Current Obesity Reports (2024) 13:667–679

https://doi.org/10.1007/s13679-024-00579-8

REVIEW

The Role of Physical Exercise as a Therapeutic Tool to Improve

Lipedema: A Consensus Statement from the Italian Society of Motor
and Sports Sciences (Società Italiana di Scienze Motorie e Sportive,
SISMeS) and the Italian Society of Phlebology (Società Italiana di
Flebologia, SIF)
Giuseppe Annunziata1,2 · Antonio Paoli3,4 · Vincenzo Manzi5 · Elisabetta Camajani6 · Francesco Laterza5 ·
Ludovica Verde7 · Xavier Capó8 · Elvira Padua6 · Antonino Bianco4,9 · Attilio Carraro4,10 ·
Angela Di Baldassarre4,11 · Laura Guidetti4,12 · Samuele Maria Marcora4,13 · Stefania Orrù4,14 ·
Antonio Tessitore4,15 · Roberto Di Mitri16,17 · Lucia Auletta17,18 · Angela Piantadosi17,19 · Mario Bellisi17,18 ·
Edmondo Palmeri17,18 · Silvia Savastano20,21 · Annamaria Colao20,21,22 · Massimiliano Caprio6,23 ·
Giovanna Muscogiuri20,21,22 · Luigi Barrea5,21

Accepted: 17 June 2024 / Published online: 3 July 2024

© The Author(s) 2024

Abstract
Purpose of Review This consensus statement from the Italian Society of Motor and Sports Sciences (Società Italiana di
Scienze Motorie e Sportive, SISMeS) and the Italian Society of Phlebology (Società Italiana di Flebologia, SIF) provides
the official view on the role of exercise as a non-pharmacological approach in lipedema. In detail, this consensus statement
SISMeS - SIF aims to provide a comprehensive overview of lipedema, focusing, in particular, on the role played by physical
exercise (PE) in the management of its clinical features.
Recent Findings Lipedema is a chronic disease characterized by abnormal fat accumulation. It is often misdiagnosed as
obesity, despite presenting distinct pathological mechanisms. Indeed, recent evidence has reported differences in adipose
tissue histology, metabolomic profiles, and gene polymorphisms associated with this condition, adding new pieces to the
complex puzzle of lipedema pathophysiology. Although by definition lipedema is a condition resistant to diet and PE, the
latter emerges for its key role in the management of lipedema, contributing to multiple benefits, including improvements in
mitochondrial function, lymphatic drainage, and reduction of inflammation.
Summary Various types of exercise, such as aquatic exercises and strength training, have been shown to alleviate symptoms
and improve the quality of life of patients with lipedema. However, standardized guidelines for PE prescription and long-term
management of patients with lipedema are lacking, highlighting the need for recommendations and further research in this
area in order to optimise therapeutic strategies.

Keywords Lipedema · Obesity · BMI · Hormones · Physical activity · Sport

Introduction

Lipedema is a chronic disease of the subcutaneous adipose

tissue (SAT) that involves pathological proliferation of adi-
Giuseppe Annunziata, Antonio Paoli and Vincenzo Manzi equally pocytes, especially, but not exclusively, in the lower extremi-
contributed to this work as co-first. ties [1], resulting in a disproportion between the upper and
lower parts of the body. In some cases, lipedema may also
Massimiliano Caprio, Giovanna Muscogiuri and Luigi Barrea affect the arms, with a clear dividing line between the hands
equally contributed to this work as co-last.
and feet (the cuff sign) [2]. On objective clinical examina-
Extended author information available on the last page of the article tion, five different types of lipedema were identified on the

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668 Current Obesity Reports (2024) 13:667–679

basis of the location of SAT accumulations, while a staging To date, the diagnosis of lipedema is still not well stand-
of lipedema (stages I-IV) was created on the basis of struc- ardised and appears challenging, frequently leading to a
tural changes in the skin [2] (Fig. 1). misdiagnosis of obesity [2]. Several clinical considerations
Lipedema is characterized by the symmetrical expansion suggest, however, that although lipedema and obesity may
of the subcutaneous adipose tissue, commonly affecting the coexist, this relationship is not a prerogative, as subjects
lower extremities and, in some cases, the upper extremities with normal weight may also be affected by lipedema. In
[3]. Such SAT expansion, accompanied by increased lipid contrast to obesity, indeed, lipedema is mostly characterised
accumulation within the adipocyte (hypertrophy), is respon- by a resistance to losing weight (and fat mass) by resort-
sible for both the recruitment of immune cells and the rear- ing to extreme diets or intense exercise [1, 6], which can
rangement of the extracellular matrix. These two events result be frustrating for women with this condition. However, it
in the beginning of inflammation and in the promotion of is speculated that this resistance to diet may have been an
pathogenic alterations in vascular and lymphatic functions, evolutionary advantage in women with lipedema since, dur-
which, in turn, result in the accumulation of interstitial fluid ing periods of famine, they may have accumulated fat (as
and expansion of the interstitial space [2]. an energy reserve) to maintain fertility and the ability to
It should be remembered that lipedema also needs to be breastfeed; this, therefore, would have allowed a continua-
interpreted as a pathology of endocrine interest. In addition tion of the species [7].
to a genetic predisposition, in fact, lipedema initiates due to It must be reported that the inability to lose weight
significant hormonal alterations mainly associated with an through diet can lead to eating disorders and increase the
abnormal expression of estrogen receptors (ERs) in adipose risk of suicide in patients with lipedema [8]. Several com-
tissue, in particular characterised by a downregulation of plications associated with lipedema, indeed, impair the
ER-α and an upregulation of ER-β in the affected areas [4, quality of life of patients suffering from it, including the
5]. The altered estrogenic environment fosters aberrant lipid abnormal accumulation of fat in the lower extremities
storage patterns, leading to a notable increase in adipocyte that alters the gait pattern [9], misaligning the joint axes and
size. This phenomenon, coupled with the preferential depo- causing a valgus deformity of the knee joint [10], and the
sition of fat in specific regions, accentuates the characteristic development of lymphoedema observed in some cases of
appearance of lipedema adipose tissue. This suggests the lipedema, leading to further mobility limitations, further wors-
need for a comprehensive view of the pathology and, there- ening patients' quality of life [11]. In previous studies, it was
fore, the use of multidisciplinary treatments. observed that leg discomfort, consisting of widespread pain,

