Lipoedema is a disorder of adipose tissue characterized by abnormal but symmetrical deposition of subcutaneous white adipose tissue (sWAT) in the proximal extremities such as the legs and arms. Estimates of its prevalence are very uncertain, but it is a disease with widespread implications for public health. There is a complete lack of understanding of the pathophysiological changes that drive the progression of this disease. Furthermore, the lack of clear- cut diagnostic markers makes this disease difficult to identify and it is frequently misdiagnosed as simple obesity1. It is widely accepted that lipoedema affects almost exclusively women, and hence it is oestrogen- dependent, and has a strong genetic component1,2. The prevalence of lipoedema does not necessarily correlate with the prevalence of high BMI, and more than 50% of patients manifest this condition during puberty2,3. Lipoedema also does not demonstrate any relationship with cellulite (that is, the herniation of sWAT within connective tissue that commonly occurs in adult women) and mechanically has the appearance of a compliant tissue3. Here, compliance relates to the ability of tissue to distort and distend upon pressure.

MMP14 (also known as MT1- MMP), which is the main pericellular collagenase in adipose tissue, is of primary importance in lipoedema. Indeed, in a 2020 study, we showed that endotrophin (a C- terminal cleavage product of the C5 domain of the α3 chain of type VI collagen (COL6α3)) is a substrate for MMP14 and that MMP14 expression is strongly induced in mouse models of obesity5. Obesity is another known comorbidity of lipoedema. Endotrophin, which is abundantly found in adipose tissue, triggers adipose tissue fibrosis6, is a chemoattractant for macrophages and can interact with endothelial cells7, thus affecting both the fibrotic and the vascular properties of sWAT. Importantly, endotrophin is also much more abundant locally in adipose tissue6 in people who have obesity than in those who are not. Of note, human MMP14 gene polymorphisms are also closely associated with human obesity and type 2 diabetes mellitus (T2DM) traits8.

MMP14 is involved in the regulation of vessel stability, probably through interactions with transforming growth factor β1 proprotein (TGFβ1)9. This observation is not surprising given that both the MMP14 receptor and the TGFβ receptor are colocalized within the caveolae of the plasma membrane and both physically interact with caveolin 1 (CAV1), which is a necessary structural component of these invaginated lipid raft structures.

In this Perspective, we outline the reasons for the observed MMP14 over-expression in hypertrophic WAT. We address whether upregulation of MMP14 can explain the main known features of lipoedema, such as adipose hypertrophy, dysfunction of blood and lymphatic vessels, the overall oestrogen dependence and the associated sexual dimorphism, and the mechanical compliance of lipoedemic sWAT (Supplementary Box).

MMP14 and CAV1 in adipose tissueMMP14 is a well- known global player in mesenchymal tissue remodelling10, and strongly interacts with other MMPs (Box 1). In mice, the absence of MMP14 in adipose tissue leads to an accumulation of small adipocytes in sWAT, the development of lipodystrophy and, consequently, almost undetectable leptin levels11.

Histologically, sWAT in lipoedema is characterized as adipose tissue with a hypertrophic phenotype that has a reduced content of fibrotic components in the extracellular matrix space4. Moderate degrees of hyperplasia can also be detected in lipoedemic sWAT4; however, hyperplastic adipose tissue expansion is considered by some authors as a secondary phenomenon1. Adipocytes in lipoedemic sWAT can reach diameters of more than 150 µm, compared with 100 µm in healthy sWAT4, reflecting a more than threefold increase in the volume of pathological tissue. Additional morphological modifications are typical in lipoedema, such as increased permeability and fragility of blood vessels, leading to an accumulation of fluids and proteins in sWAT, and malfunctioning of the lymphatic system, leading to a secondary lymphoedema, which is an established comorbidity of lipoedema2.

These pathophysiological features of lipoedema have been hypothesized to be connected with improper remodelling of the pericellular and perivascular matrix, a process predominantly mediated by matrix metalloproteinases (MMPs). Whereas various MMPs are involved in the remodelling of these structures,

The MMP14–caveolin axis and its potential relevance for lipoedemaIlja L. Kruglikov, Nolwenn Joffin and Philipp E. Scherer

Abstract | Lipoedema is associated with widespread adipose tissue expansion, particularly in the proximal extremities. The mechanisms that drive the development of lipoedema are unclear. In this Perspective article, we propose a new model for the pathophysiology of lipoedema. We suggest that lipoedema is an oestrogen- dependent disorder of adipose tissue, which is triggered by a dysfunction of caveolin 1 (CAV1) and subsequent uncoupling of feedback mechanisms between CAV1, the matrix metalloproteinase MMP14 and oestrogen receptors. In addition, reduced CAV1 activity also leads to the activation of ERα and impaired regulation of the lymphatic system through the transcription factor prospero homeobox 1 (PROX1). The resulting upregulation of these factors could effectively explain the main known features of lipoedema, such as adipose hypertrophy, dysfunction of blood and lymphatic vessels, the overall oestrogen dependence and the associated sexual dimorphism, and the mechanical compliance of adipose tissue.

