Acquired and Inherited Lipodystrophies
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《新英格兰医药杂志》
Lipodystrophies 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.
Table 1. Clinical Features and Pathogenetic Basis of Various Types of Lipodystrophies.
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 Lipodystrophies
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 (Figure 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.
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.
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 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
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 adipocytes 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 (PPAR). However, although the expression of PPAR 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 PPAR activity owing to inactivating mutations causes familial partial lipodystrophy.17,18,19
Acquired Partial Lipodystrophy (The Barraquer–Simons Syndrome)
Clinical Picture
Before the recognition of lipodystrophy in HIV-infected 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 (Figure 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 alternative 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 (Figure 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 concomitant 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
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 several years has been observed in over half the patients.33
Inherited Lipodystrophies
All forms of inherited lipodystrophies are rare yet distinct in their expression. Recent breakthroughs in our understanding of the molecular basis of the major types of inherited lipodystrophies have shed light on the pathogenesis of various accompanying clinical features and metabolic complications.
Congenital Generalized Lipodystrophy (The Berardinelli–Seip Syndrome)
Clinical Picture
Congenital generalized lipodystrophy, a rare autosomal recessive disorder, originally described by Berardinelli34 and Seip,35 has been reported in approximately 250 patients of various ethnic origins. Assuming that only 1 in 4 patients is reported, the estimated worldwide prevalence is about 1 in 10 million. The most characteristic clinical feature is nearly complete absence of adipose tissue and a consequently generalized muscular appearance recognized easily at birth (Figure 2A and Figure 2B).
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 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.
Early childhood is marked by accelerated linear growth, an advanced bone age, and a voracious appetite. Later in childhood, marked acanthosis nigricans usually develops in the neck, axilla, groin, and trunk. Hepatomegaly from fatty liver is almost universal and may ultimately lead to cirrhosis. Splenomegaly is common. Nearly all patients have a prominent umbilicus or frank umbilical hernia. An acromegalic appearance with slight enlargement of the mandible, hands, and feet is common. After 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.38,39,40 Serum leptin and adiponectin levels are extremely low.30
Molecular Basis of Congenital Generalized Lipodystrophy Type 1
Two molecularly distinct forms of congenital generalized lipodystrophy have been defined — type 1 and type 2. Some patients have neither type, so that additional genes are most likely involved.
Positional cloning was used to identify the aberrant gene — 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) — in patients from several pedigrees in which the lipodystrophy was linked to chromosome 9q34.39,41 Several homozygous or compound heterozygous mutations in the AGPAT2 gene were found in affected patients. Interestingly, almost all patients of African origin have a splice-site mutation (IVS4-2A>G) on the same haplotype, suggesting that the mutation has a common ancestral origin.
The five known isoforms of AGPAT catalyze an acylation reaction at the stereospecific number-2 position of glycerol-3-phosphate during the synthesis of triglycerides and phospholipids (Figure 3). 42,43 AGPAT2 mRNA expression is at least twice as high as that of AGPAT1 in human omental adipose tissue but is lower in the liver and far lower in the skeletal muscle.39 These observations suggest that the aberrant AGPAT2 enzyme may cause lipodystrophy by reducing the synthesis of triglycerides in adipose tissue, thus leading to adipocytes that are depleted of triglycerides, or by reducing the bioavailability of phosphatidic acid and phospholipids that are important for intracellular signaling and membrane functions.44 Affected patients lack metabolically active adipose tissue in most subcutaneous areas, intraabdominal and intrathoracic regions, and bone marrow, whereas mechanical adipose tissue, which fulfills a protective and cushioning function, such as in the joints, orbits, palms and soles, scalp, perineum, vulva, and pericalyceal regions of the kidneys, appears to be spared.45,46,47 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.
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.
Molecular Basis of Congenital Generalized Lipodystrophy Type 2
Magre and colleagues48 reported mutations in the seipin gene in patients from several large consanguineous pedigrees from Lebanon and Norway in which linkage to chromosome 11q13 had been noted. The seipin gene encodes a 398–amino-acid protein of unknown function; thus, the mechanisms causing lipodystrophy remain unclear. However, the fact that affected patients have high levels of expression of seipin mRNA in the brain yet weak expression in adipose tissue suggests that the central 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 lack both metabolically active and mechanical adipose tissue.47
Other Types of Congenital Generalized Lipodystrophy
Some patients with congenital generalized lipodystrophy (less than 20 percent) have neither mutations nor linkage to either the AGPAT2 or seipin gene, suggesting that additional loci49,50,51 and other distinct pathways are involved.
