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Acquired and Inherited Lipodystrophies Abhimanyu Garg, M.D. From the Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, and the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas. Address reprint requests to Dr. Garg at the Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9052, or at abhimanyu.
[email protected]. N Engl J Med 2004;350:1220-34. Copyright © 2004 Massachusetts Medical Society.
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ipodystrophies are clinically heterogeneous acquired or inherited disorders characterized by the selective loss of adipose tissue. Affected patients are predisposed to insulin resistance and its attendant complications, including diabetes mellitus, dyslipidemia, hepatic steatosis, and acanthosis nigricans. Features of polycystic ovary syndrome — hirsutism, oligoamenorrhea, and polycystic ovaries — may develop in affected women. The mechanisms involved in the pathogenesis of various types of lipodystrophy are listed in Table 1. More than a century after the clinical phenotype was first described,1 we are beginning to understand the molecular and cellular mechanisms underlying lipodystrophies. The genetic basis of many inherited lipodystrophy syndromes has been elucidated through the systematic characterization of phenotypes based on distinct clinical features and unique patterns of adipose-tissue distribution,2 together with techniques derived from research in molecular biology and sequencing of the human genome. This review focuses on the clinical features, underlying pathogenetic mechanisms, and management of various types of lipodystrophy.
acquired lipody strophies Acquired lipodystrophies are more common than the inherited varieties and are discussed first. Each acquired lipodystrophy has a unique clinical picture and underlying pathogenic mechanism. lipodystrophy in patients with human immunodeficiency virus infection
Clinical Picture
Lipodystrophy characterized by the loss of subcutaneous fat from the face, arms, and legs has been reported to develop in patients infected with the human immunodeficiency virus (HIV) who are receiving highly active antiretroviral therapy that includes protease inhibitors (Fig. 1A).3 Some HIV-infected patients with lipodystrophy may have concomitant deposition of excess fat in the neck and upper back, causing a double chin and a buffalo hump, respectively, and in the trunk.4 Approximately 1 million people in the United States are infected with HIV, and about 42 million are infected worldwide.5,6 In developed countries approximately half of HIV-infected persons receive antiretroviral therapy, and more than half of those take protease inhibitors.7 Lipodystrophy develops in approximately 40 percent of patients who are treated with a protease inhibitor for longer than one year.8 Thus, acquired lipodystrophy in HIV-infected patients is by far the most prevalent type of lipodystrophy, with more than 100,000 such patients in the United States. Most HIV-infected patients with lipodystrophy are otherwise relatively healthy, but insulin resistance, hypertriglyceridemia, and low serum levels of high-density lipoprotein cholesterol may develop.9 The development of hyperglycemia, however, appears to be uncommon.10 Recently, hepatic steatosis was reported among HIV-infected patients with lipodystrophy,11 but acanthosis nigricans seems to be extremely rare. Anecdotal
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Autosomal recessive Autosomal recessive
Autosomal dominant
Autosomal dominant
Autosomal recessive
ZMPSTE24
LMNA
PPARg
LMNA
seipin
AGPAT2
—
—
—
—
Gene Involved
Skeletal anomalies, loss of subcutaneous fat from the arms, legs, and trunk Skeletal anomalies, generalized loss of fat, premature renal failure, progeroid features
Loss of subcutaneous fat from the arms, legs, and trunk (sparing the face and neck) at puberty Loss of subcutaneous fat from the arms, legs, and face
Extreme lack of adipose tissue since birth, mild mental retardation, cardiomyopathy
Extreme lack of adipose tissue since birth
Loss of subcutaneous fat from small areas
Generalized loss of fat associated with tender subcutaneous nodules, autoimmune or other diseases
Loss of fat from the face, neck, arms, and trunk and sparing of legs
Loss of subcutaneous fat from the face, arms, and legs and excess fat in the neck and abdomen
Clinical Features
Defective lamin A and lamin C may disrupt nuclear function, resulting in the death of adipocytes and skeletal tissue. Zinc metalloproteinase (ZMPSTE24) is critical for post-translational processing of prelamin A to its mature form, lamin A. Thus, lack of lamin A or accumulation of abnormal prelamin A may disrupt nuclear function in several tissues.
LMNA encodes nuclear lamina proteins lamin A and lamin C. Defects in these proteins may disrupt nuclear function, resulting in the death of adipocytes. PPARg is essential for adipogenesis. Dominant negative PPARg mutations may inhibit adipocyte differentiation.
AGPATs are key enzymes involved in the biosynthesis of triglycerides and phospholipids. The AGPAT2 isoform is expressed at high levels in adipose tissue, and genetic defects may reduce triglyceride synthesis in adipocytes. The function of seipin is unknown. High levels of expression in the brain and low levels in adipocytes suggest the possibility of a central nervous system defect.
Multiple mechanisms may be involved, including local immunemediated or pressure-induced atrophy of adipocytes.
Panniculitis preceding the loss of fat and the presence of autoimmune diseases suggest immune-mediated loss of adipose tissue, although other mechanisms may be involved.
