover additional loci. In
ulates the expression of growth hormone prolactin and thyroid-­ addition, experimental studies to determine how these loci in-
stimulating hormone beta, all of which are essential for the fluence biological processes related to AT biology and lipedema-­
function of the endocrine system. However, sporadic cases com- specific clinical characteristics are also needed.
plicate the genetic interpretation, suggesting the involvement
of environmental factors or epigenetic mechanisms. Recent Lipedema predominantly affects women, often manifesting or
advances in genetic and transcriptomic analyses have begun to worsening during hormonal transitions such as puberty, preg-
shed light on potential molecular pathways involved in lipedema. nancy, or menopause, implicating estrogen and progesterone
Michelini et al. [13], have recently proposed a genetic testing in its progression [28]. In an “Opinion Article,” the concept
panel using next-­generation sequencing to identify potential ge- of lipedema as a phenotypic manifestation of a “pseudopreg-
netic variations associated with the development of lipedema. nancy” was recently proposed [29]. In this model, lipedema
The study conducted genomic sequencing on 162 Italian and could be considered a pathological condition where hormonal
American patients with lipedema, identifying 305 genes poten- and physiological processes, similar to pregnancy, lead to ab-
tially associated with the condition and overlapping diseases rel- normal fat accumulation and tissue remodeling, but without
evant to lipedema. The analysis identified 21 deleterious variants actual pregnancy occurring. Authors proposed that lipedema
across 12 genes (PLIN1, LIPE, ALDH18A1, PPARG, GHR, INSR, could be triggered by a selective accumulation of bacterial
RYR1, NPC1, POMC, NR0B2, GCKR, and PPARA) in 17 patients lipopolysaccharides (LPS), or endotoxin, in gluteofemoral
[13]. More recently, a genome-­w ide association study using an white AT. During pregnancy, intestinal permeability in-
inferred lipedema phenotype identified 18 genetic risk factors creases as part of the body's adaptive responses to support the
in adult women of European descent using the UK Biobank [14]. fetus. This condition, known as “leaky gut syndrome,” allows
Among those, loci located in or near RSPO3, GRB14-­COBLL1, for an increased entry of bacterial endotoxins into circulation,
ZNF664-­FAM101A (proximal to CCDC92), VEGFA, ADAMTS9, leading to systemic low-­g rade inflammation. In lipedema, this
LYPLAL1, and ANKRD55-­M AP 3K1 have been previously asso- enhanced permeability might be a contributing factor in the
ciated with waist-­to-­hip ratio [15–17]. Notably, these loci exhibit accumulation of LPS in AT, particularly in the gluteofemoral
stronger effects in women compared to men, highlighting po- region. This could exacerbate local inflammatory responses
tential sex-­specific genetic influences on body fat distribution. and contribute to fat accumulation and vascular dysfunction
Of note, two of these loci, namely, VEGFA and GRB14-­COBLL1, typical of lipedema. This model offers a different perspec-
were significantly associated with lipedema in an independent tive on the disease's origins, underscoring the importance of
case–control study that included clinically diagnosed lipedema understanding how systemic factors, such as gut health and

