Current Diabetes Reports

, Volume 13, Issue 6, pp 757–767

What the Genetics of Lipodystrophy Can Teach Us About Insulin Resistance and Diabetes


  • Camille Vatier
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
    • AP-HP, Hôpital Pitié-Salpêtrière, Service de Nutrition
  • Guillaume Bidault
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
  • Nolwenn Briand
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
  • Anne-Claire Guénantin
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
  • Laurence Teyssières
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
  • Olivier Lascols
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
    • AP-HP, Hôpital Saint-AntoineLaboratoire Commun de Biologie et Génétique Moléculaires
  • Jacqueline Capeau
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
    • AP-HP, Hôpital TenonService de Biochimie et Hormonologie
    • INSERM UMR_S938Centre de Recherche Saint-Antoine
    • UPMC Univ Paris 6, UMR_S938
    • ICAN, Institute of Cardiometabolism and Nutrition
    • AP-HP, Hôpital TenonService de Biochimie et Hormonologie
    • Faculté de Médecine Pierre et Marie Curie, site Saint-Antoine, UMR_S938
Genetics (TM Frayling, Section Editor)

DOI: 10.1007/s11892-013-0431-7

Cite this article as:
Vatier, C., Bidault, G., Briand, N. et al. Curr Diab Rep (2013) 13: 757. doi:10.1007/s11892-013-0431-7


Genetic lipodystrophic syndromes are rare diseases characterized by generalized or partial fat atrophy (lipoatrophy) associated with severe metabolic complications such as insulin resistance (IR), diabetes, dyslipidemia, nonalcoholic fatty liver disease, and ovarian hyperandrogenism. During the last 15 years, mutations in several genes have been shown to be responsible for monogenic forms of lipodystrophic syndromes, of autosomal dominant or recessive transmission. Although the molecular basis of lipodystrophies is heterogeneous, most mutated genes lead to impaired adipogenesis, adipocyte lipid storage, and/or formation or maintenance of the adipocyte lipid droplet (LD), showing that primary alterations of adipose tissue (AT) can result in severe systemic metabolic and endocrine consequences. The reduced expandability of AT alters its ability to buffer excess caloric intake, leading to ectopic lipid storage that impairs insulin signaling and other cellular functions (“lipotoxicity”). Genetic studies have also pointed out the close relationships between ageing, inflammatory processes, lipodystrophy, and IR.


Adipose tissueLipodystrophyLipid dropletsAdipogenesisInsulin resistanceDiabetesDyslipidemiaLiver steatosisPolycystic ovary syndromeAgeingGeneticsSeipinAGPAT2A-type laminsPPARγPerilipinCaveolin 1Cavin 1CaveolaeCIDECAkt2PSMB8ProgeriaZMPSTE24Genetics


Insulin resistance (IR), frequently associated with obesity, is a highly prevalent risk factor for cardiovascular diseases, type 2 diabetes, and fatty liver disease. A better understanding of its pathophysiology is a prerequisite for an efficient prevention and treatment in the general population. In this setting, the studies of genetic lipodystrophic syndromes, rare monogenic models of insulin resistance, have provided important clues.

Lipodystrophic syndromes are rare diseases with congenital or acquired loss of body fat. Paradoxically, the metabolic consequences of having «too little» fat (lipoatrophy) are remarkably similar to those of having «too much» fat (obesity). Excess energy, stored as lipids in ectopic sites, leads to IR, dyslipidemia, diabetes, with cardiovascular, reproductive, and liver complications.

Recent advances in molecular genetics of lipodystrophic syndromes have revealed that primary defects in biogenesis and metabolism of adipose lipid droplet (LD) are important pathophysiological issues [1, 2], highlighting the central role for AT in systemic metabolism.