Low levels of serum C3 and the presence of an autoantibody — C3 nephritic factor — suggest the presence of autoimmunemediated loss of adipose tissue.
Protease inhibitors may inhibit adipocyte differentiation, induce apoptosis of adipocytes, or cause dysregulation of transcription factors involved in adipogenesis.
Pathogenetic or Molecular Basis
* HIV denotes human immunodeficiency virus, AGPAT 1-acylglycerol-3-phosphate O-acyltransferase, and PPARg peroxisome-proliferator–activated receptor g. † Additional rare types for which the genetic basis is not known are not included.
Type B lipodystrophy
Mandibuloacral dysplasia Type A lipodystrophy
PPARg mutations
Familial partial lipodystrophy Dunnigan variety
Type 2
Congenital generalized lipodystrophy Type 1 Autosomal recessive
—
Localized lipodystrophy
Inherited†
—
—
Acquired partial lipodystrophy
Acquired generalized lipodystrophy
—
Mode of Inheritance
Lipodystrophy in HIV-infected patients
Acquired
Type of Lipodystrophy
Table 1. Clinical Features and Pathogenetic Basis of Various Types of Lipodystrophies.*
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Figure 1. Patients with Acquired Lipodystrophies. Panel A shows a 42-year-old man with human immunodeficiency virus infection and lipodystrophy. He received combination antiretroviral therapy containing indinavir, a protease inhibitor, for six years. He first noted loss of fat from the face, arms, and legs after receiving indinavir for 1 year, and a buffalo hump developed 18 months later. He also noted an increase in his waist size and had hyperlipidemia. Panel B shows a 28-year-old woman with acquired partial lipodystrophy. The loss of subcutaneous fat from the face, neck, arms, thorax, and abdomen began when she was 12 years of age. She had excessive amounts of subcutaneous fat in the legs and reduced serum C3 levels. Panel C shows a 60-year-old woman with acquired generalized lipodystrophy. The age at the onset of lipodystrophy was eight years. She had bilateral breast implants, hyperlipidemia, and hypertension, and she underwent coronary-artery bypass grafting at the age of 55 years.
reports have suggested that in patients who are treated with nucleoside analogues alone, the redistribution of fat may occur along with nausea, fatigue, weight loss, hepatic dysfunction, ascites, and lactic acidosis but not hyperinsulinemia or hyperlipidemia.12
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Pathogenetic Basis
Though the mechanisms by which protease inhibitors cause lipodystrophy remain unknown, there are interesting possibilities. Several protease inhibitors impair the differentiation of preadipocytes,13 and mild-to-moderate apoptosis of subcutaneous adi-
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pocytes was reported in biopsy specimens from the leg in 10 of 13 patients with lipodystrophy who were receiving a regimen containing protease inhibitors.14 Adipose tissue from patients with lipodystrophy who are receiving protease inhibitors has reduced messenger RNA (mRNA) expression of several key transcription factors involved in adipogenesis, including sterol regulatory element–binding protein 1c (SREBP1c) and peroxisome-proliferator– activated receptor g (PPARg). However, although the expression of PPARg protein was reduced, that of SREBP1c protein was increased.15 Interestingly, additional experimental data in transgenic mice support these findings: the overexpression of SREBP1c induces lipodystrophy.16 In humans, reduced PPARg activity owing to inactivating mutations causes familial partial lipodystrophy.17-19 acquired partial lipodystrophy (the barraquer–simons syndrome)
Clinical Picture
Before the recognition of lipodystrophy in HIVinfected persons, acquired partial lipodystrophy, originally described by Mitchell,1 Barraquer,20 and Simons,21 was the most common acquired lipodystrophy. Nevertheless, it is rare — approximately 250 patients of various ethnic origins have been described.2 The male-to-female ratio is approximately 1:4. The fat loss occurs during childhood or adolescence, affecting the face, neck, arms, thorax, and upper abdomen in a cephalocaudal fashion (Fig. 1B).1 In contrast, excess fat may be deposited in the hips and legs, particularly in affected women. Insulin resistance and its accompanying complications appear to be infrequent in this syndrome.2 In approximately 20 percent of the patients, mesangiocapillary (membranoproliferative) glomerulonephritis developed about eight years after the onset of lipodystrophy. Other autoimmune diseases, including systemic lupus erythematosus and juvenile dermatomyositis, have also developed in a few of these patients.22,23 Pathogenetic Basis
Almost all patients with acquired partial lipodystrophy have low levels of serum C3 accompanied by detectable levels of a circulating polyclonal IgG called C3 nephritic factor.24,25 Levels of other complement factors are normal. C3 nephritic factor stabilizes the enzyme C3 convertase (C3b,Bb), which splits C3, causing unopposed activation of the al-