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the microbiota, might be driving local tissue remodeling in Citation Index, to identify studies related to the pathophysiol-
lipedema. Investigating these pathways could reveal new ther- ogy, management, and treatment of lipedema. Tailored search
apeutic avenues for addressing the root causes of this complex strategies were developed for each database to maximize re-
disease. trieval of relevant publications from 1940 to 2025. Search terms
included combinations of keywords such as “lipedema,” “obe-
Microvascular and lymphatic abnormalities have been also sity,” “adipose tissue expansion,” and “body fat distribution.”
proposed to be responsible for lipedema development and pro- Additional studies were identified by screening the reference
gression. Microangiopathy refers to small blood vessel abnor- lists of relevant reviews and primary research articles. Only
malities, including structural and functional impairments. In peer-­reviewed articles published in English were considered.
lipedema, this is hypothesized to manifest as capillary fragility, The search strategy aimed to capture both foundational studies
increased permeability, and dysregulated angiogenesis. Elevated and recent advances to provide a thorough and current under-
VEGF plasma levels, as reported by Siems et al., suggest a role standing of the topic.
in promoting aberrant angiogenesis [30]. VEGF-­related changes
may contribute to the development of abnormal vasculature and
increased capillary permeability, exacerbating tissue hypoxia 3   |   Clinical Presentation
and inflammation. Increased capillary numbers and dilation
have been reported in lipedema fat [31], suggesting defective The diagnosis of lipedema is primarily clinical and relies on
angiogenesis independent of obesity. Dysfunctional venoarterial specific criteria that include (i) bilateral, disproportionate fat
reflexes, often seen in lipedema patients, may further impair deposition primarily in the lower extremities and sometimes the
microvascular function, promoting edema and local inflamma- arms while sparing hands and feet; (ii) a granular or nodular
tion [2]. However, existing studies are limited by small sample texture in the affected areas; (iii) sensitivity to pressure in the
sizes, observational designs, and variability in histological cri- affected regions, with patients frequently reporting persistent
teria. In addition, similar vascular changes can occur in obesity pain and tenderness; (iv) capillary fragility resulting in bruis-
complicating differentiation. Functional studies assessing cap- ing even with minimal trauma; and (v) absence of pitting edema
illary permeability, angiogenesis, and endothelial cell behavior [1, 2] (Figure 1). Additionally, although not diagnostic, (i) sev-
in lipedema tissue are needed. In addition, longitudinal analysis eral tools can support lipedema evaluation such as imaging (e.g.,
would help determine whether microangiopathy precedes or is ultrasound, magnetic resonance imaging (MRI), and lympho-
secondary to other pathophysiological changes typical of the scintigraphy) [32–34], which may show thickened hypodermis
disease. without dermal backflow, helping to exclude lymphedema; (ii)
body composition analysis can reveal disproportionate limb fat;
This review aims to provide a comprehensive and up-­to-­date and (iii) functional assessments, such as quality of life or physi-
overview of lipedema. It will cover (i) the clinical presentation cal function scores, help assess disease impact and progression.
of lipedema and (ii) the emerging understanding of the patho-
physiological mechanisms that contribute to disease onset and Lipedema progresses through four clinical stages, each marked
progression and will address (iii) the diagnostic challenges and by distinct histopathological and immunological features [35].
the lack of standardized diagnostic criteria. The review will also In Stage 1, the skin appears smooth, and the subcutaneous AT
evaluate (iv) current treatment modalities—ranging from con- is soft and thickened, with small palpable nodules. Early adipo-
servative approaches such as compression therapy and manual cyte hypertrophy is present, although fibrosis is minimal. Stage
lymphatic drainage to more invasive options like liposuction— 2 is characterized by an uneven skin surface and the presence of
and (v) explore whether molecular and metabolic differences larger nodules, accompanied by the onset of interstitial fibrosis
between distinct AT depots, particularly abdominal versus fem- and progressive adipocyte enlargement. By Stage 3, pronounced
oral fat, parallel the depot-­specific characteristics observed in fat deposition leads to large lobules and visible limb deformities.
classical obesity. This comparative approach may yield insights Histologically, there is substantial adipocyte hypertrophy, dense
into the unique biology of lipedema fat and help distinguish it fibrotic matrix accumulation, and increased infiltration of alter-
from obesity-­related adiposity. natively activated (M2-­like) macrophages. Stage 4, also referred
to as lipo-­lymphedema, involves secondary lymphatic dysfunc-
Finally, this review aims to dispel (vi) common misconcep- tion, chronic edema, and dermal fibrosis.
tions about lipedema, such as its misclassification as lifestyle-­
induced obesity and to provide clear, evidence-­based guidance A hallmark feature of lipedema is the abnormal gynoid distri-
for both clinicians and patients. By increasing awareness and bution of subcutaneous AT, which predominantly affects hips,
fostering a deeper understanding of the disease, we hope to thighs, and legs and occasionally the arms while typically spar-
advance clinical recognition, promote earlier diagnosis, and ing the hands and feet. This symmetrical fat deposition results
ultimately improve outcomes for individuals living with in a disproportionate body shape that distinguishes lipedema
lipedema. from other AT disorders, as well as from obesity or lymphedema
(Table 1). We recently conducted a comprehensive evaluation
of body composition in women with obesity (Obese) (BMI:
2   |   Methods 30–49.9 kg/m2) and obesity and lipedema (Obese-­LIP). Study
subjects (Obese vs. Obese-­ LIP) were matched on age, BMI,
An extensive literature search was conducted using multiple and body fat percentage to assess total body fat mass and fat
electronic databases, including Medline, PubMed, EMBASE, distribution using multiple imaging methods [21]. Using dual-­
the Cochrane Register of Systematic Reviews, and the Science energy X-­ray absorptiometry, the study quantified total body fat

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FIGURE 1    |    Clinical presentation of lipedema in women. The image is kindly provided by the Lipedema Foundation.