PERsPECTIVEs

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MMP14 colocalizes with CAV1 in the plasma membrane of different cells12–14 (Fig. 1a). Of note, CAV1 expression in adipocytes is dependent on the differentiation state, with the levels being low in pre- adipocytes and high in mature cells15. CAV1 has an essential role in cellular signalling and is considered a crucial driver (and in some instances the target) in the pathology of several different inflammatory and hyperproliferative skin conditions; furthermore, CAV1 is also involved in wound healing and skin ageing15–19. Importantly, CAV1 is a critical regulator of MMP14 and negatively regulates its activity. For example, the overexpression of CAV1 in COS-7 cells promotes the internalization of MMP14 from the cell surface20. This interaction takes place through the cytoplasmic domain of MMP14 and mutations in this domain reduce the association between MMP14 and CAV1 (reF.21). Importantly, to provide this level of regulation, MMP14 and CAV1 must be fully intact, and CAV1 has to be tyrosine phosphorylated21. Under physiological conditions, the overexpression of MMP14 induces CAV1 expression, which in turn reduces MMP14 activity. Therefore, under physiological conditions, MMP14

and CAV1 are mutually regulated (coupled) through a feedback mechanism.

High levels of MMP14 expression are observed in hypertrophic adipose tissue in obesity5, and this observation suggests that the physiological level of regulation is no longer in place and MMP14 and CAV1 are ‘uncoupled’. Such uncoupling can have different underlying mechanistic reasons. One of them could be a lack of phosphorylation of CAV1 caused by dysfunctional tyrosine kinases. Alternatively, polymorphisms in the CAV1 gene could prevent its proper physical interaction with MMP14. Of note, there is a second gene, encoding CAV2, that is closely related to CAV1. CAV1 and CAV2 are colocalized in the plasma membrane, producing a stable complex in vivo. Through this colocalization, CAV2 also interacts with MMP14. However, CAV2 is not sufficient for caveolae formation, and the interactions with MMP14 seem to be a secondary effect.

MMP14 is a target for PROX1MMP14 is a target for the transcriptional factor prospero homeobox 1 (PROX1), which is a master regulator for the lymphatic system (Fig. 1b). Overexpression

of PROX1 induces the differentiation of human adipose- derived stem cells into lymphatic endothelial- like cells22. PROX1 levels are inversely correlated with MMP14 expression in human lymphatic cells23; suppression of PROX1 leads to a serious malfunctioning of the lymphatic system24 and causes derepression of MMP14, at least in some types of cells25. Of note, whereas in some types of cells PROX1 demonstrates considerable repression of CAV1, such regulation has been reported to be absent in cells with low expression levels of CAV1 (reF.25).

On the basis of these observations, we can predict that lymphatic defects could cause an accumulation of adipose tissue. Indeed, it was shown that lymph leaking from defective lymphatic vessels in Prox1+/− mice directly stimulates the adipogenic differentiation of 3T3- L1 cells in vitro26. Moreover, the authors demonstrated that an expansion of adipose tissue occurs in two steps in Prox1+/− mice: first through the hypertrophy of adipocytes, and second through induction of adipogenic differentiation. This two- step development can explain the mixed hyperplastic–hypertrophic type of sWAT observed in the late stages of lipoedema development in humans4 as well as the comorbidities between lymphoedema and lipoedema. In vivo, Prox1+/− mice have a defective lymphatic system and develop late- onset obesity, and this obesity correlates with the severity of lymphatic defects27. Moreover, the authors also demonstrated that the restoration of lymphatic function was sufficient to rescue the obesity in the Prox1+/− mice.