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ternative complement pathway and excessive consumption of C3.26 The synthesis of C3b,Bb also involves factor D (adipsin), which is produced mainly by adipocytes.26 C3 nephritic factor–induced lysis of adipocytes that express factor D may be involved in the pathogenesis of this form of lipodystrophy.27 However, why adipose tissue in the legs is spared and whether autoimmunity is triggered by viral or other infections remain unclear. acquired generalized lipodystrophy
Clinical Picture
Acquired generalized lipodystrophy has been reported in approximately 80 patients, most of whom were white (male-to-female ratio, 1:3).28 The fat loss typically occurs during childhood and adolescence, affecting large areas of the body, particularly the face, arms, and legs (Fig. 1C). Subcutaneous fat may also be lost from the palms and soles, while retroorbital and bone marrow fat are preserved.28 The degree of loss of intraabdominal fat varies. Affected children may have a voracious appetite. Acanthosis nigricans and hepatic steatosis also develop in most patients beginning in childhood.29 Cirrhosis has been reported in about one fifth of the patients as a late sequela of hepatic steatosis or autoimmune hepatitis. Most patients have low serum levels of leptin and adiponectin.30 Pathogenetic Basis
The onset of acquired generalized lipodystrophy has been heralded by an episode of subcutaneous inflammatory nodules, termed panniculitis, in approximately 25 percent of patients.28,31 A hallmark of these lesions is the infiltration of adipose tissue with histiocytes, lymphocytes, and multinucleated giant cells, together with a granulomatous reaction. Initially, these lesions heal, with localized loss of subcutaneous fat, but subsequently fat is lost from almost all subcutaneous regions, eventually causing generalized lipodystrophy. Another 25 percent of affected patients have associated autoimmune diseases, particularly juvenile dermatomyositis.28,32 However, roughly half the patients with acquired generalized lipodystrophy have the idiopathic variety, which involves neither associated panniculitis nor autoimmune diseases.28 Patients in whom panniculitis is the initial event have less severe fat loss and a lower prevalence of diabetes and hypertriglyceridemia than do patients with the other varieties.28 In patients with antecedent panniculitis and con-
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comitant autoimmune diseases, the loss of adipose tissue is presumed to be immune mediated, but other mechanisms are probably involved in the idiopathic variety. localized lipodystrophies
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puberty, clitoromegaly and the polycystic ovary syndrome may develop in girls. Only a few affected women have had successful pregnancies, whereas affected men have normal fertility. Multiple focal lytic lesions develop in the appendicular bones after puberty.36 A few patients have hypertrophic cardiomyopathy and mild mental retardation.37,38 Severe hyperinsulinemia and hypertriglyceridemia may be present, even during infancy. Extreme hypertriglyceridemia may result in recurrent acute pancreatitis. Ketosis-resistant diabetes mellitus usually develops during adolescence or thereafter, with attendant long-term complications.38-40 Serum leptin and adiponectin levels are extremely low.30
Most people with localized lipodystrophies lose subcutaneous fat from small areas, leaving indentations. In some, large regions of the trunk or limbs may be involved. The cause of such localized fat loss varies and may be related to injected drugs such as insulin and corticosteroids, recurrent pressure, panniculitis, or unknown mechanisms.2 An unusual centrifugally spreading variety affecting abdominal fat in young children has been reported in Japan, Korea, and Singapore; spontaneous recovery after Molecular Basis of Congenital Generalized several years has been observed in over half the pa- Lipodystrophy Type 1 tients.33 Two molecularly distinct forms of congenital generalized lipodystrophy have been defined — type 1 and type 2. Some patients have neither type, so that adinherited lipodystrophies ditional genes are most likely involved. All forms of inherited lipodystrophies are rare yet Positional cloning was used to identify the abdistinct in their expression. Recent breakthroughs errant gene — 1-acylglycerol-3-phosphate O-acylin our understanding of the molecular basis of the transferase 2 (AGPAT2) — in patients from several major types of inherited lipodystrophies have shed pedigrees in which the lipodystrophy was linked to light on the pathogenesis of various accompanying chromosome 9q34.39,41 Several homozygous or compound heterozygous mutations in the AGPAT2 clinical features and metabolic complications. gene were found in affected patients. Interestingly, congenital generalized lipodystrophy almost all patients of African origin have a splice(the berardinelli–seip syndrome) site mutation (IVS4-2A>G) on the same haplotype, suggesting that the mutation has a common ancesClinical Picture Congenital generalized lipodystrophy, a rare auto- tral origin. somal recessive disorder, originally described by BeThe five known isoforms of AGPAT catalyze an rardinelli34 and Seip,35 has been reported