as well as specific fat depots in the upper and lower body. In Women with lipedema have been anecdotally reported to have
Obese-­LIP, there was a pronounced increase in fat mass in the a lower risk of developing metabolic syndrome, prompting a re-
lower extremities, particularly in the thighs and legs, leading cent study to evaluate their metabolic function in comparison to
to a higher gynoid-­to-­android fat ratio compared to the control women with obesity and to women who are lean. Key metabolic
group (Obese). MRI provided further insight into fat distribution parameters included plasma lipid profiles to evaluate dyslipid-
by measuring abdominal and thigh fat depots. Although Obese-­ emia, an oral glucose tolerance test (OGTT) to assess glucose me-
LIP and controls shared similar abdominal subcutaneous AT tabolism, and a hyperinsulinemic–euglycemic clamp procedure
(ASAT) and intraabdominal AT (IAAT) volumes, significant to measure whole-­body insulin sensitivity. The three different
differences were observed in thigh subcutaneous AT (TSAT); groups were defined as (i) the Lean group: BMI 18.5–24.9 kg/m2 ,
the Obese-­LIP group had a markedly higher TSAT compared to fasting plasma glucose concentration < 100 mg/dL, 2-­h OGTT
controls, reinforcing the notion that lipedema is characterized plasma glucose concentration < 140 mg/dL, and HbA1c ≤ 5.6%
by lower body adiposity. MRI was used to evaluate intrahepatic (≤ 38 mmol/mol); (ii) the Obese group: BMI 30–49.9 kg/m2 ,
triglyceride (IHTG) content, which was found to be comparable fasting plasma glucose concentration < 126 mg/dL, 2-­h OGTT
between groups, suggesting that the increase in subcutaneous plasma glucose concentration < 200 mg/dL, and no diagnosis or
AT in lipedema is not exclusively attributable to an increase in features of lipedema; and (iii) the Obese-­LIP group: diagnosis
lower body fat. The same study also evaluated whether mod- of lipedema based on the criteria of Wold et al. [40], BMI 30–
erate diet-­induced weight loss impacted body fat in lipedema. 49.9 kg/m2 , fasting plasma glucose concentration < 126 mg/dL,
A relative decrease (12%) in total body fat mass, leg fat mass, and 2-­h OGTT plasma glucose concentration < 200 mg/dL. The
TSAT, and ASAT volumes was reported in the Obese-­LIP group. Obese and Obese-­LIP groups were matched on age, BMI, total
In individuals with classical obesity, intentional weight loss typ- body fat mass, and percent body mass as fat. The study found no
ically leads to about 75% of the weight reduction coming from a significant differences between the Obese and Obese-­LIP groups
decrease in body fat [36], across subcutaneous abdominal and in fasting plasma lipid profiles, glucose, insulin, and C-­peptide
thigh AT depots [37–39]. AT depots associated with lipedema are concentrations, as well as in 2-­h post-­OGTT plasma glucose lev-
thought to be resistant to negative energy balance, which may els, HbA1c, or hepatic insulin sensitivity. However, whole-­body
explain the limited reduction in lower body fat mass observed insulin sensitivity was approximately 48% greater (p < 0.05) in
after weight loss [40, 41]. However, the proportion of total fat the Obese-­LIP group compared to the Obese group, suggesting
mass loss from leg fat (~33%) in the Obese-­LIP group is consis- a relative preservation of insulin sensitivity in women with li-
tent with the ~30% contribution observed in women with obesity pedema. When compared with the Lean group, the Obese-­LIP
after similar weight loss [42, 43]. In addition, results from this group exhibited markers of metabolic dysfunction, including
study are in line with a previous study that found minimal (~3%) higher fasting plasma glucose, C-­peptide, triglyceride, and 2-­h
weight loss resulted in a decrease in leg fat mass in women with OGTT glucose concentrations, elevated HbA1c, lower HDL
obesity and lipedema without any difference in the reduction in cholesterol levels, and reduced hepatic and whole-­body insulin
leg fat mass compared to controls [44]. These results challenge sensitivity. These findings suggest that although women with li-
the prevailing notion that lipedema fat is resistant to negative pedema may have better insulin sensitivity than BMI-­matched
energy balance and highlight the importance of diet-­induced women with obesity, they still exhibit significant metabolic im-
weight loss in the medical management of individuals with both pairments when compared to metabolically healthy lean indi-
obesity and lipedema. viduals. This study provides critical insights into the metabolic

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TABLE 1    |    Comparison between lipedema, obesity, and lymphedema.

Lipedema Obesity Lymphedema

Definition A chronic condition A condition marked by excessive body fat A condition involving
characterized accumulation that exceeds normal levels lymphatic fluid
by abnormal fat accumulation in tissues,
accumulation, usually leading to swelling
in the lower extremities, due to impaired
with or without upper lymphatic drainage
extremity involvement
Primary Primarily the lower Can affect any area of the body, often Primarily affects the limbs
affected areas limbs but can affect in the abdomen, thighs, and hips (legs and arms) but can also
the upper limbs, but can be more generalized involve other areas (genital
typically symmetrical region and abdomen)
Fat distribution Symmetrical and Generalized fat distribution throughout the body, Localized fat accumulation
disproportionate often centered around the abdomen and thighs (often in the form of
fat distribution in hard, fibrotic tissue)
specific areas, often alongside swelling in
“column-­like” legs the affected limbs
Edema (fluid No significant fluid No significant edema, although fluid retention Severe, persistent edema
retention) retention unless may occur in cases of metabolic dysfunction due to fluid accumulation in
lymphatic dysfunction the affected limbs, with no
is present pitting edema in later stages
Pain Often painful, with Generally not painful unless there are Can be painful due to
tenderness or sensitivity associated conditions like joint pain, swelling, stiffness, and
to touch, especially metabolic disorders, or other complications discomfort, especially
in affected limbs in the later stages
Skin changes The skin may become Skin changes are generally absent unless there Thickened, hardened
fibrotic, and “skin are associated complications like cellulitis. skin (fibrosis), often with
dimpling” or “orange a peau d'orange (orange
peel” appearance peel) appearance
may occur in
advanced stages.
Lymphatic Normal lymphatic Normal lymphatic function unless Impaired lymphatic
function function initially associated with metabolic complications function due to blockage
but may be impaired or damage of lymphatic
in advanced stages, vessels, leading to swelling
contributing to
fluid retention
Cause Genetic, hormonal, and Genetic, environmental, and lifestyle Often secondary to cancer
vascular factors, often factors (diet, lack of exercise, etc.) treatments, infections,
worsened by obesity or trauma that damages
or physical inactivity lymphatic vessels;
primary lymphedema
may be genetic.
Management/ Weight management, Weight loss through diet, exercise, and behavioral Manual lymphatic drainage
treatment compression therapy, modifications; bariatric surgery in some cases (MLD), compression
structured exercise, garments, elevation, and
lymphatic drainage, surgical options (e.g.,
and liposuction in lymphatic bypass surgery or
advanced cases liposuction in some cases)
Progression Slowly progressive; Progressive if weight is not controlled but may Progressive if untreated,
may worsen with stabilize or improve with lifestyle changes with increased swelling,
weight gain, hormonal skin fibrosis, and
changes, or aging potential disability