Not only can impaired lymphatic function cause a hypertrophic extension

Box 1 | interaction of MMP14 with other MMPs in adipogenesis

•Whereasmatrixmetalloproteinase2(MMP2)isconstitutivelyexpressedinadipocytes,MMP9isaninducibleenzyme;itsexpressionisactivatedinadipocytesduringremodellingofthecellsurface–basementmembraneinterface64.MMP9canexistinafreeformoramembrane-boundform.

•MMP2andMMP9canbeconnectedtothepericellularmatrixthroughMMP14andtissueinhibitorofmatrixmetalloproteinases2(TIMP2)65.

•Suchmembrane-boundMMP9hasthesameabilitytocleavetypeIVcollagen(COL4)asanon-boundMMP9,butitis20-foldand70-foldmoreresistanttoinhibitionbyTIMP1andTIMP2,respectively66.

a b

Adipocyte

Oestrogenreceptor

Caveolae

CAV1

MMP14

PROX1Master lymphatic regulator

CAV1Master regulator ofcell signalling

CAV1 negativelyregulates MMP14and promotes itsinternalizationfrom the cell surface

MMP14Key pericellular collagenasein adipose tissue; ‘master-switch’proteinase

Oestrogen receptorsMaster transcriptionalregulator of several celltypes (e.g. breast andendometrial cells)

MMP14 is atarget of PROX1

PROX1 repressesCAV1 expression ERβ shares target genes

with PROX1 and suppresses PROX1

ERα co-localizes withCAV1; downregulationof CAV1 activates ERα

Fig. 1 | Mutual impact of MMP14, cAV1, ProX1 and oestrogen receptors in lipoedema. a | Matrix metalloproteinase 14 (MMP14) and oestrogen receptor (ER) are colocalized within the caveolae of the plasma membrane and both physically interact with caveolin 1 (CAV1). b | MMP14 is overexpressed in hypertrophic white adipose tissue. CAV1 is a critical regulator of MMP14 and negatively regulates its activity; CAV1 also promotes the internalization of MMP14 from the cell surface. Therefore, downregulation of CAV1 should lead to the overexpression of MMP14. Reduced CAV1 activity also leads to the activation of ERα and impaired regulation of the lymphatic system through the transcriptional factor prospero homeobox 1 (PROX1).

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of WAT, but correspondingly, obesity induced by a high- fat diet can increase perilymphatic inflammation and impair lymphatic function28. Indeed, lymphatic endothelial cells isolated from obesity- prone (but not cells from obesity- resistant) mice have decreased expression of PROX1 (reF.28). Weight loss in mice with obesity induced by a high- fat diet was shown to reduce perilymphatic inflammation and restore lymphatic function29. However, attempts at weight reduction in patients with lipoedema do not alter the affected adipose tissue areas2. As a result, caloric restriction cannot provide a normalization of PROX1 levels and fails to improve the lymphatic status of patients.

Lipoedema as a compliant swellingThere are two different types of fibrotic structures in mouse sWAT: intercellular fibrosis, which mainly consists of the fibrillar collagens COL1 and COL3, and pericellular fibrosis, which contains COL4 and COL6 (reFs30–32). Pericellular fibrotic structures are assumed to restrict hypertrophic growth of adipocytes by prohibiting unlimited expansion of these cells; the appearance of pericellular fibrotic structures has also been connected with metabolic disorders that are commonly associated with obesity33. In fact, fibrotic structures that appear in different types of WAT might account for the difference between healthy and unhealthy obesity34. Similar fibrotic structures are observed in human sWAT31.

Whereas the total fibrotic volume in sWAT is almost independent of BMI, pericellular fibrosis increases by three to seven times when BMI increases from 23 to 48 kg/m2 (reF.31). Increased fibrosis in sWAT is connected with the local activity of endotrophin6, which is secreted by mature adipocytes, but not by pre- adipocytes35. Remarkably, endotrophin expression has been found to be substantially lower in the abdominal than in the gluteofemoral area, which suggests that the structure of gluteofemoral fat under normal conditions requires stronger fibrosis to restrict the potential hypertrophy of adipocytes.

Both intercellular and pericellular fibrotic structures are involved in the mechanical stability of sWAT. However, the Young’s modulus (a mechanical parameter that describes tissue stiffness) of sWAT is mainly dependent on the pericellular component36,37. Indeed, the tensile strength of sWAT in Col6a1- knockout mice was found to be approximately 50% of the value in adipose tissue from wild- type mice34. This finding suggests that sWAT with a reduced content of COL6 caused by an

increased expression of MMP14 would be mechanically more compliant, which may explain why the lipoedema appears as a compliant swelling3 (Fig. 1b).