in ap- acylation reaction at the stereospecific number-2 proximately 250 patients of various ethnic origins. position of glycerol-3-phosphate during the syntheAssuming that only 1 in 4 patients is reported, the sis of triglycerides and phospholipids (Fig. 3).42,43 estimated worldwide prevalence is about 1 in 10 AGPAT2 mRNA expression is at least twice as high million. The most characteristic clinical feature is as that of AGPAT1 in human omental adipose tissue nearly complete absence of adipose tissue and a but is lower in the liver and far lower in the skeletal consequently generalized muscular appearance rec- muscle.39 These observations suggest that the aberrant AGPAT2 enzyme may cause lipodystrophy by ognized easily at birth (Fig. 2A and 2B). Early childhood is marked by accelerated linear reducing the synthesis of triglycerides in adipose growth, an advanced bone age, and a voracious ap- tissue, thus leading to adipocytes that are depleted petite. Later in childhood, marked acanthosis nigri- of triglycerides, or by reducing the bioavailability of cans usually develops in the neck, axilla, groin, and phosphatidic acid and phospholipids that are imtrunk. Hepatomegaly from fatty liver is almost uni- portant for intracellular signaling and membrane versal and may ultimately lead to cirrhosis. Sple- functions.44 Affected patients lack metabolically acnomegaly is common. Nearly all patients have a tive adipose tissue in most subcutaneous areas, inprominent umbilicus or frank umbilical hernia. An traabdominal and intrathoracic regions, and bone acromegalic appearance with slight enlargement marrow, whereas mechanical adipose tissue, which of the mandible, hands, and feet is common. After fulfills a protective and cushioning function, such as
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A
B
C
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Figure 2. Patients with Congenital Generalized and Familial Partial Lipodystrophies. Panel A shows a 33-year-old woman with congenital generalized lipodystrophy type 1, characterized by a generalized lack of fat, extreme muscularity, acanthosis nigricans in the groin and over the anterior abdomen, and acromegaloid features. She had compound heterozygous mutations in the 1-acylglycerol-3-phosphate O-acyltransferase 2 gene. Panel B shows a 19-year-old man with congenital generalized lipodystrophy type 2 due to a homozygous mutation in the seipin gene. He had a generalized lack of fat, extreme muscularity, acanthosis nigricans in the axillae, and acromegaloid features. He also had mild mental retardation and hypertrophic cardiomyopathy. Panel C shows a 37-year-old woman with familial partial lipodystrophy of the Dunnigan variety resulting from a heterozygous missense mutation in the gene that encodes lamins A and C. She had loss of fat from the arms, legs, and trunk beginning at puberty and had excess accumulation of fat in the face and neck. Panel D shows a 64-year-old woman with familial partial lipodystrophy resulting from a heterozygous missense mutation in the peroxisome-proliferator–activated receptor g gene. She had loss of fat from the arms, legs, face, and neck and had excess accumulation of fat in the truncal region. The fat loss was more prominent in the forearms and calves than in the upper arms and thighs.
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Figure 3. Biosynthesis of Triglyceride and Phospholipids from Glycerol-3-Phosphate. The initial step involves glycerol-3-phosphate acyltransferase (GPAT), which acylates glycerol-3-phosphate at the stereospecific number (sn)–1 position to form lysophosphatidic acid. The 1-acylglycerol-3-phosphate acyltransferase (AGPAT) catalyzes the acylation of lysophosphatidic acid at the sn-2 position to form phosphatidic acid. Defects in the AGPAT 2 (AGPAT2) isoform in patients with congenital generalized lipodystrophy type 1 can interrupt the conversion of lysophosphatidic acid to phosphatidic acid. Dephosphorylation of phosphatidic acid by the enzyme phosphatidic acid phosphatase (PAP) forms 1,2-diacylglycerol, which is acylated to form triacylglycerol or triglyceride with the use of diacylglycerol acyltransferase (DGAT). Phosphatidic acid and 1,2-diacylglycerol are important intermediates in the synthesis of various phospholipids, such as phosphatidylinositol, cardiolipin, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Each of these four enzymes has two or more isoforms. CoA denotes coenzyme A.
HO
C H2C
OH H OPO32–
Glycerol-3-phosphate Acyl-CoA CoA O
GPAT
C
H2C
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C
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OPO32–
C O
Phosphatidylinositol cardiolipin
H2O Pi O
PAP O
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R2
Molecular Basis of Congenital Generalized Lipodystrophy Type 2
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in the joints, orbits, palms and soles, scalp, perineum, vulva, and pericalyceal regions of the kidneys, appears to be spared.45-47 The preservation of mechanical adipose tissue in patients with AGPAT2 mutations may be due to the increased expression of other AGPAT isoforms in these adipose-tissue depots.