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profile of lipedema, reinforcing the need for further research to medium diameter C/Aδ fibers, whereas vibration is mediated by
understand its implications for disease progression and poten- large diameter Aβ fibers [50]. The absence of abnormalities in
tial therapeutic interventions. quantitative sensory testing in women with lipedema implies
that sensory nerve conduction, stimulus detection, and trans-
Lipedema subcutaneous AT exhibits several unique character- mission were intact. Because central integration appeared un-
istics that distinguish it from other conditions characterized by affected in women with lipedema, it is plausible that systemic
fat expansion, such as obesity or lymphedema [2]. These fea- sensitization (e.g., from systemic inflammation or hormonal
tures, which highlight its distinct pathophysiology and clinical changes) may not play a primary role in lipedema pain. It has
presentation, include (i) nonpitting nature: Unlike lymphedema, been proposed that a more rigid ECM might amplify pressure
where swelling often creates pitting when pressed, lipedema transmission, leading to increased nociceptive fiber activation,
subcutaneous AT remains firm and nonpitting, reflecting lack despite the paradoxical expectation that tissue amassing would
of significant interstitial fluid accumulation; (ii) anatomical dampen pressure transmission [47]. An increased collagen den-
distribution: The abnormal adiposity characteristically stops sity or altered ECM composition, as recently reported [21], could
at the ankle, creating a distinct cuff-­like appearance at the create a stiffer microenvironment, enhancing pressure trans-
malleoli that highlights the condition's localized effect on the mission to nociceptive fibers (C/Aδ). ECM rigidity may also
lower extremities, sparing the feet, which is not typically seen impair lymphatic function, leading to localized edema and sub-
in generalized obesity; (iii) granular texture: Palpation reveals tle tissue ischemia, which might indirectly contribute to pain.
a “sand grain” feel, possibly due to the presence of micronodule Although the exact cause of lipedema pain remains speculative,
or macronodules within the AT; (iv) nodular phenotype: In more these findings narrow the scope of possible mechanisms. The
advanced cases, the subcutaneous AT may feel like “beans in a focus on ECM rigidity and mechanotransduction pathways of-
bag,” reflecting larger nodules or fibrotic changes in the tissue; fers promising avenues for future investigation.
and (v) easy bruising: Patients with lipedema are prone to easy
bruising, indicative of fragile subdermal capillaries [2]. This vas-
cular fragility may stem from microvascular dysfunction, such 4   |   Lipedema Pathogenesis and Pathophysiology
as weakened capillary walls, increased permeability, or altered
extracellular matrix (ECM) support. Telangiectasias or spider Lipedema was first described in the 1940s [40, 51]; however,
veins in lipedema-­affected areas further point to capillary fra- disease pathogenesis and pathophysiology remain poorly un-
gility and localized vascular abnormalities. These features are derstood continuing to pose challenges for diagnosis, manage-
in line with the proposed hypotheses of compromised microvas- ment, and treatment development. Several studies have now
cular integrity contributing to lipedema pathophysiology. consistently reported that AT expansion in lipedema is associ-
ated with adipocyte hypertrophy [31, 52]. Adipose-­derived stem
Pain or a sensation of heaviness in the affected extremities is cells (ADSCs) isolated from lipedema AT and grown in a 2D
a defining feature of lipedema, clearly distinguishing it from monolayer exhibit a higher adipogenic differentiation potential
conditions like obesity or lymphedema, which are typically non- compared to ASCs isolated from healthy individuals [53]. When
painful. Although the exact etiology of lipedema pain remains comparing lipedema and non-­lipedema ADSCs, transcriptional
unclear, it is believed to result from a combination of chronic in- profiling revealed differential expression of over 3400 genes,
flammation, mechanical stress, and possibly neuropathic alter- many of which are involved in ECM and cell cycle/proliferation
ations [45, 46]. A recent study by Dinnendahl et al. [47] assessed signaling. Of note, Bub1, also known as Benzimidazole 1, was
psychometric and/or sensory alterations in nonobese women found to be upregulated in lipedema ADSCs. Bub1 encodes a
with lipedema and in BMI-­matched controls according to the cell cycle regulator that is central to the kinetochore complex
protocol of the German Research Network on Neuropathic Pain and controls various histone proteins involved in cell prolifer-
[48]. The study found that all participants scored within normal ation [54]. Downstream signaling analysis of lipedema ADSCs
ranges for depression, anxiety, and stress (measured with the showed enhanced activation of histone H2A, a critical driver of
DASS questionnaire), suggesting that stress did not significantly cell proliferation and a target of Bub1. Notably, hyperprolifera-
influence their pain experiences. However, lipedema patients tion in lipedema ADSCs was suppressed by the serine/threonine
reported a significantly lower quality of life in terms of social, kinase inhibitor 2OH-­BNPP1, which is a Bub1 inhibitor, and fol-
mental, and physical functioning, consistent with previous lowing CRISPR/Cas9-­mediated depletion of the Bub1 gene [55].
findings [49]. Additional results from the study revealed altered A different study, using an elegant and comprehensive multio-
sensory thresholds, further differentiating lipedema from obe- mics approach, reported a localized reduction in inflammatory
sity and lymphedema. Specifically, the z-­score for pressure pain signaling coupled with enhanced mitochondrial function in
threshold (PPT), measured at the quadriceps femoris and thenar lipedema AT [56]. In addition, metabolomic and lipidomic pro-
eminence, was reduced by twofold, aligning with the reported filing showed broader metabolic disturbances, including altered
tenderness and discomfort in the affected extremities. The z-­ levels of glutamic acid, glutathione, and sphingolipids [56].
score for vibration detection threshold (VDT), assessed at the
patella and the processus styloideus ulnae, was increased by two Lower body fat accumulation (gluteofemoral obesity) is usu-
and a half times, indicating altered somatosensory processing ally associated with protective effects against cardiovascular
and sensory nerve dysfunction. This change may contribute to disease and type 2 diabetes mellitus when adjusted for total fat
the characteristic sensations of heaviness and discomfort ob- mass [57]. Conversely, upper body fat accumulation, commonly
served in women with lipedema. Notably, both thresholds were referred to as abdominal obesity, is strongly linked to an ele-
selectively altered in the affected thigh but not in the unaffected vated risk of cardiovascular disease [58], insulin resistance [59],
hand. Pressure pain is hypothesized to be mediated by small or type 2 diabetes mellitus [60], and even all-­cause mortality [61].