Dunnigan Variety of Familial Partial Lipodystrophy
Clinical Picture
Familial partial lipodystrophies are heterogeneous, autosomal dominant disorders with several distinct 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 (Figure 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.55,59,60,61,62,63
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 (Figure 4A and Figure 4B). The LMNA gene contains 12 exons and encodes lamins A and C (Figure 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 (Figure 4B).66
Figure 4. 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, nesprin-1, and lamina-associated polypeptide 1C and 2 (LAP1C and LAP2, respectively) interact with lamins A and C, whereas lamina-associated polypeptide 2 (LAP2), 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 nuclear-envelope 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 carboxy-terminal amino acids (indicated by the triangle) by a zinc metalloproteinase (ZMPSTE24). The lamins have an amino-terminal head, central -helical rod, and carboxy-terminal 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.
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 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 (Figure 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,61,62,63 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 PPAR Gene Mutations
Recently, my colleague and I described a heterozygous missense mutation — Arg397Cys — in the PPAR gene in a 64-year-old woman with diabetes, hypertriglyceridemia, hypertension, hirsutism, and marked loss of subcutaneous fat from her arms, legs, and face (Figure 2D and Figure 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 PPAR gene (either Pro467Leu or Val290Met) were recognized to have familial partial lipodystrophy (Figure 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.
Figure 5. The Structure of Peroxisome-Proliferator–Activated Receptor (PPAR) and Its Role in Adipogenesis.
Panel A shows the structure of PPAR 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 PPAR in adipogenesis. The activation of PPAR 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 PPAR, causing a conformational change. Synthetic thiazolidinedione compounds can also activate PPAR. A heterodimeric complex is then formed with retinoid X receptor (RXR). Various coregulators can further induce or repress the complex formed by PPAR 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 , , and (C/EBP, C/EBP, and C/EBP, 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.
The PPAR protein is a ligand-inducible nuclear transcription factor expressed at high levels in adipose tissue that has an essential role in adipogenesis (Figure 5B).72 The Arg397Cys mutation is predicted to disrupt the formation of a salt bridge between arginine at position 397 and glutamic acid at position 324 (Figure 5A). The other three mutant PPAR proteins were found to be transcriptionally impaired, had reduced ligand binding, and inhibited the action of coexpressed wild-type PPAR in a dominant negative manner.18,19,71 Thus, although mutations in the PPAR 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 PPAR 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, bird-like 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
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 post-translational proteolytic processing of prelamin A have been reported in a woman with severe mandibuloacral dysplasia, progeria, and generalized lipodystrophy 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
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 identified in a man with gradual onset of generalized lipodystrophy at puberty, cardiomyopathy, and depigmented skin papules.84
Mechanisms of Insulin Resistance and Metabolic Complications
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 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.
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 fat in nonlipodystrophic regions.
Improving Cosmetic Appearance
The loss of facial fat is becoming a special concern among HIV-infected patients with lipodystrophy. Various types of cosmetic surgery, including silicone and bovine-collagen implants, transplantation of fascia and fat from the thighs, reinjection of autologous fat, and the use of free flaps from the anterolateral thigh, anterior abdomen, or temporalis muscle, have been employed to improve the appearance of patients with lipodystrophy who have an extreme loss of facial fat.88,89 Transplantation of adipose tissue from the thigh or hip to the face is successful in only some patients with acquired partial lipodystrophy.
Weight loss can reduce excess deposits of fat in nonlipodystrophic regions. Nonetheless, excess fat deposits in the neck region in patients with familial partial lipodystrophy and in HIV-infected patients with lipodystrophy may require repeated surgical removal by liposuction or lipectomy.
Although the ability of thiazolidinediones to induce adipogenesis in lipodystrophic regions is limited,90 these drugs also improve glycemic control to some extent and may be a particularly attractive approach to the treatment of familial partial lipodystrophy resulting from PPAR mutations.19 However, thiazolidinediones may exacerbate the deposition of fat in nonlipodystrophic regions.
Management of Dyslipidemia
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 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.