Since 1999, more than 10 genes involved in lipodystrophies have been identified [3, 4, 5, 6, 7, 8, 9, 10, 11, 12••] (Table 1). In addition, complex syndromes associating lipodystrophy and premature aging or auto-inflammatory features have revealed that AT can be damaged by senescence and/or immuno-inflammatory processes [1317, 18••, 19]. Due to the growing availability of powerful genetic tools, new genes will probably be linked to still undeciphered lipodystrophic syndromes.
Table 1

Human genetic lipodystrophic syndromes and main affected genes

Main role of affected protein



AD or AR transmission


Partial lipodystrophy


Protein of the nuclear envelope


LMNA / lamin A/C


Protein of the nuclear envelope

Metabolic laminopathies

LMNA / lamin A/C


Protein of the nuclear envelope


LMNA / lamin A/C


Key transcription factor for adipocyte differentiation




Lipolysis regulation of the adipocyte lipid droplet


PLIN1 / perilipin


Structure of the adipocyte lipid droplet




Serine threonine kinase involved in insulin signaling


AKT2 / Akt2


Protein of the nuclear envelope


LMNB2 / lamin B2

risk factor


Generalized lipodystrophy


Enzyme of triglyceride and glycerophospholipid synthesis




Formation of lipid droplet


BSCL2 / seipin


Structural protein of caveolae and adipocyte lipid droplet


CAV1 / caveolin 1


Structural protein of caveolae and adipocyte lipid droplet


PTRF / cavin 1


Protein of the nuclear envelope

Hutchinson-Gilford progeria

LMNA / lamin A/C


de novo


Endoprotease involved in lamin A maturation


ZMPSTE24 / Zmpste24


Immunoproteasome subunit




AD autosomal dominant, AGPAT2 acylglycerol-3-phosphate O-Acyltransferase, APL acquired partial lipodystrophy, AR autosomal recessive, BSCL Berardinelli-Seip congenital lipodystrophy, FPLD familial partial lipodystrophy, JMP joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy MAD mandibuloacral dysplasia, PSMB8 proteasome subunit, beta-type, 8

AT is now well-known not only as a metabolic tissue, but also as an important paracrine and endocrine organ [20, 21]. Among many adipose secretory products, leptin, which plasma levels generally reflect the AT mass, regulates food intake and energy consumption, but also distribution of cellular storage. Adiponectin also modulates insulin sensitivity. Several proteins of the renin-angiotensin system, produced by AT, influence its development and functions and could link both obesity and lipodystrophy to hypertension [22]. Moreover, adipokines secreted by AT contribute to immune and inflammatory processes [23] and their role as important cancer microenvironment factors has recently emerged [24].

In this review, we report how genetic studies of monogenic forms of lipodystrophic syndromes have offered the unique opportunity to reveal the importance of AT for the whole body metabolism.

Murine Models of Lipodystrophies

Several mouse models of generalized lipodystrophy have been generated, using knock-out or overexpression of key genes. Models of generalized lipodystrophy recapitulated most of the features of human diseases, but partial lipodystrophy phenotypes were more difficult to generate, probably because of important differences in AT distribution between mice and humans. Nevertheless, murine models have been important tools showing that loss of AT initiates both lipodystrophy and metabolic consequences [25, 26]. In accordance, transplantation of healthy AT [27] but not leptin-deficient ob/ob AT [28] reversed insulin resistance in lipodystrophic mice, showing the major role of both fat-storing capacities and leptin for metabolic homeostasis. Metabolic improvements obtained in lipodystrophic mice with leptin infusion or overexpression [29] have allowed initiation of successful therapeutic trials of leptin treatment in human lipodystrophies.

Human Inherited Lipodystrophies


The worldwide prevalence of genetic lipodystrophies is not precisely known. It was evaluated at about 1 per 10 million for congenital generalized lipodystrophies (CGL) in the US [30]; in France our records suggest that it could be of 1 to 5 per million. The prevalence of familial partial lipodystrophies (FPLD) is also probably under-estimated. Patients, and more specifically men, in whom the morphotype is frequently moderate, are frequently diagnosed with a metabolic syndrome without any search for molecular alterations, an android distribution of fat being frequent in metabolic syndrome and type 2 diabetes.