Fig. 1  Types and stading of

lipedema. Abbreviation: SAT,
subcutaneous adipose tissue
Current Obesity Reports (2024) 13:667–679 669

tenderness, and painful anguish, was a prominent symptom confused with this metabolic disease [20–22]. In fact, this
in about half of the subjects with lipedema [6]. Other nota- condition differs from severe obesity in several aspects: (i) it
ble signs and symptoms that are more frequent in patients mainly affects women [23, 24], (ii) although many patients
with stage 2 and 3 lipedema than in stage 1 are obstructive are with overweight, many women with lipedema have a
sleep apnoea, blood clots, nausea, constipation, increased normal weight and present disproportionately enlarged lower
body temperature, flu-like symptoms, and burning skin pain extremities, (iii) and patients with overweight and lipedema
[12]. This condition, therefore, leads people to suffer from do not see any decrease in the size of the lower extremities
a low quality of life and develop psychological signs of with diet or weight loss [24]. This evidence suggests, there-
depression [13]. fore, that other parameters besides body weight and body
From a nutritional point of view, it has been previ- mass index (BMI) need to be monitored for early assessment
ously reviewed that studies on different types of diets can and management of patients with lipedema, since this condi-
shed light on this aspect of the disease [7]. In general, a tion can also occur in women with normal body weight. As
ketogenic dietary approach (i.e., low-carbohydrate high-fat well, in addition to BMI, other parameters should be taken
diets) appears to be effective in promoting weight (and fat into account for the differential diagnosis.
mass) loss in women with lipedema, acting through some
metabolic changes (i.e., reduction of basal insulin levels and Beyond the BMI
HoMA-IR index), and reducing inflammation and oxidative
stress [2, 14, 15]. In the case of lipedema, BMI may not accurately reflect
This implies, therefore, the need to find effective strate- the adiposity index. This is because BMI is based only on
gies for the management of women with lipedema in order the measurement of weight and height, without distinguish-
to improve both nutritional status and quality of life. In this ing between different types of adipose tissue or consider-
sense, many conservative treatments to alleviate symptoms ing the distribution of body fat. Therefore, in the context of
and increase quality of life include physical exercise (PE) lipedema, it is important to consider other measurements and
[16], which, however, is not always feasible due to the debili- clinical evaluations to accurately assess the body composi-
tating clinical condition. This may lead to muscle weakness, tion and general health of the patient, as discussed above. In
as reported in subjects with lipedema [16]. However, it is this sense, Brenner and colleagues conducted a retrospective
not fully clear whether the observed weakness is part of study on more than 600 women with a diagnosis of lipedema,
the pathology or is caused by decreased physical activity proposing the use of the Waist-to-Height Ratio (WHtR) as an
(PA). Furthermore, decreased PA has been correlated with alternative [25]. The authors pointed out that WHtR is inde-
increased symptom complaints, muscle weakness, fatigue, pendent of total weight, thereby not influenced by variations
and weight gain [16]. in leg or arm weight, and offers a more accurate reflection
This consensus statement from the Italian Society of of nutritional condition, resulting in a more suitable measure
Motor and Sports Sciences (Società Italiana di Scienze Moto- for assessing metabolic risks in research studies. The main
rie e Sportive, SISMeS) and the Italian Society of Phlebol- aim of Brenner’s study was the identification of WHtR
ogy (Società Italiana di Flebologia, SIF) provides the offi- values in patients with lipedema who were also classified
cial view on the role of exercise as a non-pharmacological as with overweight or obesity. In addition, they compared
approach in lipedema. In detail, this consensus statement the WHtR values with those of the general population [25],
SISMeS—SIF aims to summarise the available literature using a German study of over 5000 women as a reference
in order to provide an overview of lipedema, its complica- [26]. The study highlighted a limitation in using BMI alone
tions, and phenotypes, focusing on the role that PA plays in to evaluate patients with lipedema, suggesting that relying
improving the clinical features of this disabling condition, solely on BMI not only overestimates metabolic risks but
as well as to identify the optimal prescription of PA for this can also result in misdiagnosing obesity due to the dispro-
class of patients. portionate distribution of SAT characteristic of lipedema.
The authors, thus, recommended using WHtR as an alternative
measure to evaluate or rule out obesity in lipedema patients.
Lipedema: Not Just a BMI Matter They further suggested that if both BMI and WHtR are uti-
lized, a normal WHtR alongside an increased BMI indirectly
Lipedema is often confused with obesity and has not, until indicates a disproportionate increase in SAT. However, they
now, been considered a distinctive phenotype of obesity. clarify that neither BMI nor WHtR are diagnostic tools for
Genetic analyses may, therefore, be crucial to distinguish lipedema [25].
lipedema from genetic obesity, primary lymphoedema and Having clarified that the use of BMI may be inadequate,
lipodystrophies [17–19]. It is important to note, however, or at least inaccurate, for subjects with lipedema, interest-
that lipedema can coexist with obesity, but it should not be ing evidence adds a new piece to the complex puzzle of the
670 Current Obesity Reports (2024) 13:667–679