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FIGURE 2    |    VEGF-­C/VEGFR3 signaling pathway regulates adiposity. (A) VEGF-­C binds to VEGFR3 activating MAPK/ERK and PI3K/AKT
signaling pathways important for lymphangiogenesis. Altered VEGF-­C/VEGFR3 axis due to either (B) VEGFR3 tyrosine kinase inactivation or (C)
blockade of VEGF-­C (or VEGF-­D) affects AT remodeling in preclinical mouse models.

Lower body fat exhibits slower lipid turnover, an enhanced ca- lymphatic and vascular systems rather than the metabolic dys-
pacity to accommodate redistributed fat in response to weight function typically observed in classical obesity. Lipedema TSAT
gain [62]. Abdominal fat depots, instead, are marked by rapid showed reduced expression of genes (i) VEGFC, vascular endo-
uptake of diet-­derived lipids and high lipid turnover [63, 64], thelial growth factor (VEGF)–C, and its cognate receptor FLT4
which is readily stimulated by adrenergic receptor activation (protein is VEGFR-­3), which have canonical roles in blood and
[65]. Lower body adiposity also demonstrates fewer signs of in- lymphatic vessel proliferation and function [69–71]; (ii) CLD11,
flammatory insult, reinforcing its protective role in metabolic claudin 11, which regulates lymphatic valve development [72];
health [57, 66, 67]. Pinnick et al. [66] have elegantly shown that (iii) SOX17, which is important for endothelial regeneration fol-
functional differences between upper and lower body adipose lowing injury [73, 74]; (iv) THBS4, thrombospondin 4, which
depots are regulated by site-­specific developmental genes in- regulates endothelial ECM interaction [75]; and (vi) ANG, angio-
cluding members of the homeobox (HOX) family (e.g., SHOX2 genin, which regulates angiogenesis [76]. AT expansion in pre-
and IRX2), and T-­box genes (e.g., TBX15 and TBX5) [66]. These clinical models of obesity is associated with lymphatic vascular
transcriptional regulators are generally involved in early em- disorganization, as well as irregular lymphatic branching and
bryonic development, body patterning, and cell specification. rarefication [77–79], resulting in impaired lymphatic drainage,
The HOX genes may regulate differentiation of adipocytes [68]. interstitial fluid stasis, and immune cell trapping. Conversely,
HOXA6, HOXA5, HOXA3, IRX2, and TBX5 are highly expressed deletion of key lymphangiogenic genes in preclinical models is
in subcutaneous abdominal AT, whereas HOTAIR, SHOX2, and often associated with abnormal AT expansion and fat accumula-
HOXC11 are instead highly expressed in the gluteofemoral AT tion in tissues. VEGFR3 is a tyrosine kinase receptor encoded by
[66]. These genes are regulated through epigenetic mechanisms the FLT4 gene that regulates lymphangiogenesis [80]. VEGF-­C
however, the meaning of these regional signatures of develop- binding to VEGFR3 induces receptor dimerization, autophos-
mental genes remains unclear, and whether they actively influ- phorylation, and internalization and activates PI3K/AKT and
ence functional characteristics of AT remains to be determined MAPK/ERK signaling pathways important for lymphangiogen-
in lipedema fat. esis [81] (Figure 2a). Our group and others have shown that aber-
rant VEGFR3 signaling in preclinical models due to a mutation
Our recent study investigated whether the molecular and meta- inactivating the receptor tyrosine kinase is associated with leaky
bolic differences between abdominal and femoral AT depots in lymphatics and fat accumulation in tissues [82, 83] (Figure 2b).
lipedema resemble those observed in classical obesity [21]. Bulk In a different study, the blockade of circulating VEGF-­C and
RNA sequencing compared TSAT and ASAT in women with VEGF-­D in mice was associated with metabolically healthy AT
obesity and lipedema (Obese-­LIP). The study found that TSAT expansion during a high-­fat diet [84], mimicking key clinical
exhibits a downregulation in biological pathways related to de- features of lipedema (Figure 2c). Elevated levels of circulat-
velopmental programming and specification that included genes ing VEGF-­C85 are reported in lipedema compared to age-­and
such as HOXA3, HOXA5, and IRX2 and in pathways related to BMI-­matched controls, but it is unclear whether VEGFR3 sig-
lymph/angiogenesis. In contrast, TSAT showed an upregulation naling remains functional. The combination of downregulated
of pathways related to immune response and inflammation. lymphangiogenic/angiogenic genes in the Obese-­LIP cohort is
These findings suggest that although TSAT in lipedema may be in line with the clinical features of interstitial fluid accumu-
inflammatory in nature, its metabolic profile and pathophysio- lation [86], along with increased tissue sodium and adipose
logical mechanisms could differ significantly from fat expansion deposition [87–89] commonly observed in lipedema, suggest-
in classical obesity. Specifically, lipedema-­related fat expansion ing that compromised lymphatic function plays a central role
may be driven more by structural and functional changes of the in the disease's pathophysiology. This dysfunction likely leads

