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GENETICS (TM FRAYLING, SECTION EDITOR)
What the Genetics of Lipodystrophy Can Teach Us About
Insulin Resistance and Diabetes
Camille Vatier & Guillaume Bidault & Nolwenn Briand &
Anne-Claire Guénantin & Laurence Teyssières &
Olivier Lascols & Jacqueline Capeau & Corinne Vigouroux
#
Springer Science+Business Media New York 2013
Abstract Genetic lipodystrophic syndromes are rare diseases
characterized by generalized or partial fa t atrophy (lipoatrophy)
associated with severe metabolic complications such as insulin
resistance (IR), diabetes, dyslipidemia, nonalcoholic fatty liver
disease, a nd ovarian hy perandrog enism. 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 mu-
tated 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.
Keywords Adipose tissue
.
Lipodystrophy
.
Lipid droplets
.
Adipogenesis
.
Insulin resistance
.
Diabetes
.
Dyslipidemia
.
Liver steatosis
.
Polycystic ovary syndrome
.
Ageing
.
Genetics
.
Seipin
.
AGPAT2
.
A-type lamins
.
PPARγ
.
Perilipin
.
Caveolin 1
.
Cavin 1
.
Caveolae
.
CIDEC
.
Akt2
.
PSMB8
.
Progeria
.
ZMPSTE24
.
Genetics
Introduction
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 congeni-
tal or acquired loss of body fat. Paradoxically, the metabolic
consequences of having «too little» fat (lipoatrophy) are re-
markably 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.
C. Vatier
:
G. Bidault
:
N. Briand
:
A.<C. Guénantin
:
L. Teyssières
:
O. Lascols
:
J. Capeau
:
C. Vigouroux
INSERM UMR_S938, Centre de Recherche Saint-Antoine,
75012 Paris, France
C. Vatier
:
G. Bidault
:
N. Briand
:
A.<C. Guénantin
:
L. Teyssières
:
O. Lascols
:
J. Capeau
:
C. Vigouroux
UPMC Univ Paris 6, UMR_S938, 75012 Paris, France
C. Vatier
:
G. Bidault
:
N. Briand
:
A.<C. Guénantin
:
L. Teyssières
:
O. Lascols
:
J. Capeau
:
C. Vigouroux
ICAN, Institute of Cardiometabolism and Nutrition, Paris, France
C. Vatier
AP-HP, Hôpital Pitié-Salpêtrière, Service de Nutrition, 75013 Paris,
France
O. Lascols
AP-HP, Hôpital Saint-Antoine, Laboratoire Commun de Biologie et
Génétique Moléculaires, 75012 Paris, France
J. Capeau
:
C. Vigouroux
AP-HP, Hôpital Tenon, Service de Biochimie et Hormonologie,
75020 Paris, France
C. Vigouroux (*)
Faculté de Médecine Pierre et Marie Curie, site Saint-Antoine,
UMR_S938, 27 rue Chaligny, 75012 Paris, France
e-mail: corinne.vigouroux@inserm.fr
Curr Diab Rep
DOI 10.1007/s11892-013-0431-7
Since 1999, more than 10 genes involved in lipodystro-
phies 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 fea-
tures have revealed that AT can be damaged by senescence
and/or immuno-inflammatory processes [13–17, 18••, 19].
Due to the growing availability of powerful genetic tools,
new genes will probably be linked to still undeciphered
lipodystrophic syndromes.
AT is now well-known not only as a metabolic tissue, but
also as an important paracrine and endocrine organ [20, 21].
Among ma ny adipose secretory products, leptin, w hich
plasma levels generally reflect the AT mass, regulates food
intake and energy consumption, but also distribution of
cellular storage. Adiponectin also m odulates i nsulin sensi-
tivity. Several proteins of the renin-angiotensin system,
produced by AT, influence its development and functions
and could link both obesity and lipodystrophy to hyperten-
sion [22]. Moreover, adipokines secreted by AT contribute
to immune and i nflammatory processes [23]andtheirrole
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 gene s.
Models of generalized lipodystrophy recapitulated most of the
features of human diseases, but partial lipodystrophy pheno-
types 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, transplanta-
tion 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
Epidemiology
The worldwide prevalence of genetic lipodystrophies is not
precisely known. It was evaluated at about 1 per 10 million for
Table 1 Human genetic lipodystrophic syndromes and main affected genes
Main role of affected protein Disease Gene/protein AD or AR transmission
Partial lipodystrophy
Protein of the nuclear envelope FPLD2 LMNA / lamin A/C AD
Protein of the nuclear envelope Metabolic laminopathies LMNA / lamin A/C AD
Protein of the nuclear envelope MAD-A LMNA / lamin A/C AR
Key transcription factor for adipocyte differentiation FPLD3 PPARG /PPARγ AD
Lipolysis regulation of the adipocyte lipid droplet FPLD4 PLIN1 / perilipin AD
Structure of the adipocyte lipid droplet FPLD CIDEC / CIDEC AR
Serine threonine kinase involved in insulin signaling FPLD AKT2 / Akt2 AD
Protein of the nuclear envelope APL LMNB2 / lamin B2 risk factor
Generalized lipodystrophy
Enzyme of triglyceride and glycerophospholipid synthesis BSCL 1 AGPAT2 /AGPAT2 AR
Formation of lipid droplet BSCL 2 BSCL2 /seipin AR
Structural protein of caveolae and adipocyte lipid droplet BSCL3 CAV1 /caveolin1 AR
Structural protein of caveolae and adipocyte lipid droplet BSCL4 PTRF / cavin 1 AR
Protein of the nuclear envelope Hutchinson-Gilford progeria LMNA / lamin A/C Heterozygous,
de novo
mutations
Endoprotease involved in lamin A maturation MAD-B ZMPSTE24 / Zmpste24 AR
Immunoproteasome subunit JMP PSMB8 / PSMB8 AR
AD autosomal dominant, AGPA T2 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
Curr Diab Rep
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 mod-
erate, are frequently diagnosed with a metabolic syndrome
without any search for molecular alterations, an android dis-
tribution of fat being frequent in metabolic syndrome and type
2diabetes.