pathophysiology of lipedema, suggesting the existence of into obesity (BMI 30.0 to 40.0 kg/m2, Ob) and non-obesity
common clinical features in this class of patients that are (BMI 20.0 to 30.0 kg/m2, N-Ob) [27]. Histologically, authors
independent of body weight and BMI, including SAT his- observed heterogeneity in adipocyte size in both Ob and
tology [27], metabolomic profile [28], and gene polymor- N-Ob lipedema groups, but significant increased cell size
phisms [29] (Fig. 2). in the N-Ob lipedema (NOL) group compared to the N-Ob
control (NOc) group. This suggests that adipocyte size
Histological Differences in SAT heterogeneity is not a reliable marker of lipedema fat, but
adipocyte hypertrophy in lipedema occurs independently of
As already mentioned, the main characteristic of lipedema is obesity. Furthermore, an increase in macrophages in both
the symmetrical expansion of the SAT, which is commonly skin and fat was observed in the NOL group, which resem-
found in the lower limbs and, in some cases, in the upper bles the results in non-lipedema obesity. The presence of
limbs [3]. This expansion of the SAT, together with a hyper- crown-like structures (CLS) in lipedema fat, typically indic-
trophic condition, results in both the recruitment of immune ative of metabolically poor tissue, was noted regardless of
cells and the rearrangement of the extracellular matrix, obesity status. Angiogenesis was observed in the skin of
which, taken together, are responsible for the establishment NOL women, with increased blood vessel numbers in the
of an inflammatory state and the promotion of pathogenic papillary dermal layer, possibly indicating underlying angio-
changes in the vascular and lymphatic functions; these, in genesis in lipedema. In addition, NOL women exhibited sig-
turn, promote the accumulation of interstitial fluid and the nificant capillary dilation in fat compared to controls, along
expansion of the interstitial space [2]. with evidence of angiogenesis and fibrosis. The authors
Al-Ghadban and colleagues conducted a study to com- also noted variations in lymphatic vessel morphology with
pare lipedema SAT to non-lipedema SAT in groups of 49 Ob-lipedema (OL), women showing an increase in vessel
women (30 with lipedema and 19 without), categorised size and area/perimeter ratio. Overall, the study provides

Fig. 2  Lipedema, beyond

BMI. The main features
commonly present in patients
with lipedema, independently
of body weight and BMI.
Abbreviation: CLS, crown-like
structures; His, Histidine; Phe,
Phenylalanine; Gly, Glycine;
Gln, glutamine; IL, interleukin
Current Obesity Reports (2024) 13:667–679 671