Clinical Characteristics

In inherited lipodystrophies, lipoatrophy could be present at birth or later in life, the extent of fat loss varying from partial to complete. In addition to lipoatrophy, clinical signs of IR, thought to be linked to effects of severe hyperinsulinemia on IGF1 receptors, can help diagnosis: skin lesions of acanthosis nigricans, a brownish lesion of axillae, neck and other body folds; acromegaloid features, striking at the level of face and extremities; muscular hypertrophy, even more visible due to the lack of subcutaneous adipose tissue (SAT); ovarian hyperandrogenism with hirsutism or virilization and oligomenorrhea in the context of polycystic ovary syndrome or hyperthecosis.

Patients with CGL are characterized by total absence of AT evident from birth [31], marked muscular appearance with prominent veins, severe acromegaloid features, acanthosis nigricans, hepatomegaly, and umbilical prominence. They often have a voracious appetite and children frequently show an accelerated linear growth.

In FPLD, lipoatrophy mostly involves the extremities with variable fat loss from the trunk. The body fat distribution is unremarkable at birth and during childhood, progressive loss of fat occurring during late childhood or after puberty. In lamin A-linked forms, peripheral lipoatrophy contrasts with accumulation of subcutaneous fat (SAT) over the face, chin, supraclavicular and dorsocervical regions, and frequently intra-abdominal fat stores [32, 33]. Similar to patients with CGL, acanthosis nigricans and hepatomegaly can be prominent, and female patients frequently show features of polycystic ovarian syndrome [34]. CGL and FPLD are of autosomal recessive or dominant inheritance, depending on the gene involved (Table 1).

Both partial and generalized lipodystrophy have also been reported in patients with premature ageing syndromes, as presented below.

Biological Signs

Metabolic alterations can be mild or absent during childhood, and increase with age. Lipid alterations associate increased triglyceride (TG) level and decreased HDL-cholesterol, with a high risk of acute pancreatitis. Striking hyperinsulinemia is usually able to control glycemia in childhood, but glucose intolerance and then diabetes frequently occur around puberty. Serum adiponectin and leptin concentrations are reduced in proportion to the extent of fat loss [35]. In CGL2, a surprisingly detectable adiponectin level has been reported [36].


Whole-body dual-energy X-ray absorptiometry (DEXA) evaluates the total body fat amount, and the distribution of AT. It can help for phenotypic characterization of lipodystrophies, in particular in precocious identification of partial forms [37]. Computerized tomography (CT) or magnetic resonance imaging (MRI) at the lumbar L4 level, assessing abdominal fat, distinguishes between subcutaneous and visceral fat depots [38].

Hepatomegaly and nonalcoholic fatty liver disease are evaluated using ultrasound, CT, and MRI. Hepatic elastometry helps to diagnose liver fibrotic changes.

As patients with CGL could present with bone lesions [39] (see below), conventional bone radiographies and CT are needed. Cardiovascular investigations are also useful for the phenotype characterization and the medical care in lipodystrophic patients; cardiac rhythm and conduction disturbances have to be checked carefully in case of lamin A-linked lipodystrophies [40, 61].


Chronic complications are related to diabetes and dyslipidemia (microangiopathy, recurrent acute pancreatitis, cardiovascular diseases), to nonalcoholic fatty liver disease (steatohepatitis and cirrhosis), and to reproductive abnormalities due to ovarian hyperandrogenism (infertility).

Early-onset and severe hypertension is frequent, particularly in peroxisome proliferator-activated receptor gamma (PPAR-γ) -linked forms.

Differential Diagnosis

Genetic lipodystrophies can be difficult to differentiate first from primary syndromes of IR and second from acquired lipodystrophic syndromes.