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H
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OH
R1
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Magre and colleagues48 reported mutations in the 1,2-Diacylglycerol Phosphatidylethanolamine Phosphatidylserine seipin gene in patients from several large consanAcyl-CoA DGAT guineous pedigrees from Lebanon and Norway in CoA which linkage to chromosome 11q13 had been notO ed. The seipin gene encodes a 398–amino-acid proO H2C O C R1 tein of unknown function; thus, the mechanisms causing lipodystrophy remain unclear. However, R2 C O C H O the fact that affected patients have high levels of exC R H2C O 3 pression of seipin mRNA in the brain yet weak expression in adipose tissue suggests that the central Triacylglycerol nervous system is involved. Patients with seipin mutations have a higher prevalence of mild mental retardation and hypertrophic cardiomyopathy than do those with AGPAT2 mutations.38,39 Type 2 patients gesting that additional loci49-51 and other distinct lack both metabolically active and mechanical adi- pathways are involved. pose tissue.47 Other Types of Congenital Generalized Lipodystrophy
dunnigan variety of familial partial lipodystrophy
Some patients with congenital generalized lipodys- Clinical Picture trophy (less than 20 percent) have neither mutations Familial partial lipodystrophies are heterogeneous, nor linkage to either the AGPAT2 or seipin gene, sug- autosomal dominant disorders with several distinct
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phenotypes. The most prevalent, with more than 200 cases reported, mainly among patients of European extraction, was originally described by Dunnigan and colleagues.52 The distribution of body fat is normal during childhood, but with puberty, subcutaneous fat gradually disappears from the arms and legs, resulting in a muscular appearance.52 Variable and progressive loss of fat from the anterior abdomen and chest occurs later.53 Many patients, particularly women, gain fat in the face, neck, and intraabdominal region, resulting in a cushingoid appearance (Fig. 2C). Acanthosis nigricans and the polycystic ovary syndrome are relatively uncommon. The diagnosis is relatively easy to make in women, but is difficult in men, since many normal men have a muscular habitus. Whole-body magnetic resonance imaging reveals subcutaneous fat loss but increased intermuscular fat in the arms and legs and excess intraabdominal fat.53 Diabetes, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, and atherosclerotic vascular disease are more prevalent in female patients than in male patients.54 Diabetes usually develops after the second decade of life, associated with multiparity and excess fat in nonlipodystrophic regions in affected women.55 Marked hypertriglyceridemia has been associated with acute pancreatitis.54 Though fatty liver occasionally develops, cirrhosis has not yet been reported in these patients.56 Molecular Basis
The identification of a locus for the Dunnigan variety of familial partial lipodystrophy, on chromosome 1q21–22,57 led to the identification of a missense mutation in the gene encoding lamins A and C (LMNA) in affected members of a Canadian pedigree.58 Subsequently, many more missense LMNA mutations have been reported.55,59-63 Lamins belong to the intermediate filament family of proteins that compose the nuclear lamina — a polymeric structure intercalated between chromatin and the inner nuclear membrane (Fig. 4A and 4B). The LMNA gene contains 12 exons and encodes lamins A and C (Fig. 4C) by alternative splicing within exon 10.64,65 Lamins provide structural integrity to the nuclear envelope and associate with chromatin and several other nuclear proteins (Fig. 4B).66 Loss of adipocytes associated with LMNA mutations are most likely due to a disruption of nuclear function resulting in cell death or to a disruption of the interaction between lamins and transcription
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factors such as SREBP1c.67 Fibroblasts from patients with the Dunnigan variety of familial partial lipodystrophy have abnormal nuclear blebbing and disorganized nuclear lamina meshwork.68 The mechanisms underlying the regional differences in fat loss, however, remain unclear, since no differences in the expression of lamins A and C were noted in adipocytes from the omentum and subcutaneous abdominal and neck regions.69 The site of missense mutations influences the phenotype.62,70 Approximately three fourths of patients have mutations substituting glutamine, leucine, or tryptophan for the arginine residue at position 482 (Fig. 4C).55,70 In a few of these patients, mild myopathy, muscular dystrophies, cardiomyopathy, and conduction-system disturbances such as atrial fibrillation requiring the implantation of a pacemaker,61-63 also develop, leading to the hypothesis that LMNA mutations cause a multisystem dystrophy syndrome in which the severity and age at onset of various clinical manifestations may differ depending on the site of mutations.62 The interaction of certain domains of lamins A and C with other nuclear-envelope proteins with tissue-restricted expression may confer tissue-specific abnormalities. familial partial lipodystrophy associated with pparg gene mutations