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); ovar-
ian 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 re gions, and frequently
intra-abdominal fat stores [32, 33]. Similar to patients with
CGL, acanthosis nigricans and hepatomegaly can be promi-
nent, and female patients frequently show features of polycys-
tic 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 surpris-
ingly detectable adiponectin level has been reported [36].
Imagery
Whole-body dual-energy X-ray absorptiometry (DEXA) eval-
uates 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 im-
aging (MRI) at the lumbar L4 level, assessing abdominal fat,
distinguishes between subcutaneous and visceral fat depots
[38].
Hepatomegaly and nonalcoholic fatty liver disease are eval-
uated 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 need-
ed. Cardiovascular investigatio ns are also useful for the pheno-
type 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].
Complications
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, particular-
ly in peroxisome prolifer ator-activat ed receptor gam ma
(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-Me ndenhall syndrome).
These syndromes of extreme insulin resistance expressed in
newborns or children are developmental disorders, with dys-
morphic 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-
Curr Diab Rep
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 gluco-
neogenesis is impaired, leading to hyperglycemia and
hyperinsulinemia, but the insulin-stimulated lipogenesis path-
way 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 anom-
aly and teething delay), another developmental disorder asso-
ciated with insulin resistance and generalized paucity of fat, is
a syndrome of prima ry 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 un-
known origin, often associated with peripheral neuropathy
and increased alcohol intake, and variable metabolic alter-
ations. 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 fea-
tures. 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)
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 geno-
type, 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.
AGPAT2
Bi-allelic mutations affecting AGPAT2 [7]onchromosome
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 reticu-
lum (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
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 re-
sponsible for motor neuron diseases [52], with decreased
neuronal TG content and endoplasmic reticulum stress [53].
Caveolin-1
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].
Curr Diab Rep
PTRF/Cavin-1
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]orLMNA 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
posttranslati onally processed with a step of farnesylation follow-
ed 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
Fig. 1 Proteins involved in genetic lipodystrophic syndromes. Pluripo-
tent 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
Curr Diab Rep
nucleus shape and interact with the cytoskeleton. Also found in
the nucleoplasm, they interact with chromatin, DNA, and tran-
scription 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],andtowell-
characterized accelerated ageing syndromes [13–15](seebelow).
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 hu-
man 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 line-
ages [72••, 73••]. In addition, LMNA mutations perturb the
balance between proliferation and differentiation in adult stem
cells [74–76]. Defects in specific tissular differentiation in
response to different A-type lamins alterations could underlie
the heterogeneous laminopathic phenotypes.
PPARγ
The transcription factor PPARγ plays a leading role in
adipogenesis and also exerts anti-inflammatory and antioxi-
dant 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 cel lular renin -
angiotensin system in cells from the vascular wall [79
•].
Akt2
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
CIDEC participates in adipose LD formation and contributes
to the preadipocyte differentiation process [80]. A homozy-
gous 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
Perilipin (now called perilipin-1) is localized at the surface of
LD in adipocytes and steroidogenic cells. Perilipin-1 reduces
basal lipolysis, but also activa tes 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 het-
erozygous mutations in LMNB2, encoding lamin B2, a partner
of A-type lamins at the nuclear envelope. These genetic alter-
ations 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 mu-
tations of LMNA are responsible for the typical form of
Hutchinson-Gilford progeria, due to the synthesis of a perma-
nently 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 dis-
eases point to the involvement of farnesylated prelamin A,
Curr Diab Rep
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 dur-
ing infancy, affects mainly the upper part of the body.
Homozygous mutations affected PSMB8 , encoding a catalytic
subunit of the immunoproteasome [18••]. Several groups con-
firmed 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 subcuta-
neous 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 syn-
drome 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 homeo-
static processes, including blood pressure control, insulin
sensitivity, and regulation of inflammation and immune pro-
cesses through the secretion of numerous adipokines [20–24].
Most of the proteins mutated in human lipodystrophies are
directly involved in adipogenesis (PPARγ,probablylaminA/
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 stre ss, re cruitment of mac rophages, release of
proinflammatory cytokines and of free fatty acid (FFA) and
decreased adiponectin and leptin, leading t o lipotoxicity.
Genetically limited expansion of fat in lipodystrophies lowers
the se t 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 physi-
cal activity, particularly aerobic exercise, can notably improve
metabolic complications in lipodystrophy.
Medications
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
Curr Diab Rep
triglycerides supplementation and /or omega-3 polyunsaturat-
ed 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 recombi-
nant metreleptin, has resulted in markedly improved metabol-
ic homeostasis and regression of liver steatosis, particularly in
severe lipoatrophic and hypoleptinemic patients [93–96].
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 sur-
gery, in particular for patients with partial lipodystrophy [99].
Conclusions
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 het-
erogeneously the different insulin signaling pathways.
Therefore, studies on human lipodystrophies help to un-
derstand 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.
Acknowledgments 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”, Insti tute of Cardiometabol ism 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 Insti-
tute 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 n o 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.
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