insights into the histological characteristics of lipedema fat, the presence of high pyruvate levels in lipedema could indi-
highlighting similarities and suggesting potential markers cate an alteration in the citric acid cycle. If pyruvate is not
for disease progression [27]. utilized effectively in the Krebs cycle, it accumulates, caus-
ing its high levels. The researchers also observed low lev-
Metabolomic els of acetic acid, glycine, glutamine, and lactic acid in the
lipedema group, suggesting dysfunction in various metabolic
The application of metabolomic in lipedema research in pathways [28]. The decrease in acetic acid could indicate an
order to identify complex metabolic alterations and poten- alteration in lipid metabolism, particularly in the oxidation
tial biomarkers for early diagnosis, prognosis, and treatment or synthesis of fatty acids [37]. In addition, acetic acid plays
strategies was recently evaluated in an interesting study con- a role in body weight regulation and adipose tissue function
ducted on groups of 25 women with lipedema, 25 women [38]. As for glycine, its serum levels correlate positively
with obesity, and 25 normal weight women [28]. The main with SAT and negatively with visceral adipose tissue (VAT)
results revealed that the metabolic and lipidomic profiles of [39], suggesting a potential involvement of this amino acid
patients with lipedema differed significantly from those of in the distribution of adipose tissue, understanding of the
controls without lipedema. Among the 39 metabolites exam- underlying mechanisms of which would provide insight into
ined, nine were significantly altered in lipedema. In particu- the different phenotypes of lipedema (e.g. hyperglycolytic
lar, patients with lipedema showed lower levels of histidine phenotype showing serine and glycine overproduction), as
and phenylalanine, whereas pyruvic acid was elevated in well as guide potential lines of treatment, such as glycine
comparison to controls. Furthermore, histidine, phenyla- supplementation [28]. Glutamine, on the other hand, is
lanine, and pyruvic acid concentrations showed promising implicated in energy production [40], nitrogen metabolism
diagnostic accuracy in distinguishing patients with lipedema [41], and neurotransmitter synthesis [42], as well as exert-
from those with obesity but without lipedema, with pyruvic ing an action in reducing adipose tissue and inflammation
acid showing the most promise. Subgroup analysis within [43], so a decrease in its levels may reflect changes in these
BMI ranges indicated that differences in pyruvic acid, phe- processes. A reduction in lactate levels could signal a change
nylalanine, and histidine levels are likely to be associated in metabolism, both glycolytic and oxidative [44]. Lactic
with lipedema rather than changes in BMI [28]. These find- acid has several functions and has been observed to promote
ings provide important insights into the metabolic altera- the transformation of adipocytes into beige adipocytes [45],
tions associated with lipedema. In particular, according to which, by expressing high levels of uncoupling protein 1,
the authors, the lower levels of histidine and phenylalanine produce heat [46]. Finally, differences in LDL-transported
found in women with lipedema could indicate alterations lipids were also observed in patients with lipedema com-
in protein metabolism, amino acid utilization, and related pared to controls, suggesting an association with lipedema
metabolic pathways. Since histidine and phenylalanine are pathology rather than adiposity [28]. Metabolomics, thus,
precursors of essential molecules [28], such as hormones presents itself as a valuable tool for understanding meta-
and neurotransmitters [30, 31], their disruption could affect bolic alterations in lipedema and investigating the underly-
crucial processes such as protein synthesis, energy produc- ing mechanisms [28].
tion, and neurotransmitter regulation. These changes suggest
potential alterations in amino acid metabolism in lipedema IL‑6 Gene Polymorphism
patients [28]. Pyruvate is a key molecule in adipocyte metab-
olism [32], contributing to several crucial processes. These The clinical study conducted by Di Renzo and colleagues
include energy production, triglyceride synthesis, fatty acid identified new indices and predictive parameters based on
production, and glucose regulation [33, 34]. In Kempa's body composition and IL-6 gene polymorphism (rs1800795)
study, the authors observed a weak correlation between that could distinguish individuals with lipedema from those
pyruvate levels and BMI, suggesting that lipedema, per se, with normal weight-obesity (NWO) and obesity [29]. This
might increase pyruvate levels independently of BMI [28]. study examined the complex genetic interactions related to
Pyruvate metabolism is tightly regulated to meet the energy body fat accumulation in patients with lipedema and found
and storage demands of adipocytes in response to nutritional significant differences in fat distribution in women carrying
and physiological stimuli [35]. An alteration in pyruvate or not carrying the IL-6 gene polymorphism (rs1800795). In
metabolism in adipocytes can lead to the accumulation of particular, being a carrier of the mutation increases the risk
triglycerides [35]. In fact, the availability of acetyl-CoA of developing lipedema by almost 6-fold [29]. IL-6 plays
derived from pyruvate is essential for the de novo synthesis an important role in regulating body fat, as it is released
of fatty acids [36], which, despite its minimal contribution, from adipocytes and its levels are elevated in obesity, indi-
may influence some of the metabolic alterations observed in cating the presence of an inflammatory state [47–49]. The
lipedema. In addition, according to Kempa and colleagues, IL-6 gene polymorphism (rs1800795), which affects IL-6
672 Current Obesity Reports (2024) 13:667–679

transcription, has been identified as a cause of the onset ERα-mediated gene expression, reduced inhibition of ERβ,
of overweight [47]. Previous studies have also shown that resulting in increased activation of PPARγ by ERα, elevated
IL-6 concentration correlates positively with fat mass per- entry of free fatty acids into adipocytes for triacylglycerol
centage in the GG genotype and negatively in the CC geno- production through increased lipoprotein lipase activity,
type [47–49]. The authors suggest, therefore, that the leg decreased lipolysis due to increased lipoprotein lipase activ-
index, abdominal index, trunk index, and total index, com- ity, a decrease in lipolysis due to ERα-induced upregulation
bined with genetic analysis of the IL-6 gene polymorphism of anti-lipolytic α-adrenoreceptor, ERα-induced increase in
(rs1800795), can be used as promising clinical tools to diag- glucose uptake through enhanced insulin-stimulated GLUT4
nose the phenotype of lipedema and predict the evolution of translocation, an increase in angiogenesis through ERα-
the disease [29]. induced upregulation of VEGF, and finally a decrease in
mitochondriogenesis and mitochondrial function [54].
The GH/IGF1 pathway displays profound effects on adi-
An Endocrine Outlook for Lipedema pocyte metabolism, given that GH is a powerful stimulator
of lipolysis; such effects are not mediated by IGF-1, whereas
Emerging evidence suggests potential links between IGF-1 is a pivotal regulator of the terminal phases of adi-
lipedema and hormonal influences [50]. This section aims pose cell differentiation. So far, no studies have investigated
to elucidate the complex interplay between estrogens, adi- the GH/IGF-1 axis in patients with lipedema; interestingly,
pose tissue, and the effects of PE, offering novel insights for an in vitro study performed on adipose stem cells obtained
tailored therapeutic interventions. from lipoaspirate demonstrated a higher expression of IGF-1
Estrogens exert multiple effects on adipose tissue, con- during the proliferative activity in stem cell cultures from
tributing to body fat distribution and adipose depot remod- patients with lipedema in comparison with control stem cells
eling, mostly mediated by ERα; they positively influence [55].
mitochondrial function and curb inflammation [51]. Altera- It is well known that the prevalence of hypothyroidism is
tions in estrogen activity or the lack of estrogen receptors higher in women than in men [56] and in patients with obe-
(ERs) result in the accumulation of subcutaneous adipose sity than in normal weight subjects [57]. For these reasons,
tissue (SAT), a phenomenon observed in patients with thyroid status could be easily altered in lipedema. In fact, in
lipedema [52]. Furthermore, according to Al-Ghadban, women affected by lipedema, a higher prevalence of hypo-
ERα knockout mice have shown that a reduction in estrogen thyroidism than in the normal population has been reported
resulted in increased adipose tissue inflammation with the by more studies [55, 58] with a progressively higher increase
upregulation of pro-inflammatory markers, such as inter- with the severity of the clinical stage. Similarly, the prev-
leukins IL-1β, IL-6, and tumor necrosis factor-alpha [53]. alence of autoimmune thyroiditis in female patients with
Moreover, estrogens act as central mediators for food lipedema was higher than in the normal population [55].
intake and energy consumption in the hypothalamus [50].
The site-specific localization of adipose tissue, especially
in the lower limbs of women with lipedema, appears strictly Lipedema and Physical Exercise
linked to estrogen levels [2].
Women with lipedema often exhibit notable alterations The Multiple Beneficial Effects of Physical
in ER expression, with a predominant focus on ERα [54]. Exercise on Lipedema
Dysregulation in ERα, characterized by aberrant expres-
sion levels or impaired signalling pathways, disrupts the PE emerges as a cornerstone in the multifaceted manage-
finely tuned balance maintained by estrogen in adipose tis- ment of lipedema [59]. PE, particularly endurance training,
sue. These receptor-specific alterations play a pivotal role indeed, stands out as a potent modulator of mitochondrial
in deciphering the pathophysiology of the condition [54]. function within SAT [60]; the enhancement of mitochondrial
According to Katzer and colleagues, ERα and ERß may activity through PE may be considered an effective thera-
play a role in the dysregulated adipose tissue characterized peutic tool for individuals with lipedema, contributing to
by lipedema, and the proposed estrogen-mediated dysregu- improved lipid metabolism and potentially countering aber-
lation, associated with the characteristic accumulation of rant lipid storage patterns. A compelling aspect of PE in the
excessive SAT in the lower body characteristic of lipedema, context of lipedema lies in its potential to modulate inflam-
could operate through two distinct mechanisms [54]. In mation and lipolysis [60]. An expanding body of evidence
particular, some authors hypothesised that the adipocytes has consistently demonstrated a general and white adipose
of subjects with lipedema may display a higher ERα/ERβ tissue (WAT)-related, anti-inflammatory impact of chronic
expression ratio than in subjects without lipedema [54]. exercise training [61]. Before recognizing such an exercise-
This could lead to lower ERβ-induced suppression of induced effect, specifically in WAT, it had already been
Current Obesity Reports (2024) 13:667–679 673