Indeed, syndromes of severe IR due to mutations of the insulin receptor are associated with a generalized paucity of body fat when both alleles are affected (leprechaunism or Donohue syndrome and Rabson-Mendenhall syndrome). These syndromes of extreme insulin resistance expressed in newborns or children are developmental disorders, with dysmorphic features and growth delay [41]. Notable differences with lipodystrophic syndromes are the usual absence of dyslipidemia and liver steatosis, and the high adiponectin levels, consistent with the generalized impairment of insulin-stimulated pathways. In contrast, in lipodystrophies, primary adipose tissue defects induce insulin resistance at a post-receptor level: the ability of insulin to suppress hepatic gluconeogenesis is impaired, leading to hyperglycemia and hyperinsulinemia, but the insulin-stimulated lipogenesis pathway is preserved, with increased production of TG by the liver [42]. Through a collaborative study, we have recently shown that the SHORT syndrome (short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Reiger anomaly and teething delay), another developmental disorder associated with insulin resistance and generalized paucity of fat, is a syndrome of primary insulin resistance due to PIK3R1 mutations affecting a proximal intermediate of the insulin signaling pathways [43].

Other anomalies of fat distribution must be distinguished from genetic lipodystrophic syndromes. Among them, the Launois-Bensaude lipomatosis is characterized by multiple localized fat tumors of the proximal limbs and neck, of unknown origin, often associated with peripheral neuropathy and increased alcohol intake, and variable metabolic alterations. In rare cases, lipomatosis is associated with other diseases linked to altered mitochondrial DNA. Acquired lipodystrophic syndromes occurring in late infancy or young adulthood, are frequently associated with autoimmune features. Some HIV antiretrovirals or endogenous or exogenous hypercortisolism also lead to lipodystrophic syndromes. Finally, the aging process leads to fat redistribution with relative peripheral lipoatrophy and visceral fat accumulation and increased risk of metabolic disturbances [2].

Human Genetic Lipodystrophic Syndromes Are Heterogeneous Monogenic Diseases (Table 1 and Fig. 1)
Fig. 1

Proteins involved in genetic lipodystrophic syndromes. Pluripotent mesenchymal stem cells can differentiate into preadipocytes depending upon the signals from hormones such as insulin, steroids and other adipogenic transcription factors, mainly CCAAT (cytidine-cytidine-adenosine-adenosine-thymidine)-enhancer-binding proteins (C/EBP) β/δ, PPARγ, C/EBPα, and sterol regulatory element-binding protein (SREBP) 1c. Seipin, AGPAT2 and AKT2 may also be involved in adipocyte differentiation. Other proteins involved in lipodystrophies are critical for maturation of preadipocytes and/or maintenance of mature adipocyte phenotype

In the last 14 years, mutations in more than 10 genes have been found to be responsible for lipodystrophic syndromes, bearing new light on the relationships between AT and metabolism.

Congenital Generalized Lipodystrophies (CGL)

The genetic defect underlying CGL (or BSCL, Berardinelli-Seip congenital lipodystrophy), of recessive inheritance, has been identified in more than 90 % of cases, with 1 of 2 main genes involved in most cases (encoding seipin (BSCL2) [6], or AGPAT2 (1-acylglycerol-3-phosphate-O-acyltransferase 2) (BSCL1) [7]. Far less often caveolin-1 (BSCL3) [9] or cavin-1/PTRF (polymerase I and transcript release factor) (BSCL4) are involved [11]. All the mutated proteins act on the pathways of TG synthesis and/or storage in the adipocyte LD (Fig. 1).

If clinical presentation is very similar whatever the genotype, patients with BSCL2 have the most severe phenotype (lipoatrophy implicating all fat depots with also paucity of mechanical fat, hypertrophic cardiomyopathy) [44, 45], with frequent mild mental retardation whereas AGPAT2 mutations are frequently associated with skeletal alterations (osteoblastic nodules, diffuse bone sclerosis, lytic lesions [39]) and cavin-1/PTRF mutations with muscular dystrophy.


Bi-allelic mutations affecting AGPAT2 [7] on chromosome 9q34, are expected to entirely abrogate protein function or expression.

AGPAT2 is an enzyme that catalyses the synthesis of phosphatidic acid from acyl-CoAs in the endoplasmic reticulum (ER) of adipocytes, the site of LD formation [46•]. AGPAT2 deficiency might thus prevent TG synthesis and mature lipid adipocytes droplet formation. In addition, it could also impair the synthesis of other lipids involved in adipocyte differentiation [47].


Seipin is encoded by BSCL2 on chromosome 11q13 [6]. CGL is linked to BSCL2 bi-allelic inactivating mutations.