Oestrogen dependence in lipoedemaLipoedema demonstrates a strong sexual dimorphism and affects almost exclusively women2, which is primarily connected with sex differences in sWAT. Indeed, in animal models, it is known that hypertrophic expansion of sWAT in obese animals is associated with increased cellular death of adipocytes, accompanied by tissue infiltration of macrophages and secondary fibrosis in males, whereas females demonstrate greater expandability of adipocytes, which protects them from such a response38. This model has gained additional support from the observation that the level of COL6A3 mRNA expression in human sWAT is substantially lower in women than in men39.

Expression of oestrogen receptors (ERα and ERβ) in adipocytes is essential for the regulation of adipose tissue inflammation and fibrosis. A reduction of ERα levels in mouse adipocytes results in increased hypertrophy of these cells, both in males and in females, whereas inflammation and fibrosis after such a reduction of ERα are typically seen only in males40. These receptors essentially interact with CAV1 (Box 2). For example, downregulation of CAV1 in human epithelial cells leads to activation of ERα41. Of note, expression of ERβ almost completely suppressed both mRNA and protein expression of PROX1 in SW480 colorectal cancer cells, and it was stated that ERβ shares target genes with PROX1, which could represent an oestrogen dependence of PROX1 (reF.42).

Under ‘quasi- physiological’ conditions, CAV1 negatively regulates the activity of MMP14 (reF.20). Therefore, the downregulation of CAV1 in adipocytes could lead to both the overexpression of MMP14 and the activation of ERα, thereby making adipose tissue more oestrogen- sensitive and reducing its fibrotic constituents. However, such a physiological interaction will be dysregulated when CAV1 cannot be phosphorylated or when the gene

encoding this protein has a polymorphism. To be causally involved in lipoedema, CAV1 polymorphism should demonstrate oestrogen dependence and a strong sexual dimorphism.

Polymorphisms of CAV1CAV1 demonstrates numerous polymor-phisms, which are connected with various pathologies. These polymorphisms have been investigated especially thoroughly in different types of cancer43 and in ocular diseases44 (Box 3).

A SNP, rs4236601, at the CAV1–CAV2 locus was reported to be common in white populations but rare in East Asian populations45. Moreover, this polymorphism demonstrates significant sexual dimorphism in white populations, with greater odds ratios and significantly higher statistical significance in women46,47. For example, the odds ratios (P values) for the polymorphism rs4236601 were found to be 1.11 (0.432) and 1.37 (0.004) for white men and women in the USA, respectively46.

Which type of polymorphism might be responsible for the uncoupling of CAV1 and MMP14 remains to be elucidated in future research (Fig. 2).

Ethnic differences in lipoedemaSome authors have found no differences in lipoedema rates across populations with different ethnic backgrounds48; however, it is not clear whether Asian populations

Box 2 | interaction of oestrogen receptors with cAV1

•Oestrogenreceptor-α(ERα)colocalizeswithcaveolin1(CAV1)invariouscelltypes67,68.ThedownregulationofCAV1inhumanepithelialcellsleadstoaconsiderableactivationofERα(butnotofERβ)41.

•InductionofCAV1expressionindifferenttypesofcellsleadstothetranslocationofERαfromthecytosoltotheplasmamembrane67.

•AdministrationofoestrogenscaninduceorsuppressCAV1expression,dependingonthecelltype67,whichhighlightstheirreciprocalinteraction.

Box 3 | Polymorphism of CAV1

ThecombinedtotalincidenceofallCAV1-relatedmutationsinoestrogenreceptor-α(ERα)-positivebreastcancersisabout35%45.SuchmutationsarenotobservedinERα-negativebreastcancers,whichpointstotheiroestrogendependence.TheincidenceoftheCAV1P132Lmutation

inERα-positivebreastcancerindifferentethnicgroupsisabout16–19%45,46.The‘G-allele’fortheCAV1polymorphism

rs1758872andthe‘A-allele’fortheCAV1polymorphismrs4236601arestatisticallysignificantlycorrelatedwithdecreasedCAV1mRNAexpressioninadiposetissueandskinofwhiteindividuals47,69–71.

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have lower rates of this disease than white populations. This is an important question that should be addressed by an epidemiological effort on a larger scale.