established that exercise training leads to a decrease in circu- muscle strengthening exercises, gait training, neuromuscu-
lating inflammatory markers. This effect has been observed lar re-education, and deep abdominal breathing to increase
not only in people with obesity but also in subjects with lymphatic flow and stimulate the parasympathetic system
increased inflammation. [58]. Beyond weight management, PE positively influences
It is worthy to mention that acute exercise exerts, instead, adipocyte health. Moreover, a recent review by Esmer and
a temporary increase of inflammatory cytokines necessary colleagues confirms that complex decongestive physiother-
to stimulate the exercise adaptation mechanisms related to apy, gait training, hydrotherapy, aerobic exercise, and resist-
performance and physical fitness improvement [62]. Given ance exercise training are all effective in the management of
the robust connection between inflammation in WAT and lipedema [10].
systemic inflammation, it is reasonable to hypothesize that Many authors suggest the importance of regular PE in
PE may directly influence the inflammatory status of WAT the management of lipedema. In particular, self-manage-
[61]. Interestingly, PE training promotes the browning of ment techniques emphasise the importance of low-impact
WAT via multiple mechanisms, one of the most attractive PE for lipedema sufferers, taking into account the patient's
of which is the increasing levels of the myokine irisin [63, preferred activities [71]. Furthermore, the importance of
64]. Specifically, PE stimulates PGC-1α, which, in turn, increasing muscle strength in the conservative treatment of
upregulates the expression of fibronectin type III in skeletal lipedema is emphasised [16]. PE, in fact, not only counter-
muscle. The cleavage of fibronectin III domain 5 releases acts the main symptoms, such as fatigue and muscle weak-
irisin, which, upon entering the circulation, reaches the adi- ness, but is crucial to encourage patients to include PA as
pose tissue, where it promotes WAT browning through an part of their daily routine in order to maintain a healthy life-
increase in Ucp1 mRNA and the number of Ucp1-positive style [16]. As another important positive effect of PE, exer-
cells [63, 64]. Regular PA exerts a suppressive influence cises involving the leg and calf muscles have been shown
on the pro-inflammatory milieu observed in lipedema SAT. to increase lymphatic drainage and venous flow, reducing
This anti-inflammatory effect, attributed to increased cat- or preventing oedema [72]. This insight adds another valu-
echolamine secretion and alternative macrophage activation, able piece to the mosaic of the multiple benefits of PE in
represents a critical pathway through which PE enhances the management of lipedema [10]. Poor adherence to PE
adipose tissue health [10]. There is, in fact, evidence indicat- and PA could be solved by selecting graded exercises [73]
ing that PE induces the phenotypic switch from M1 to M2 and manipulating intrinsic and extrinsic motivation, where
macrophages in adipose tissue, particularly in subjects with intrinsic refers to the individual's enjoyment of performing
obesity. More specifically, it has been shown that PE inhibits the activity, while extrinsic motivation is related to tangible
the infiltration of M1 macrophages into the adipose tissue benefits such as material or social rewards, or to avoid pun-
and increases the expression of CD163, a specific marker of ishment [74]. By studying these psychological aspects, it is
M2 macrophages. This macrophage phenotypic switching possible to structure a tailor-made conservation programme
contributes to inhibiting the chronic inflammatory state in that could also be extended to a healthy lifestyle in general.
adipose tissue [65]. Also, PE orchestrates additional ben- Psychological problems associated with lipedema
eficial changes within lipedema SAT by promoting angio- patients, such as depression and anxiety [10], could be man-
genesis and augmenting antioxidant defences. Improved aged with PE [75]. According to several authors, after aero-
vascularization in muscle induced by PE enhances tissue bic exercise, participants show increased pressure-pain toler-
perfusion and oxygenation, potentially mitigating hypoxic ance [76–78]. Consequently, these forms of PE could play
conditions observed in advanced lipedema stages. Further- a key role in addressing the pain characteristic of patients
more, the boostering of antioxidant defences aligns with the with lipedema [59].
broader goal of enhancing tissue resilience and mitigating The PE effect is also crucial for other signs and symp-
oxidative stress [10]. Pioneering studies by Stallknecht in toms found most frequently in patients with stage 2 and 3
1991 demonstrated PE-induced improvements in mitochon- lipedema, such as obstructive sleep apnea [12]. Indeed, it has
drial function within adipocytes, suggesting PE's broader been shown that PE can be beneficial for the management
impact on adipose tissue health [66]. of obstructive sleep apnea, beyond simple weight loss [79].
PE positively influences adipose tissue health through
mechanisms such as exosome and myokine release [67–70],
catecholamine release, AMPK activation, and angiogenesis. The Optimal Physical Exercise Prescriptions
Exploring how these mechanisms interact with hormonal
modifications in the context of lipedema is important for As described above, the main goal of lipedema treatments
developing novel therapeutic strategies. According to the is to manage pain and reduce functional limitations due
standard of care for lipedema in the United States, people to excessive limb volume. However, lipedema patients do
with lipedema may benefit from postural and core exercises, not respond to caloric restriction and intense PA [6, 80],
674 Current Obesity Reports (2024) 13:667–679