Seipin is an integral protein of the ER involved in the adipogenesis process [48•]. At the ER level, it mediates the lipidation of nascent LDs and their maintenance [49, 50, 51•] and regulates fatty acid monoinsaturation [48•, 50]. To note, gain-of-toxic-function heterozygous BSCL2 mutations are responsible for motor neuron diseases [52], with decreased neuronal TG content and endoplasmic reticulum stress [53].


Mutations in CAV1, encoding caveolin-1 were identified in a patient with CGL, short stature, and resistance to vitamin D [9] (homozygous nonsense mutation) and thereafter in cases of atypical partial lipodystrophy (heterozygous mutations) [54].

Caveolin-1 is the major coating protein of caveolae, plasma membrane invaginations particularly abundant in adipocytes, but can also be found at the LD surface [55, 56]. Caveolin-1 regulates several signaling pathways in adipocytes, including insulin signaling and lipolysis. Defects in insulin and lipolytic responses in caveolin-1 deficient adipocytes may contribute to a nutrient shortage, leading to autophagy [57•]. In addition, caveolin-1 deficient adipocytes show a global alteration of phospholipid composition of the LD surface, suggesting a regulatory role of caveolin-1 on LD expandability [58].


Mutations affecting both alleles of cavin-1/PTRF lead to a mixed phenotype of generalized lipodystrophy and muscular dystrophy [11]. Pyloric stenosis and cardiac arrhythmia have also been described [59].

Cavin-1 is colocalized with caveolin-1 on the adipocyte LD [58] and is involved in the stabilization and last phase of biogenesis of caveolae [60]. Loss of cavin-1 causes loss of caveolae and a reduced expression and mislocalization of the caveolins [10].

Causes of Genetic Partial Lipodystrophies

Partial forms of genetic lipodystrophies, collectively named FPLD, are more common than generalized forms. FPLD are generally dominantly inherited, except some forms, due to mutations in Cell death-inducing DFF45-like effector C (CIDEC) [10] or LMNA in rare cases [61, 62], which are codominantly or recessively transmitted.

Lamin A/C

The most typical form of FPLD is the Dunnigan type (or FPLD2), linked to heterozygous LMNA mutations. Mutations in this gene cause a group of rare disorders (laminopathies), of wide clinical heterogeneity ranging from cardiac and muscular phenotypes to lipodystrophic syndromes and premature aging syndromes [63].

The 2 major A-type lamins, prelamin A and lamin C, arise from alternative splicing of the LMNA gene. Prelamin A is posttranslationally processed with a step of farnesylation followed by ZMPSTE24-mediated cleavage, resulting in mature non-farnesylated lamin A release. A-type lamins, expressed in most differentiated cells, form with B-type lamins the lamina network beneath the inner nuclear membrane, which maintains the nucleus shape and interact with the cytoskeleton. Also found in the nucleoplasm, they interact with chromatin, DNA, and transcription factors, and regulate several functions including gene transcription [64].

FPLD2 is mainly due to p.R482 heterozygous substitutions affecting the C-terminal domain of A-type lamins, involved DNA and the adipogenic transcription factor SREBP-1c binding [4, 5]. The phenotype of the disease is more severe in women than in men [65, 66]. In addition to lipoatrophy, FPLD2 is characterized by an expansion of dystrophic facio-cervical fat [67•].

Other LMNA mutations result in atypical lipodystrophies [40, 68] and/or in mixed phenotypes with muscular or cardiac dystrophies or progeria-like features [69, 70], and to well-characterized accelerated ageing syndromes [1315] (see below).

The pathophysiology of the different laminopathies, which affect highly specialized tissues but are due to alterations in ubiquitously expressed proteins, remains to be clarified. Both cellular mechanical stress and alterations of gene expression could be involved. We and others described the toxicity of farnesylated R482-mutated prelamin-A, leading to premature cellular senescence [17, 71]. However, we observed that human homozygous LMNA p.T655fsX49 mutation, resulting in the expression of non-farnesylated prelamin A without mature lamin A, led to a lipodystrophic syndrome [61], showing that permanent farnesylation of mutated lamin A is not the unique factor leading to LMNA-linked lipodystrophies.