A comparison of a mixed group of 18 men and 4 women of Southeast Asian descent with age- matched and BMI- matched white individuals revealed much higher expression of COL6A3 mRNA, in both abdominal and gluteal sWAT, in Southeast Asian men and women30. This result was confirmed in a separate study49, which compared COL6A3 mRNA expression in sWAT of Southeast Asian and white populations without obesity, and demonstrated that COL6A3 mRNA expression was almost twofold higher in Southeast Asian people. These results correlate with a higher ratio of small to large adipocytes in sWAT of Southeast Asian people than in sWAT of white people50.

As mentioned already, the CAV1 polymorphism rs4236601 is common in white populations but rare in Asian populations45. As this polymorphism leads to decreased CAV1 mRNA expression in adipose tissue of white individuals, it might affect the interactions between CAV1 and MMP14 and/or ERα differently in various ethnic groups. We propose that both the higher content of endotrophin and the absence of this CAV1 polymorphism lead to higher fibrotic content in sWAT of Asian

individuals than sWAT of white individuals, and thus the risk of lipoedema in Asian individuals is lower.

Potential interventionsThere are some physical methods that modulate expression of CAV1 (and correspondingly also MMPs); among them is thermomechanical stress15–19. Moreover, some pharmacological interventions can also substantially modulate CAV1 expression. These include retinoids, corticosteroids, curcumin, statins and others. In a 2020 article, we analysed the relevance of CAV1- modulating interventions for hyperproliferative and inflammatory skin disorders19. Especially interesting is the role of CAV1 in drug resistance, which seems to be more and more evident not only in oncology, but also in dermatology19.

Relevance for syndromic featuresSome syndromic features of lipoedema are now described in the literature. Among others, these are a reduced risk of T2DM, an elevated risk of morbid obesity, adipose tissue pain, bruising and joint hypermobility, high resistance of the affected adipose tissue to diet and exercise, a high likelihood of a strong genetic component connected with autosomal dominant inheritance, and fatigue51. Here, we briefly summarize the

possible involvement of a dysregulation of the MMP14–CAV1 axis in the appearance of some of these syndromic features.

Reduced risk of T2DM. Several groups have reported that women with lipoedema demonstrate a reduced prevalence of T2DM compared with the general population of women in the affected age group52. The activation of MMP2, MMP9 and MMP14 expression is generally associated with deficiency of angiotensin- converting enzyme 2 (ACE2) and thus with the proper functioning of the renin–angiotensin system53. A large genome- wide association study including almost 900,000 records of patients with T2DM revealed that the appearance of the disease is causally linked with high probability to an increased expression of ACE2 (reF.54). Insulin admini-stration reduces ACE2 expression in different types of diabetic mouse models55, whereas administration of antidiabetic PPARγ agonists upregulates ACE2 expression in different organs and tissues in rats56.

Elevated risk of morbid obesity. Obesity is a known comorbidity of lipoedema. However, women with lipoedema are also thought to have an increased risk of developing morbid obesity51. These observations correspond to our finding in 2020 that endotrophin and MMP14 levels are strongly increased in the obese state in a mouse model and in humans5.

Tenderness on palpation. Patients with lipoedema display a tenderness on palpation, which normally disappears upon removal of adipose tissue in the affected area57. Development of neuropathic pain in affected areas of adipose tissue is connected with increased expression of the gelatinases MMP2 and MMP9 (reF.58). MMP14 is an activator of MMP2, and MMP14 overexpression normally stimulates the expression of MMP2. Local adipose tissue removal should reduce the MMP2 and MMP14 expression, thus also reducing the neuropathic pain. However, this hypothesis requires more experimental validation.

Bruising and joint hypermobility. Bruising and joint hypermobility are reported to be typical in lipoedema, thus connecting this condition with hypermobile- type Ehlers–Danlos syndrome (hEDS)52,59. hEDS is a non- inflammatory disorder of connective tissue, which is connected with mutations in COL3A1. No mutations of this gene have been found in lipoedema60.