so conservative treatments, including PE, are proposed to walk test, which was approximately 80% of the theoretical
alleviate the symptoms and improve the quality of life. maximum heart rate. Strengthening exercises, on the other
In the literature, some studies have included PE in con- hand, consisted of resistance exercises for the major muscle
servative treatments to alleviate the symptoms associated groups. The main findings were that limb volume measure-
with lipedema; Table 1. Atan & Bahar-Özdemir and col- ments decreased significantly in the CDT group compared
leagues [81], compared the effectiveness of three different to the other two groups and that IPCT applied in addition to
conservative treatments. Patients were randomised into three PE was not superior to the PE-only group in patients with
groups: Group 1 (Complete Decongestive Therapy (CDT) severe lipedema [81]. In another study [82], the therapeutic
plus PE), Group 2 (intermittent pneumatic compression potential of physical therapy was evaluated by prescribing
therapy (IPCT) plus PE), and Group 3 (control PE-only). a 60-minute therapeutic session. The session consisted of
The training protocol was structured as follows: 5 days a manual therapy (including manual lymphatic drainage) and
week for 6 weeks, with each workout consisting of a warm- a customised PE guide that provided guidance on posture,
up, aerobic exercises, strengthening exercises, and stretch- joint protection, movement and PE, compression require-
ing. The aerobic section was individualised, prescribing ments, diaphragmatic breathing, and healthy eating. The
the same heart rate achieved at the end of the 6-minute PE programme was customised and aimed at lower-body

Table 1  Summary of the studies that have analysed the effect of exercise, often combined with other conservative therapies, on patients affected
by lipedema
Ref. Exercise proposed Variables analysed

[6] - Cyclical walking Guideline

- Running movements
- Swimming /aqua jogging/ aqua gymnastic
[3] - Swimming Guideline
- Aqua jogging-aerobics-cycling
[76] - Regular aquatic physical exercise • QuASiL questionnaire
• Volumes and proportions
[75] - Tailored exercise programs addressed lower body strengthening, • Tesla sodium and water MRI
flexibility, and conditioning, focusing on long-term adherence. • Biophysical measurements
• Questionnaires measuring function
• Questionnaires QoL (patient-specific functional scale, PSFS, and
RAND-36)
• VAS
[15] - increasing muscle strength in conservative treatment for lipedema • Muscle strength of the quadriceps was assessed with dynamometer
• 6-min walk test
[74] - Warm-up • Limb volume measurements
- Aerobic exercise at 80% of the maximal theoretical heart rate • Anthropometric measurements
- Strengthening exercises • 6-min walk test
• VAS
• fatigue severity scale
• Beck Depression Inventory
• Short Form Health Survey-36
[79] - Water sports • VAS
• DLQI
• Health-related quality of life according to Short Form 36 (SF-36)
• World Health Organization Quality of Life-abbreviated version of
the WHOQOL 10 (WHOQOL-BREF)
• Patient Health Questionnaire-9 (PHQ-9)
• Leg circumference
• Lower
• Extremity Functional Scale, LEFS
• Body fat percentage
• Hematoma tendency
• Occurrence of leg oedema
[4] - Weight loss exercise schedule Guideline