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to a cycle of fluid retention and localized swelling, which wors- the structural properties of connective tissues, which may con-
ens as lymphatic bulk transport becomes increasingly impaired tribute to the clinical features of lipedema.
[90–93]. However, reports of lymphatic anatomy in lipedema are
inconsistent, ranging from normal [85] to an increase in lym- Lipedema increases the risk of developing VTE [5] compared to
phatic vessel area [31] or dilated lymphatics [34] to lymphatic BMI-­matched control, supporting the hypothesis that elevated
microaneurysms [94]. These discrepancies could be related to BMI alone may not be the primary driver of thrombosis [103].
differences in the methods used to assess lymphatic anatomy Recent analyses of platelet transcriptomes from patients with li-
and function, inadequate numbers of participants to detect sta- pedema as well as from those with lymphedema have revealed
tistically significant effects, and inconsistent criteria to match important differences in gene expression that may offer valuable
patients and controls. insights into the distinct pathophysiological mechanisms un-
derlying each condition. The transcriptomic profile of platelets
Alterations in the function of both vascular and lymphatic ves- from lipedema patients showed a greater expression of genes
sels play a crucial role in the accumulation of immune cells and related to glycolipid modifications, protein dephosphorylation,
inflammatory cytokines within affected tissues. These changes and cytoplasmic protein translation. In contrast, platelets from
disrupt normal fluid balance and promote a pro-­inflammatory patients with lymphedema displayed reduced signals for angio-
environment, which in turn exacerbates tissue inflammation genesis and inhibited mitosis [6]. Elevated levels of platelet fac-
[77]. Ultrastructural analysis by electron microscopy has re- tor 4 (PF4/CXCL4) were reported in circulating blood plasma
vealed endothelial abnormalities that may underlie adipocyte exosomes of patients with lipedema [104]. PF4 is a chemokine re-
hypertrophy, disrupted calcium metabolism, and macrophage leased by activated platelets, involved in coagulation, inflamma-
infiltration [95]. These findings suggest that endothelial dysfunc- tion, and vascular remodeling [105, 106]. Elevated PF4 levels in
tion, marked by increased endothelial proliferation and pericyte blood plasma exosomes strongly correlate with lymphatic dys-
density, contributes to the pathological remodeling of lipedema-­ function, making it a reliable indicator of lymphatic pathology.
associated AT [31, 96]. It has been hypothesized that the con- This finding not only supports the hypothesis that lymphatic de-
tinuous accumulation of immune cells, coupled with sustained fects might be an important contributor to lipedema pathophys-
cytokine release, perpetuates a cycle of localized inflammation, iology but also provides a potential diagnostic tool.
potentially contributing to tissue damage and the progression of
lipedema [1]. In line with this, it was recently reported that the
Obese-­LIP cohort exhibits increased pro-­inflammatory M1-­like 5   |   Treatment Options for Lipedema
macrophage infiltration in TSAT assessed by flow cytometric
analysis and increased expression of genes involved in inflam- In the absence of an etiological treatment, a multidisciplinary
mation, including macrophage and T cell markers, as well as approach is essential to optimize outcomes for patients with
markers of T cell activation compared to ASAT [21]. However, lipedema. Current strategies focus on alleviating symptoms,
these findings are in conflict with Wolf et al [97] reporting a shift improving function, and preventing disease progression rather
in AT macrophages toward a more immunosuppressive M2-­like than addressing the root cause of the condition. Collaboration
state characterized by high levels of immunosuppressive mark- between healthcare providers, including specialists in vascular
ers CD206, CD163, and Clever-­1. The differences in results could medicine, physical therapy, psychology, and surgery, is crucial
be due to differences in experimental design and methodology to address the complex needs of these patients [7, 107].
to profile macrophages and stage of lipedema.