Interestingly, studies using induced pluripotent stem cells (iPSC), which express wild-type or mutated A-type lamins during differentiation, have shown that mutated A-type lamins lead to defects in the mesenchymal and smooth muscle lineages [72••, 73••]. In addition, LMNA mutations perturb the balance between proliferation and differentiation in adult stem cells [7476]. Defects in specific tissular differentiation in response to different A-type lamins alterations could underlie the heterogeneous laminopathic phenotypes.


The transcription factor PPARγ plays a leading role in adipogenesis and also exerts anti-inflammatory and antioxidant effects [77].

Rare dominant-negative and loss-of-function heterozygous mutations affecting the ligand- or the DNA-binding domains of PPARγ have been identified in patients with FPLD (FPLD3) [3, 78]. Severe hypertension linked to FPLD3 may result from the ability of mutated PPARγ to activate the cellular renin-angiotensin system in cells from the vascular wall [79•].


AKT2 encodes the protein kinase B, an important intermediate of insulin signaling, has been involved in one FPLD family [8]. Post-receptor insulin resistance sparing the lipogenesis pathway has been reported in this family [42••].


CIDEC participates in adipose LD formation and contributes to the preadipocyte differentiation process [80]. A homozygous truncating non-sense mutation of CIDEC (p.E186X) has been identified in a case of partial lipoatrophic syndrome, leading to decreased fat mass and multiloculated adipose LD [10].


Perilipin (now called perilipin-1) is localized at the surface of LD in adipocytes and steroidogenic cells. Perilipin-1 reduces basal lipolysis, but also activates lipolysis in response to catecholamines.

Heterozygous inactivating mutations of the perilipin gene (PLIN1), inducing a sustained constitutive lipolysis [12••, 81], are responsible for FPLD4 [12••], with inflammation and fibrosis of fat tissue, and whole body metabolic consequences (ie, insulin resistance and dyslipidemia).

“Acquired” Partial Lipodystrophy and Lamin B2

Barraquer-Simons syndrome, also called acquired generalized lipodystrophy (APL), with lipoatrophy affecting progressively the face and upper body, was classically considered as an immune disease, since it is associated with auto-immune disorders and/or membrano-proliferative glomerulonephritis. However, 5 patients with AGL have been reported with heterozygous mutations in LMNB2, encoding lamin B2, a partner of A-type lamins at the nuclear envelope. These genetic alterations could be risk factors for the disease [82, 83].

Lipodystrophies Associated With Premature Ageing

Generalized or partial forms of lipoatrophy are observed in several premature ageing syndromes. First, heterozygous mutations of LMNA are responsible for the typical form of Hutchinson-Gilford progeria, due to the synthesis of a permanently farnesylated mutated prelamin A, [14, 15] and to other progeroid syndromes [69, 70], characterized by post-natal growth retardation, craniofacial dysmorphy, skeletal and skin abnormalities, and generalized lipoatrophy. Other rare, biallelic, LMNA mutations lead to A-type mandibuloacral dysplasia (MAD), with alterations of the same tissues and FPLD-like partial lipodystrophy [13]. Homozygous mutations of the zinc metalloproteinase ZMPSTE24, which cleaves farnesylated prelamin A into mature lamin A, can lead to MAD type B, with generalized lipoatrophy [16]. These diseases point to the involvement of farnesylated prelamin A, which, by altering its binding properties, especially for the membranes, leads to cellular senescence. In accordance, the inhibition of ZMPSTE24 by some HIV protease inhibitors could also contribute to the antiretroviral-linked lipodystrophic syndromes [17, 84]. However, the therapeutical benefits of farnesyl-transferase inhibitors in children with Hutchinson-Gilford progeria were only partial, improving predominantly vascular stiffness [85••].