Guidelines suggested the activity described considering the typical symptoms and characteristics of the disease
QuASiL Questionário de Avaliação Sintomática do Lipedema, MRI magnetic resonance imaging, QoL Quality of Life, PSFS Patient-Specific
Functional Scale, VAS Visual analogue scale, DLQI Dermatology Life Quality Index, LEFS Lower Extremity Functional Scale
Current Obesity Reports (2024) 13:667–679 675

Fig. 3  PE as a therapeutic tool

to improve lipedema

strengthening, flexibility, and conditioning, focusing on lower-limb oedema at the end of the day, often related to
long-term adherence. Over the 6-week protocol period, the orthostasis and heat [84]. In this sense, Gianesini et al. [85]
results reported a decrease in pain perception, as assessed by designed a specific aquatic protocol that demonstrated a
the visual analogue pain scale, an improvement in quality of positive impact on chronic leg swelling. Table 1 shows a
life, and a tendency to sodium reduction, as assessed by MRI summary of studies that have analyzed the effect of exercise
[82]. However, it should be emphasised that, as designed, on lipedema patients.
the study by Donahue and colleagues [82] does not allow
unequivocal discrimination as to which was individually the
effect of PE and which was that of manual therapy. Conclusion
Research evaluating the effects of aquatic exercise is more
frequent. Amato and Benitti [83] studied the use of aquatic This is a consensus statement from the Italian Society of
exercise combined with diet, lymphatic drainage, and anti- Motor and Sports Sciences (Società Italiana di Scienze
oxidant herbal drugs in five cases of lipedema assessed with Motorie e Sportive, SISMeS) and the Italian Society of Phle-
the Lipedema Symptom Assessment Questionnaire, one for bology (Società Italiana di Flebologia, SIF) which provides
each stage of the disease. The results showed a positive the official view on the role of exercise as a non-pharmaco-
effect of these treatments [83]. The lack of specificity of the logical approach in lipedema.
applied aquatic PEs, however, calls for further investigation. Lipedema is a particularly complex and multifactorial
Again, no conclusions can be drawn about the effect of PE condition that requires, at its base, a careful diagnosis and,
on lipedema. above all, a multidisciplinary approach for its management
Overall, experimental studies that have applied PEs to that takes into account the etiopathogenetic, endocrine-
lipedema are limited; however, many guidelines suggest metabolic, and nutritional aspects. Treatments must, inevi-
their possible application based on the rationale of the tably, consider the pathology from a holistic prespective,
disease. The guidelines by Reich-Schupke et al. [59] and and be appropriately tailored to the patient's needs. In this
Kruppa et al. [4] recommend PA, particularly emphasising perspective, PE plays a major role (Fig. 3). The body of
the effectiveness of water-based exercises such as swim- available literature emphasises the potential benefits of PE
ming, aqua jogging, and water aerobics. Floating in water in the holistic management of lipedema. Structured exercise
relieves joint pressure, promotes lymphatic drainage, and training, particularly water exercise, emerges as a promis-
contributes to calorie burning, making it a favourable option ing intervention, offering not only physiological benefits
for the management of lipedema [59]. Aquatic activities such as weight control, functional activity, joint relief, and
might be suitable for patients who complain of worsening lymphatic drainage but also psychological benefits, with a
676 Current Obesity Reports (2024) 13:667–679

positive impact on self-esteem, mood, and quality of life. 4. Kruppa P, Georgiou I, Biermann N, Prantl L, Klein-Weigel P,
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Author Contributions G.A., A.P., and V.M. wrote the main manuscript otherapy and rehabilitation applications in lipedema manage-
text. G.A. prepared all figures. E.C., F.L., L.V., and X.C. did the major- ment: A literature review. Lymphology. 2020;53:88–95.
ity of the literature searches and created the initial draft, including its 11. Shavit E, Wollina U, Alavi A. Lipoedema is not lymphoedema:
organization. L.B. conceived and supervised the work. E. P., A. B., A. A review of current literature. Int Wound J. 2018;15:921–8.
C., A. D. B., L. G., S. M. M., S. O., A. T., R. D. M., L. A., A. P., M. B., 12. Chava Y, Hanne C. Lipedema fat and signs and symptoms of
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All authors approved the final version of the manuscript. 13. Dudek JE, Białaszek W, Ostaszewski P, Smidt T. Depression
and appearance-related distress in functioning with lipedema.
Funding Open access funding provided by Università degli Studi di Psychol Health Med. 2018;23:846–53.
Napoli Federico II within the CRUI-CARE Agreement. 14. Sørlie V, De Soysa AK, Hyldmo ÅA, Retterstøl K, Martins
CNS. Effect of a ketogenic diet on pain and quality of life in
Data Availability No datasets were generated or analysed during the patients with lipedema: The LIPODIET pilot study. Obes Sci
current study. Pract. 2022;8:483–93.
15. Cannataro R, Michelini S, Ricolfi L, et al. Management of
lipedema with ketogenic diet: 22-month follow-up. Life (Basel,
Compliance with Ethical Standards Switzerland). 2021;11:1402.
16. van Esch-Smeenge J, Damstra RJ, Hendrickx AA. Muscle
Conflict of Interest The authors declare no competing interests.
strength and functional exercise capacity in patients with
lipoedema and obesity: A comparative study. J Lymphoedema.
Human and Animal Rights and Informed Consent This article does not
2017;12:27–31. https://​hbo-​kenni​sbank.​nl/​detai​ls/​hanze​pure:​
contain any studies with human or animal subjects performed by any
oai:​resea​rch.​h anze.​n l:​p ubli​c atio​n s%​2 Fa23​3 bf2b-​0 7b2-​4 001-​
of the authors.
bc49-​ae96d​843c3​bc.
17. Paolacci S, Precone V, Acquaviva F, Chiurazzi P, Fulcheri E,
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the article’s Creative Commons licence and your intended use is not Lipedema: An overview of its clinical manifestations, diagnosis
permitted by statutory regulation or exceeds the permitted use, you will and treatment of the disproportional fatty deposition syndrome -
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Authors and Affiliations