Recently, my colleague and I described a heterozygous missense mutation — Arg397Cys — in the PPARg gene in a 64-year-old woman with diabetes, hypertriglyceridemia, hypertension, hirsutism, and marked loss of subcutaneous fat from her arms, legs, and face (Fig. 2D and 5A).17 Her fat loss was more prominent in her forearms and calves than in her upper arms and thighs. Her truncal region was spared, and no excess fat was noted in her neck.17 Subsequently, three persons with insulin resistance, diabetes, hypertension, hypertriglyceridemia, and a heterozygous mutation in the PPARg gene (either Pro467Leu or Val290Met) were recognized to have familial partial lipodystrophy (Fig. 5A).19,71 Recently, another missense mutation, Phe388Leu, has been associated with familial partial lipodystrophy.18 The age at onset and pattern of progression of fat loss associated with this type of lipodystrophy remain unclear. The PPARg protein is a ligand-inducible nuclear transcription factor expressed at high levels in adipose tissue that has an essential role in adipogenesis (Fig. 5B).72 The Arg397Cys mutation is predicted to disrupt the formation of a salt bridge between
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arginine at position 397 and glutamic acid at position 324 (Fig. 5A). The other three mutant PPARg proteins were found to be transcriptionally impaired, had reduced ligand binding, and inhibited the action of coexpressed wild-type PPARg in a dominant negative manner.18,19,71 Thus, although mutations in the PPARg gene may cause lipodystrophy by inhibiting the differentiation of adipocytes, the reasons for the isolated loss of peripheral subcutaneous fat remain unclear. other types of familial partial lipodystrophy
A few women with diabetes, hypertriglyceridemia, loss of adipose tissue from the arms and legs, normal amounts of facial fat, and excess truncal fat have been described.73,74 Some patients with familial partial lipodystrophies appear to have other unique phenotypes without evident mutations in the LMNA or PPARg gene, suggesting additional loci.17,74 lipodystrophy associated with mandibuloacral dysplasia
Clinical Picture
Mandibuloacral dysplasia, an extremely rare autosomal recessive disorder described in approximately 40 patients,75,76 is characterized by mandibular and clavicular hypoplasia, acro-osteolysis, joint contractures, mottled cutaneous pigmentation, birdlike facies, dental abnormalities, skin atrophy, alopecia, and lipodystrophy. Affected patients have two distinct patterns of lipodystrophy: type A involves the loss of subcutaneous fat from the arms and legs but normal or excess deposition of fat in the face and neck, and type B is characterized by a more generalized loss of subcutaneous fat.76 Hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes mellitus, and hyperlipidemia have been reported in some patients.76,77
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Figure 4 (facing page). The Structures of the Nuclear Envelope (Panel A), Its Proteins (Panel B), and Lamins A and C (Panel C). Panel A shows the structure of the nuclear membrane, with nuclear lamina inside the inner nuclear membrane. Panel B shows the organization of the nuclear lamina and the proteins of the inner nuclear membrane. Lamins A, C, B1, and B2 form central, coiled-coil structures in the rod domain by means of dimerization. Emerin, nesprin1a, and lamina-associated polypeptide 1C and 2a (LAP1C and LAP2a, respectively) interact with lamins A and C, whereas lamina-associated polypeptide 2b (LAP2b), lamin B receptor, and LAP1C interact with lamins B1 and B2. The way in which nurim and MAN1 interact with lamins is not clear. Lamins also interact with chromatin and retinoblastoma protein. Disruption of the interaction between lamins A and C and other nuclearenvelope proteins may cause the tissue-specific expression of lamin-induced dystrophies. Panel C shows the structure of lamins A and C and the sites of mutations described in patients with familial partial lipodystrophy of the Dunnigan variety. Lamins A and C are identical for the first 566 amino acids (shown in red). Lamin C has six unique carboxy-terminal amino acids, and the precursor of lamin A, prelamin A, has 98 unique carboxy-terminal amino acids (shown in green). The generation of mature lamin A from prelamin A requires farnesylation, carboxymethylation, and a two-step cleavage of 18 carboxyterminal amino acids (indicated by the triangle) by a zinc metalloproteinase (ZMPSTE24). The lamins have an amino-terminal head, central a-helical rod, and carboxyterminal tail domains. The lamins form homodimers and heterodimers through their rod domains. Most of the mutations in familial partial lipodystrophy are located in the tail region. Specific phenotypic features associated with various mutations are given in parentheses.
dystrophy who died of renal failure at the age of 24 years.80 Some patients with mandibuloacral dysplasia have no apparent alterations in either the LMNA or ZMPSTE24 gene, suggesting the existence of other as yet unmapped loci for this disorder.80 other inherited lipodystrophies
Molecular Basis
Recently, 12 patients with mandibuloacral dysplasia and partial lipodystrophy (type A) were reported to have a homozygous Arg527His mutation in the LMNA gene.78,79 The parents and siblings who were heterozygous for this mutation reportedly had neither skeletal abnormalities nor lipodystrophy. Compound heterozygous mutations in the zinc metalloproteinase (ZMPSTE24) gene involved in posttranslational proteolytic processing of prelamin A have been reported in a woman with severe mandibuloacral dysplasia, progeria, and generalized lipo-