A compelling hypothesis for the pathogenesis of lipedema sug- 5.1   |   Compression Therapy and Complex
gests that improper remodeling of the ECM could play a central Decongestive Lymphatic Therapy
role in abnormal AT expansion. The composite expression of
genes encoding 12 collagen isoforms and expression of key regu- Compression therapy and complex decongestive lymphatic
lators of AT fibrosis and fibrogenesis—such as LOX1, SEMA3C, therapy (CDP) represent cornerstone interventions in improv-
CCN2, and VCAN—were all greater in TSAT than ASAT [21]. ing symptoms and enhancing the quality of life. Compression
These findings are consistent with prior reports of a fibrotic garments help alleviate the tenderness and heaviness of affected
profile in lipedema fat [35, 52]. In particular, the uncoupling limbs by improving tissue support, venous return, and lymphatic
of the matrix metallopeptidase 14, MMP-­14-­caveolin 1 axis in drainage, which overall reduce limb swelling. CDP instead is
adipocytes may disrupt normal matrix processing, leading to particularly effective for patients with lipo-­ lymphedema—a
aberrant ECM remodeling [98]. This disruption could drive the common complication of lipedema involving concurrent lym-
hypertrophic expansion of subcutaneous AT, contributing to phatic dysfunction. CDP consists of (i) manual lymph drainage
the abnormal fat deposition characteristic of lipedema. Women (MLD), a specialized massage technique to stimulate lymphatic
with lipedema often report symptoms such as joint hypermobil- flow and reduce swelling; (ii) multilayered and multicomponent
ity [99], reduced skin elasticity [100], and aortic stiffness [101], compression bandaging, essential for maintaining postdrainage
all of which suggest a potential involvement of connective tis- volume reduction and improving venous return; and (iii) skin-
sue dysfunction. A reduction in the expression of the ELASTIN care, which prevents skin breakdown and infections that may
gene was found in lipedema TSAT compared to ASAT [21]. exacerbate symptoms. Intermittent pneumatic compression can
Interestingly, individuals with Williams syndrome, a connec- enhance the effects of CDP by improving venous flow and de-
tive tissue disease where a deletion of the elastin gene has been creasing lymph production [108]. A clinical study comparing
implicated [102], develop a lipedema-­like phenotype in the lower CDP with and without IPC demonstrated significant lower limb
extremities. These observations point to possible alterations in volume reduction in both groups, with reductions of 6.2% and

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8.9%, respectively, highlighting the utility of IPC as a comple- body fat mass, leg fat mass, TSAT volume, and ASAT volume in
mentary therapy, particularly for patients requiring additional women with obesity and lipedema [21] and that the proportion
volume reduction. of total fat mass loss from leg fat (~33%) in the Obese-­LIP group
is consistent with the ~30% contribution previously observed
in women with obesity after similar weight loss [42, 43]. These
5.2   |   Structured Exercise results align with earlier studies showing that even minimal
weight loss (~3%) in women with obesity and lipedema resulted
Although fat volume remains unaffected, strength training in a significant reduction in leg fat mass, comparable to women
and low-­impact activities are reported to alleviate pain and without lipedema [44]. Therefore, these results contradict the
improve mobility [109, 110]. A consensus statement from the dogma that lipedema fat is resistant to negative energy balance
Italian Society of Motor and Sports Sciences (SISMeS) and the supporting the importance of diet-­induced weight loss in the
Italian Society of Phlebology (SIF) emphasizes the importance medical management of people with obesity and lipedema.
of structured exercise as a key component in the conservative
management of lipedema [111]. According to this consensus, Women with lipedema exhibit relatively preserved insulin sen-
personalized exercise programs that integrate muscle strength- sitivity compared to BMI-­matched women with obesity [21].
ening and flexibility training are essential for addressing the Furthermore, moderate diet-­induced weight loss (~9%) in the
multifaceted challenges of lipedema. These programs should be Obese-­LIP group led to significant metabolic improvements,
tailored to each individual's disease stage and physical capacity, including increased hepatic and whole-­body insulin sensitivity,
ensuring a gradual and safe progression to optimize therapeutic alongside reductions in IHTG content and plasma LDL choles-
outcomes. terol concentration. These beneficial changes are key factors in
reducing the risk of type 2 diabetes and cardiovascular disease.
Structured exercise training, particularly water-­based exercise, Collectively, these results provide a mechanistic explanation
has been shown to offer both physiological and psychological for the lower incidence of type 2 diabetes observed in women
benefits for individuals with lipedema because of its low-­impact with lipedema compared to those with obesity alone [118, 119].
nature, which reduces joint stress while promoting lymphatic Additionally, the study highlights the therapeutic metabolic
drainage, enhancing functional mobility, and providing joint re- benefits of moderate weight loss in women with lipedema, em-
lief. These effects are crucial in managing lipedema symptoms, phasizing its role in improving insulin sensitivity and mitigating
which often include pain, limited mobility, and fluid reten- cardiometabolic risk factors.
tion. Additionally, such exercise aids in weight control, muscle
strengthening, and improving flexibility. Beyond its physical Diet-­induced weight loss (~9%) did not significantly alter the
benefits, structured exercise also contributes significantly to expression of genes associated with inflammation or ECM re-
mental well-­being. Research has demonstrated improvements modeling and lymphatics in either ASAT or TSAT [21]. Notably,
in self-­esteem, mood, and overall quality of life, which are es- weight loss was linked to the upregulation of genes involved in
pecially important for individuals with lipedema who may face angiogenesis and vascular remodeling specifically in TSAT. The
emotional challenges related to the visible effects of the con- observed increase in angiogenic and vascular remodeling in
dition [112]. Incorporating exercise into a comprehensive care TSAT post-­weight loss—without corresponding changes in lym-
plan can address both the physical and psychological aspects of phatic gene expression—may represent an adaptive mechanism
the disease, promoting long-­term adherence to treatment and to support tissue repair or restructuring. This warrants further
improving overall patient self-­management [113]. exploration into its functional significance in the context of li-
pedema and its potential impact on therapeutic strategies. Diet-­
Despite these promising interventions, there is a critical need induced weight loss in women with lipedema has been reported
for large-­scale studies to establish standardized exercise pre- to improve pain and enhance quality of life [114–116]. Although
scriptions tailored to the various stages of lipedema. Such re- the underlying mechanisms remain poorly understood, ex-
search would enhance our understanding of optimal exercise cess body weight likely contributes to joint stress, heightened
strategies, ensuring that treatment plans are evidence-­based, inflammation, and increased mechanical strain, all of which
individualized, and effective in improving the quality of life for exacerbate discomfort and hinder mobility. Therefore, weight
individuals affected by this often misunderstood condition. management should be emphasized as a cornerstone of a multi-
disciplinary approach to lipedema treatment to enhance overall
well-­being and mitigate disease progression.
5.3   |   Nutritional Approaches