Giuseppe Annunziata1,2 · Antonio Paoli3,4 · Vincenzo Manzi5 · Elisabetta Camajani6 · Francesco Laterza5 ·
Ludovica Verde7 · Xavier Capó8 · Elvira Padua6 · Antonino Bianco4,9 · Attilio Carraro4,10 ·
Angela Di Baldassarre4,11 · Laura Guidetti4,12 · Samuele Maria Marcora4,13 · Stefania Orrù4,14 ·
Antonio Tessitore4,15 · Roberto Di Mitri16,17 · Lucia Auletta17,18 · Angela Piantadosi17,19 · Mario Bellisi17,18 ·
Edmondo Palmeri17,18 · Silvia Savastano20,21 · Annamaria Colao20,21,22 · Massimiliano Caprio6,23 ·
Giovanna Muscogiuri20,21,22 · Luigi Barrea5,21

* Giovanna Muscogiuri Francesco Laterza

[email protected] [email protected]
Giuseppe Annunziata Ludovica Verde
[email protected] [email protected]
Antonio Paoli Xavier Capó
[email protected] [email protected]
Vincenzo Manzi Elvira Padua
[email protected] [email protected]
Elisabetta Camajani Antonino Bianco
[email protected] [email protected]
Current Obesity Reports (2024) 13:667–679 679

6
Attilio Carraro Department of Human Sciences and Promotion
[email protected]; [email protected] of the Quality of Life, San Raffaele Roma Open University,
Rome, Italy
Angela Di Baldassarre
7
[email protected]; [email protected] Department of Public Health, University of Naples Federico
II, Via Sergio Pansini 5, 80131 Naples, Italy
Laura Guidetti
8
[email protected]; [email protected] Translational Research In Aging and Longevity (TRIAL)
Group, Health Research Institute of the Balearic Islands
Samuele Maria Marcora
(IdISBa), 07120 Palma, Spain
[email protected]
9
Sport and Exercise Sciences Research Unit, Department
Stefania Orrù
of Psychology, Educational Science and Human
[email protected]
Movement, University of Palermo, Via Giovanni Pascoli 6,
Antonio Tessitore 90144 Palermo, Italy
[email protected] 10
Faculty of Education, Free University of Bozen-Bolzano,
Roberto Di Mitri Bozen, Italy
[email protected] 11
Department of Innovative Technologies in Medicine
Lucia Auletta and Dentistry, “G. d’Annunzio” University of Chieti Pescara,
[email protected] Via dei Vestini 31, 66100 Chieti, Italy
12
Angela Piantadosi Department Unicusano, University “Niccolò Cusano”,
[email protected] 00166 Rome, Italy
13
Mario Bellisi Department of Quality of Life Sciences, University
[email protected] of Bologna, Rimini, Italy
14
Edmondo Palmeri Department of Movement Sciences and Wellness, University
[email protected] Parthenope, 80133 Naples, Italy
15
Silvia Savastano Department of Movement, Human and Health Sciences,
[email protected] University of Rome “Foro Italico”, 00135 Rome, Italy
16
Annamaria Colao Center for Diagnosis and Treatment of Vascular Diseases,
[email protected] San Rossore Clinic Pisa, Pisa, Italy
17
Massimiliano Caprio Italian Society of Phlebology (Società Italiana Di Flebologia,
[email protected] SIF), Caserta, Italy
18
Luigi Barrea “Paolo Giaccone” University Hospital, Palermo, Italy
[email protected]; [email protected] 19
Serapide Physiotherapy Center – Pozzuoli, (Naples), Italy
1 20
Facoltà di Scienze Umane, Della Formazione e dello Unità di Endocrinologia, Diabetologia e Andrologia,
Sport, Università Telematica Pegaso, Via Porzio, Centro Dipartimento di Medicina Clinica e Chirurgia, Università
Direzionale, Isola F2, 80143 Naples, Italy degli Studi di Napoli Federico II, Via Sergio Pansini 5,
2 80131 Naples, Italy
Department of Experimental Medicine, University
21
of Campania “Luigi Vanvitelli”, Naples, Italy Centro Italiano per la cura e il Benessere del Paziente con
3 Obesità (C.I.B.O), Unità di Endocrinologia, Diabetologia e
Department of Biomedical Sciences, University of Padua,
Andrologia, Dipartimento di Medicina Clinica e Chirurgia,
Padua, Italy
Università degli Studi di Napoli Federico II, Via Sergio
4
Italian Society of Motor and Sports Sciences, (Società Pansini 5, 80131 Naples, Italy
Italiana di Scienze Motorie e Sportive, SISMeS), Verona, 22
Cattedra Unesco “Educazione Alla Salute E Allo Sviluppo
Italy
Sostenibile”, University Federico II, 80131 Naples, Italy
5
Department of Wellbeing, Nutrition and Sport, Pegaso 23
Laboratory of Cardiovascular Endocrinology, IRCCS San
Telematic University, Centro Direzionale Isola F2, Via
Raffaele, Rome, Italy
Porzio, 80143 Naples, Italy