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A distinctive lipodystrophy affecting the face, the arms, and occasionally the trunk, with relative sparing of the legs, has been reported in patients with short stature, hyperextensible joints, ocular depression, Rieger’s anomaly (defective development of the iris and cornea), and teething delay (the SHORT syndrome).81,82 Another variety, characterized by the nearly total absence of subcutaneous fat from birth but sparing of the sacral and gluteal areas, occurs in patients with autosomal recessive, neonatal progeroid syndrome.83 Recently, a heterozygous Arg133Leu mutation in the LMNA gene was identi-
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A Outer nuclear membrane
Nuclear-pore complex
Inner nuclear membrane
Nuclear lamina Chromatin
Nucleolus
Rough endoplasmic reticulum
B
Emerin
Inner nuclear membrane
LAP1C C
C Lamin B receptor
LAP2b C
Nurim
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C
MAN1 C
N
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Lamin A or C
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N
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N LAP2a Chromatin
C
Head
Rod
Tail Lamin C 572 COOH
NH2
Lamin A 664
Arg419Cys Arg28Trp
Arg62Gly
(cardiomyopathy, mild myopathy)
(cardiomyopathy)
Gly465Asp Lys515Glu Arg482Trp
Arg60Gly
(mild myopathy)
(cardiomyopathy)
Arg482Gln Arg482Leu
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Lys486Thr Lys486Asn
Arg584His Arg582His
Arg527Pro (mild lipodystrophy) (cardiomyopathy, limb-girdle muscular dystrophy, Emery–Dreifuss muscular dystrophy)
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Figure 5. The Structure of Peroxisome-Proliferator–Activated Receptor g (PPARg) and Its Role in Adipogenesis. Panel A shows the structure of PPARg and the residues — valine at position 290 (Val290), phenylalanine at position 388 (Phe388), arginine at position 397 (Arg397), and proline at position 467 (Pro467) — that are mutated in patients with familial partial lipodystrophy. Glutamic acid at position 324 (Glu324, shown in blue) forms a salt bridge with arginine at position 397 (Arg397) that is disrupted by the substitution of cysteine for arginine (Arg397Cys). Panel B shows the role of PPARg in adipogenesis. The activation of PPARg by adipogenic factors such as hormones results in the binding of natural ligands such as linoleic acid, linolenic acid, eicosapentaenoic acid, and 15-deoxy-prostaglandin J2, to PPARg, causing a conformational change. Synthetic thiazolidinedione compounds can also activate PPARg. A heterodimeric complex is then formed with retinoid X receptor (RXR). Various coregulators can further induce or repress the complex formed by PPARg and RXR. The complex binds to peroxisome-proliferator response elements (PPREs) on DNA to induce the transcription of a variety of adipocyte-specific genes that have a role in the differentiation of adipocytes, metabolism of lipids, and action of insulin. The complex also interacts with several other families of transcription factors, such as CCAAT/ enhancer binding proteins a, b, and d (C/EBPa, C/EBPb, and C/EBPd, respectively), and sterol-regulatory element–binding protein 1c (SREBP1c), which is also called adipocyte determination and differentiation factor 1, during the process of adipocyte differentiation.
fied in a man with gradual onset of generalized lipodystrophy at puberty, cardiomyopathy, and depigmented skin papules.84
Phe388Leu Val290Met
Pro467Leu
Glu324
Arg397Cys
B
SREBP1c Adipogenic factors Ligands
Coregulator
C/EBPa
PPARg
C/EBPb C/EBPd
RXR
PPREs
The mechanisms underlying insulin resistance and metabolic complications in patients with lipodystrophies are unclear. Since these complications are observed both in patients with various types of lipodystrophies and in several animal models2,16,37,85 and since the extent of fat loss determines the severity of these complications, a common mechanism seems likely. Only limited quantities of triglycerides can be stored in unaffected fat depots in patients with marked loss of fat. Excess triglyceride may then accumulate in the liver and skeletal muscles, contributing to insulin resistance.46,56,86 Although hyperinsulinemia may initially compensate for insulin resistance and maintain euglycemia, gradual onset of islet amyloidosis and beta-cell atrophy may lead
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to overt hyperglycemia, as occurs in type 2 diabetes mellitus.40,56 Besides causing lipodystrophy, there is some evidence that treatment with protease inhibitors may directly induce insulin resistance by reducing the selective intrinsic transport activity of glucose transporter 4.15,87 The polycystic ovary syndrome, acanthosis nigricans, and acromegalic features may be related to the growth-promoting effects of extreme hyperinsulinemia directly by means of insulin receptors or indirectly through insulin-like growth factor I receptors.
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control mitigates hypertriglyceridemia. If hypertriglyceridemia persists despite changes in diet, regular exercise, and maintenance of euglycemia, patients should be treated with fibrates and high doses of fish oils containing n¡3 polyunsaturated fats. Estrogens, whether taken for contraception, the polycystic ovary syndrome, or postmenopausal symptoms, may exacerbate hypertriglyceridemia and should be avoided.56 Patients with hypertriglyceridemia and hepatic steatosis should avoid drinking alcohol.