Other premature ageing syndromes, linked to DNA repair defects, can also associate with IR and altered fat repartition. Our group recently showed that partial lipodystrophy and severe IR can reveal Werner syndrome, due to inactivating biallelic mutations of WRN, a DNA helicase. Increased lamin B1 expression could play a role in premature senescence of WRN-mutated cells [86]. In addition, Weedon et al recently observed that heterozygous mutations in POLD1, encoding DNA polymerase δ, which cooperates with WRN to maintain genome stability, also lead to a multisystem disorder with lipodystrophy [87].

Lipodystrophy Associated With Autoinflammation

Inflammatory or immune processes can lead to inflammation then fibrosis of AT, as observed in localized lipoatrophies due to iatrogenic aggression of AT (for example injections of corticosteroid, insulin, or antibiotics) [88].

Recently, Garg et al deciphered the molecular basis of the JMP syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy) associated with autoinflammation (recurrent fever with osteo-articular and muscular symptoms). Partial lipoatrophy, developed during infancy, affects mainly the upper part of the body. Homozygous mutations affected PSMB8, encoding a catalytic subunit of the immunoproteasome [18••]. Several groups confirmed the alterations of this gene in similar phenotypes denominated CANDLE or JASP (Japanese autoinflammatory syndrome) [19].

Metabolic Consequences of Lipodystrophies (Fig. 1)

Patients with lipodystrophies present metabolic consequences that are remarkably similar to those observed in obesity, but generally more severe, showing that maintaining a healthy fat amount is an essential requirement for metabolic homeostasis. In addition, these diseases also illustrate the fact that subcutaneous fat of the lower part of the body is mostly metabolically favorable, being able to buffer fat excess and protect against lipotoxicity [89]. Conversely, in the upper part of the body, limited fat expansion leads to overwhelming of fat and ectopic lipid deposition in other tissues, as liver, muscles, heart and vessels, and pancreas [90]. However, Barraquer-Simons syndrome with the reverse distribution of fat compared with FPLD2, can be associated, although less frequently, with severe insulin resistance.

AT has emerged as an integrator of a wide array of homeostatic processes, including blood pressure control, insulin sensitivity, and regulation of inflammation and immune processes through the secretion of numerous adipokines [2024].

Most of the proteins mutated in human lipodystrophies are directly involved in adipogenesis (PPARγ, probably lamin A/C, seipin, AGPAT2), the synthesis and maintenance of the LD (seipin, perilipin, CIDEC, caveolin 1 and cavin-1) or are acting in the pathways leading to lipid synthesis or storage, at the level of the nucleus, ER or caveolae (lamins A/C through their binding to SREBP-1c, AGPAT2, caveolin 1, and cavin-1).

It is considered that AT expandability is finite up to a particular set point that varies on an individual basis. Beyond this set point, additional energy excess results in AT failure with oxidative stress, recruitment of macrophages, release of proinflammatory cytokines and of free fatty acid (FFA) and decreased adiponectin and leptin, leading to lipotoxicity. Genetically limited expansion of fat in lipodystrophies lowers the set point for fat storage leading to ectopic deposition of lipids and severe metabolic deregulation.

Therapeutic Options for Lipodystrophic Syndromes

Diet and Exercise

A well-balanced diet is particularly important for lipodystrophic patients, who are not capable to correctly store excess energy as fat. Reduction of energy intake, particularly dietary fat, is very useful to avoid ectopic lipid deposition, and thus metabolic disturbances, but excess consumption of carbohydrates, which enhances de novo lipogenesis, should also be avoided. However, reduction of energy intake is frequently difficult for lipodystrophic patients, due to a voracious appetite resulting from very low levels of leptin. In addition, diet should be carefully monitored in children to allow adequate growth and development.

Similarly, increasing energy expenditure with daily physical activity, particularly aerobic exercise, can notably improve metabolic complications in lipodystrophy.


Due to insulin resistance, diabetes is generally difficult to control in lipodystrophies. Insulin sensitizers are the first line of therapy. However metformin therapy has not been studied specifically in patients with lipodystrophies. A treatment with thiazolidinediones was beneficial in several patients, even those with mutations in PPARγ, but it is no longer available in France and its use is restricted in several countries. Very high doses of insulin are frequently required. Medium chain triglycerides supplementation and /or omega-3 polyunsaturated fatty acids from fish oils could contribute to lower TG [91]. Otherwise, hypolipidemic drugs such as fibrates are required to avoid major hypertriglyceridemia [92].