CAV1

MMP14

Overexpression of MMP14• Hypertrophic phenotype in sWAT• Reduced expression of PROX1 leading

to malfunctioning of lymphatic system• Cleavage of perivascular matrix,

increase of permeability and fragilityof blood vessels

• Reduced content of fibrotic componentsin ECM

Polymorphism of CAV1• Much more common in white people than in

Asian people, suggesting ethnic differences• Oestrogen-dependent effect (reduction of

ER in adipocytes leads to adipocytehypertrophy in women)

Uncoupling ofMMP14 and CAV1

Fig. 2 | cellular consequences of a disruption of the cAV1–MMP14 interaction. In lipoedema, caveolin 1 (CAV1) is dysfunctional, which can be caused either by the lack of its phosphorylation due to a dysfunctional tyrosine or by polymorphisms in the CAV1 gene. Dysfunctional CAV1 in adipose tissue becomes uncoupled from key feedback loops with matrix metalloproteinase 14 (MMP14), oes-trogen receptor (ER) and prospero homeobox 1 (PROX1). This uncoupling causes morphologi-cal changes in subcutaneous white adipose tissue (sWAT), malfunctioning of the lymphatic system, increased permeability and fragility of blood vessels, and reduction of fibrotic content in the extracellular matrix (ECM).

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However, administration of the broad- spectrum MMP inhibitor, doxycycline, led to improvement in a mouse model of hEDS61. This finding points to a relationship between hEDS and expression of MMPs and highlights the possible similarities in pathogenic pathways in hEDS and lipoedema. Further research is needed to check the possible role of MMP14 in hEDS.

Resistance of affected adipose tissue to diet and exercise. Whereas adipose tissue in people who are healthy and in those with obesity can be reduced by the individuals undertaking extreme dieting or exercise, lipoedemic adipose tissue remains resistant. As we demonstrated in a 2020 study5, overexpression of MMP14 causes a substantial upregulation of perilipin 1, which is involved in the stabilization of lipid droplets, making adipose tissue less sensitive to lipolysis. This finding might also be reflected in a low rate of dyslipidaemia observed in patients with lipoedema52.

Heritability. Lipoedema is thought to have a strong genetic component with autosomal dominant inheritance. A positive family history of lipoedema is found in up to 64% of affected women, and several gene mutations have been considered as a reason for lipoedema appearance60. According to the theory presented in this article, more attention should be paid to the polymorphism in MMP14 and CAV1.

Fatigue. Some studies have found high rates of fatigue in patients with lipoedema59. Among others, fatigue was associated with peripheral overexpression of inflammatory cytokines62. Such production is associated with decreased expression of CAV1, and CAV1 deficiency leads to a massive increase in interleukin production in affected tissues. In a 2011 study, such a mechanism was associated with atopic dermatitis63. This topic must be investigated more carefully in lipoedema.

ConclusionsOn the basis of the mechanism of action proposed here, we suggest that lipoedema is an oestrogen- dependent disorder of adipose tissue, which is triggered by a dysfunction of CAV1. This malfunctioning can be caused by defective phosphorylation of CAV1 or by a polymorphism. Such disturbance causes the uncoupling of CAV1 from MMP14 cell surface expression as well as an uncoupling of feedback mechanisms between CAV1 and ERα (Fig. 1). The first uncoupling triggers overexpression of

MMP14, which leads to increased cleavage events in the pericellular and perivascular matrix, producing a hypertrophic expansion of sWAT. The second uncoupling event leads to the activation of ERs, rendering adipose tissue more oestrogen sensitive. In addition, dysfunction of CAV1 will disturb the PROX1–CAV1 axis, thereby influencing the functioning of lymphatic vessels. CAV1 expression, its polymorphisms and its possible role in lipoedema must be carefully investigated in future research.Ilja L. Kruglikov1, Nolwenn Joffin2 and Philipp E. Scherer 2 ✉

1Scientific Department, Wellcomet GmbH, Karlsruhe, Germany.2Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

✉e- mail: philipp.scherer@utsouthwestern.edu

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AcknowledgementsN.J. acknowledges the support of a postdoctoral fellowship from the Lipedema Foundation (LFA #18). P.E.S. acknowl-edges the support of NIH grants R01- DK55758, R01- DK099110, RC2- DK118620, P01- DK088761 and P01- AG051459, and is also supported by an unrestricted grant from the Novo Nordisk Research Foundation.

Author contributionsThe authors contributed equally to all aspects of this article.

Competing interestsI.L.K. is the managing partner of Wellcomet GmbH. Wellcomet GmbH provided support in the form of salaries for I.L.K., but did not have any additional role in decision to publish or preparation of the manuscript. The commercial affiliation of I.L.K. with Wellcomet GmbH does not alter the adherence to all journal policies on sharing data and materials. The other authors declare no competing interests.

Peer review informationNature Reviews Endocrinology thanks K. Herbst, G. Szolnoky and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary informationSupplementary information is available for this paper at https://doi.org/10.1038/s41574-020-0395- z. © Springer Nature Limited 2020

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