therapeutic approaches
The main causes of morbidity and mortality in patients with lipodystrophies are diabetes mellitus and its long-term complications, recurrent episodes of acute pancreatitis from extreme hypertriglyceridemia, cirrhosis resulting from long-standing hepatic steatosis, and atherosclerotic vascular disease. Many affected patients also have severe psychological distress because of their appearance, particularly with respect to the loss of facial fat and subcutaneous fat elsewhere, as well as to the excess accumulation of management of hyperglycemia fat in nonlipodystrophic regions. The presence of hyperglycemia may necessitate the improving cosmetic appearance use of oral hypoglycemic drugs or insulin.37,39,91 The loss of facial fat is becoming a special concern Metformin, which may additionally reduce appetite, among HIV-infected patients with lipodystrophy. induce weight loss, and improve the polycystic ovary Various types of cosmetic surgery, including silicone syndrome and hepatic steatosis, is a particularly atand bovine-collagen implants, transplantation of tractive therapeutic choice.92,93 Highly concentrated fascia and fat from the thighs, reinjection of autol- insulin (500 U per milliliter) is indicated for patients ogous fat, and the use of free flaps from the antero- who require more than 400 U of insulin per day. Aglateral thigh, anterior abdomen, or temporalis mus- gressive glycemic control is pivotal for the prevencle, have been employed to improve the appearance tion of the long-term complications of diabetes. of patients with lipodystrophy who have an extreme loss of facial fat.88,89 Transplantation of adipose tis- additional considerations for hivsue from the thigh or hip to the face is successful in infected patients with lipodystrophy only some patients with acquired partial lipodys- Switching HIV-infected patients with proteaseinhibitor–induced lipodystrophy to alternative antrophy. Weight loss can reduce excess deposits of fat in tiretroviral regimens may improve their serum lipid nonlipodystrophic regions. Nonetheless, excess fat levels but may not reverse the loss of subcutaneous deposits in the neck region in patients with familial fat.94 Many statins, such as simvastatin, lovastatin, partial lipodystrophy and in HIV-infected patients and atorvastatin, are metabolized by cytochrome with lipodystrophy may require repeated surgical P-450 isoform 3A4, which is inhibited by protease inhibitors95; therefore, pravastatin, ezetimibe, and removal by liposuction or lipectomy. Although the ability of thiazolidinediones to in- plant stanols or sterols may be safer alternatives. duce adipogenesis in lipodystrophic regions is lim- Both nucleoside analogues and metformin can ited,90 these drugs also improve glycemic control cause lactic acidosis, and thus metformin should be to some extent and may be a particularly attractive used with caution. Although recombinant human approach to the treatment of familial partial lipo- growth hormone may reduce the deposition of visdystrophy resulting from PPARg mutations.19 How- ceral fat, its ability to induce insulin resistance, hyever, thiazolidinediones may exacerbate the depo- perglycemia, and other adverse effects renders its use unwise.96 sition of fat in nonlipodystrophic regions. management of dyslipidemia
other therapeutic options
Patients with hypertriglyceridemia should be advised to eat an extremely-low-fat diet, preferably one in which less than 15 percent of total energy is from fat, in order to avoid the development of chylomicronemia. In addition, they should engage in a regular program of dynamic exercise to improve insulin sensitivity and dyslipidemia. Aggressive glycemic
The efficacy of corticosteroids or other immunosuppressive drugs to prevent further fat loss in patients with acquired generalized and partial lipodystrophies has not been systematically studied. Patients with hepatic steatosis may be treated with ursodiol, since this agent is somewhat efficacious in treating nonalcoholic hepatic steatosis in patients
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without lipodystrophy.97,98 A few patients have required hepatic transplantation for end-stage liver disease associated with hepatic steatosis99 or renal transplantation for end-stage renal disease related to diabetic nephropathy or mesangiocapillary glomerulonephritis.88 My colleagues and I recently reported that subcutaneous recombinant leptin appeared to be safe and effective in nine women with severe lipodystrophies and hypoleptinemia.91 Fasting blood glucose and glycosylated hemoglobin values decreased markedly after four months of therapy in the eight patients with diabetes, and serum triglyceride levels declined in all nine. Five patients who were receiving high doses of insulin or other hypoglycemic drugs were able to discontinue such therapy and maintain normoglycemia. Testing in seven patients showed a 40 percent reduction in energy intake, and all but one patient lost weight, which itself may be partly responsible for the metabolic improvement. In addition, leptin therapy appeared to reduce hepatic steatosis, decrease intramyocellular lipid levels, and
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improve insulin sensitivity.91,100,101 The use of recombinant leptin, however, remains investigational.
conclusions Further understanding of the molecular mechanisms underlying inherited and acquired lipodystrophies may lead to improved insights into the biology of adipocytes and insulin resistance in disorders of adipose tissue. Such knowledge may also lead to the discovery of therapeutic approaches to prevent the loss of adipocytes, induce adipogenesis in lipodystrophic regions, and prevent or delay the onset of metabolic complications in patients with lipodystrophy. Supported in part by grants (R01-DK54387, R01-56583, R0163656, and M01-RR00633) from the National Institutes of Health and by the Southwestern Medical Foundation. I am indebted to Drs. Anoop Misra and Anil K. Agarwal for their assistance with the manuscript; to Dr. Richard Auchus for providing the drawing of the PPARg ribbon structure; and to Drs. Dolores Peterson, Margo A. Denke, and David Feinstein for referring patients.
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Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876-80. 94. Carr A, Hudson J, Chuah J, et al. HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS 2001;15:1811-22. 95. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002;16:569-77. 96. Schwarz JM, Mulligan K, Lee J, et al. Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 2002;87:942-5. 97. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23: 1464-7. 98. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-31. 99. Cauble MS, Gilroy R, Sorrell MF, et al. Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation. Transplantation 2001;71:8925. 100. Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002;109:1345-50. 101. Simha V, Szczepaniak LS, Wagner AJ, DePaoli AM, Garg A. Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy. Diabetes Care 2003;26:30-5. Copyright © 2004 Massachusetts Medical Society.
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