In women with lipodystrophies, ethinylestradiol should be used with caution because of the risks of hypertriglyceridemia and acute pancreatitis.

Substitution with leptin, administered as human recombinant metreleptin, has resulted in markedly improved metabolic homeostasis and regression of liver steatosis, particularly in severe lipoatrophic and hypoleptinemic patients [9396]. Leptin therapy reduces appetite and results in weight loss, which contributes to metabolic improvement. In addition, leptin can enhance insulin sensitivity by activating muscular adenosine monophosphate kinase (AMPK), thus decreasing lipotoxicity. Our recent results showed an improvement in insulin secretion in leptin-treated lipodystrophic patients (Vatier et al in preparation). Metreleptin is available through compassionate programs for the moment.

Other therapeutic options have been proposed, but have not been evaluated in humans. Among them, AMPK activators [97], adiponectin replacement, which has been reported to lower plasma glucose and FFA levels in mouse models of lipodystrophy or diabetes [98], inhibitors of 11β-HSD1 or glucocorticoid receptor inhibitors, which could reduce IR, and inhibitors of pancreatic endoplasmic reticulum kinase, which may reduce endoplasmic reticulum stress.

Plastic Surgery

The altered body fat repartition can benefit from plastic surgery, in particular for patients with partial lipodystrophy [99].


Lipodystrophies represent a heterogeneous group of severe diseases leading to early complications. Genetic studies of these diseases, showing the involvement of several proteins involved in adipocyte differentiation and/or in adipocyte LD biogenesis and metabolism, enlightened the leading role of adipose tissue for global metabolic homeostasis. In addition, metabolic studies have shown that primary defects of adipose tissue resulted in secondary insulin resistance, affecting heterogeneously the different insulin signaling pathways.

Therefore, studies on human lipodystrophies help to understand the complex physiology and pathophysiology of fat. They point to new genes and new targets, which could lead to the discovery of new and innovative therapeutic clues that could also offer new perspectives for metabolic syndrome and type 2 diabetes.


The researches of the authors are supported by Institut de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), and Agence Nationale de la Recherche (program “Investments for the Future”, Institute of Cardiometabolism and Nutrition [ICAN]; grant no. ANR-10-IAHU).

C. Vatier is the recipient of a PhD grant from the Conseil Régional d’Ile de France (Cardiovasculaire-Obésité-Diabète Domaine d’Intérêt Majeur), G. Bidault. of a PhD grant from the Fondation pour la Recherche Médicale, N. Briand of post-doctoral grant from Région Ile-de-France (DIM Biotherapies), A-C. Guénantin of a post-doctoral grant from Institute of Cardiometabolism and Nutrition (Innovative projects 2012) and L. Teyssières of a master grant from Agence Régionale de Santé Limousin.

Compliance with Ethics Guidelines

Conflict of Interest

Camille Vatier has been on the Advisory board on lipodystrophy and leptin for Astra-Zeneca; has received the SFE 2012 Oral communication award from Novartis; has received honoraria from Sanofi; has received payment for manuscript preparation from Elsevier Masson; and has received travel/accommodations expenses covered or reimbursed for meetings from Novo-Nordisk, Servier, and Lilly.

Guillaume Bidault declares that he has no conflict of interest. Nolwenn Briand declares that she has no conflict of interest. Anne-Claire Guénantin declares that she has no conflict of interest. Laurence Teyssières declares that she has no conflict of interest. Olivier Lascols declares that he has no conflict of interest. Jacqueline Capeau declares that she has no conflict of interest. Corinne Vigouroux has been on the Advisory board on lipodystrophy and leptin for Astra-Zeneca; and has received travel/accommodations expenses covered or reimbursed for meetings from Boehringer-Ingelheim, Novo-Nordisk, Edimark Santé, and Vitalaire.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Copyright information

© Springer Science+Business Media New York 2013