It is widely believed that the AT depots affected by lipedema are 5.4   |   Surgical Options
resistant to negative energy balance, making it difficult to reduce
lower body fat mass through weight loss. However, recent find- Liposuction is the primary surgical intervention for managing
ings challenge this assumption and provide new insights into the lipedema, particularly in advanced cases where conservative
role of weight management in lipedema [44, 114–116]. Positive measures are insufficient. The two most employed methods—
effects on lipedema body composition and diet-­induced weight tumescent anesthesia (TA) liposuction and water-­ a ssisted
loss have been reported in one case study [117] and interven- liposuction (WAL)—are tailored to address the unique charac-
tional studies [44, 116] using a ketogenic, low-­carbohydrate diet teristics of lipedema fat while minimizing complications [120].
or a Mediterranean diet. A recent study found that diet-­induced In TA, a solution containing saline, local anesthetics (e.g., li-
weight loss induces a similar (~12%) relative decrease in total docaine), and epinephrine is injected into the subcutaneous

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tissue causing swelling of fat cells for easier removal and con- In addition to advancing research and diagnostics, clinician
striction of blood vessels, which reduces bleeding. Fat is then training programs should be implemented to enhance the abil-
gently suctioned from the targeted areas using blunt microcan- ity of healthcare providers to differentiate lipedema from other
nulas. TA presents many advantages including minimal blood conditions such as obesity, lymphedema, and metabolic disor-
loss due to vasoconstriction from the tumescent solution and ders. Equipping physicians, endocrinologists, dermatologists,
enhances precision and safety, particularly in delicate areas. vascular specialists, and other healthcare professionals with the
WAL consists of a high-­pressure controlled spray of tumes- knowledge and tools to recognize lipedema will lead to earlier
cent fluid that dislodges fat cells from surrounding connec- interventions and improved patient outcomes.
tive tissues. In WAL, fat and tumescent fluid are aspirated
simultaneously. The water jet gently separates fat from tissues, Multidisciplinary care must also be prioritized to provide
preserving lymphatic structures and reducing postoperative comprehensive management strategies for individuals with li-
swelling, ideal for areas with dense fibrous fat or those prone pedema. This includes conservative therapies such as compres-
to damage during traditional methods. Unlike traditional li- sion therapy, manual lymphatic drainage, and exercise programs
posuction, both TA and WAL liposuction use local anesthet- tailored to lipedema patients, as well as surgical interventions
ics, avoiding the risks associated with general anesthesia, and like liposuction for advanced cases. Additionally, addressing the
focus on lymphatic sparing techniques, crucial for lipedema psychological burden of lipedema through mental health sup-
patients to prevent secondary lymphedema. Both methods port, patient education, and community-­based resources will
have their merits, and the choice often depends on the sur- be essential in improving quality of life. Developing specialized
geon's expertise, the patient's condition, and the goals of treat- training programs and establishing standardized treatment
ment. Long-­term management postsurgery typically includes guidelines will ultimately ensure that individuals affected by
compression therapy and lifestyle adjustments to maintain re- lipedema receive the appropriate care and support.
sults and prevent progression [120].

Author Contributions
6   |   Conclusions: Raising Awareness About
Vincenza Cifarelli conceived and wrote the article.
Lipedema

Lipedema is a chronic, progressive disease that affects millions Acknowledgments

of individuals worldwide, predominantly women, yet it remains This study was supported by the Lipedema Foundation and Saint Louis
widely underdiagnosed and misunderstood. Characterized by University startup fund. The Lipedema Foundation generously pro-
the disproportionate accumulation of subcutaneous fat in the vided the image of patients.
lower and sometimes upper extremities, lipedema is often mis-
taken for general obesity or lymphedema, leading to misdiag- Conflicts of Interest
nosis and delayed interventions. The lack of awareness among V.C. serves on the Scientific Advisory Board for HAB Nutritional
healthcare providers and the general public results in signifi- Center. No other potential conflicts of interest relevant to this article
cant delays in receiving appropriate care, exacerbating symp- were reported.
toms such as pain, osteoarthritis, and mobility limitations.
Without timely recognition and management, lipedema can se-
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