Management of Hyperglycemia
The presence of hyperglycemia may necessitate the use of oral hypoglycemic drugs or insulin.37,39,91 Metformin, which may additionally reduce appetite, induce weight loss, and improve the polycystic ovary syndrome and hepatic steatosis, is a particularly attractive therapeutic choice.92,93 Highly concentrated insulin (500 U per milliliter) is indicated for patients who require more than 400 U of insulin per day. Aggressive glycemic control is pivotal for the prevention of the long-term complications of diabetes.
Additional Considerations for HIV-Infected Patients with Lipodystrophy
Switching HIV-infected patients with protease-inhibitor–induced lipodystrophy to alternative antiretroviral regimens may improve their serum lipid levels but may not reverse the loss of subcutaneous fat.94 Many statins, such as simvastatin, lovastatin, and atorvastatin, are metabolized by cytochrome P-450 isoform 3A4, which is inhibited by protease inhibitors95; therefore, pravastatin, ezetimibe, and plant stanols or sterols may be safer alternatives. Both nucleoside analogues and metformin can cause lactic acidosis, and thus metformin should be used with caution. Although recombinant human growth hormone may reduce the deposition of visceral fat, its ability to induce insulin resistance, hyperglycemia, and other adverse effects renders its use unwise.96
Other Therapeutic Options
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 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 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, R01-63656, 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 PPAR ribbon structure; and to Drs. Dolores Peterson, Margo A. Denke, and David Feinstein for referring patients.
Source Information
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.garg@utsouthwestern.edu.
References
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Related Letters:
Acquired and Inherited Lipodystrophies
Walker U. A., Schott M., Scherbaum W. A., Bornstein S. R., Garg A.(Abhimanyu Garg, M.D.)
Table 1. Clinical Features and Pathogenetic Basis of Various Types of Lipodystrophies.
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 Lipodystrophies
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 (Figure 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.
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.
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 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
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 adipocytes 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 (PPAR). However, although the expression of PPAR 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 PPAR activity owing to inactivating mutations causes familial partial lipodystrophy.17,18,19
Acquired Partial Lipodystrophy (The Barraquer–Simons Syndrome)
Clinical Picture
Before the recognition of lipodystrophy in HIV-infected 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 (Figure 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 alternative 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 (Figure 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 concomitant 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
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 several years has been observed in over half the patients.33
Inherited Lipodystrophies
All forms of inherited lipodystrophies are rare yet distinct in their expression. Recent breakthroughs in our understanding of the molecular basis of the major types of inherited lipodystrophies have shed light on the pathogenesis of various accompanying clinical features and metabolic complications.
Congenital Generalized Lipodystrophy (The Berardinelli–Seip Syndrome)
Clinical Picture
Congenital generalized lipodystrophy, a rare autosomal recessive disorder, originally described by Berardinelli34 and Seip,35 has been reported in approximately 250 patients of various ethnic origins. Assuming that only 1 in 4 patients is reported, the estimated worldwide prevalence is about 1 in 10 million. The most characteristic clinical feature is nearly complete absence of adipose tissue and a consequently generalized muscular appearance recognized easily at birth (Figure 2A and Figure 2B).
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 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.
Early childhood is marked by accelerated linear growth, an advanced bone age, and a voracious appetite. Later in childhood, marked acanthosis nigricans usually develops in the neck, axilla, groin, and trunk. Hepatomegaly from fatty liver is almost universal and may ultimately lead to cirrhosis. Splenomegaly is common. Nearly all patients have a prominent umbilicus or frank umbilical hernia. An acromegalic appearance with slight enlargement of the mandible, hands, and feet is common. After 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.38,39,40 Serum leptin and adiponectin levels are extremely low.30
Molecular Basis of Congenital Generalized Lipodystrophy Type 1
Two molecularly distinct forms of congenital generalized lipodystrophy have been defined — type 1 and type 2. Some patients have neither type, so that additional genes are most likely involved.
Positional cloning was used to identify the aberrant gene — 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) — in patients from several pedigrees in which the lipodystrophy was linked to chromosome 9q34.39,41 Several homozygous or compound heterozygous mutations in the AGPAT2 gene were found in affected patients. Interestingly, almost all patients of African origin have a splice-site mutation (IVS4-2A>G) on the same haplotype, suggesting that the mutation has a common ancestral origin.
The five known isoforms of AGPAT catalyze an acylation reaction at the stereospecific number-2 position of glycerol-3-phosphate during the synthesis of triglycerides and phospholipids (Figure 3). 42,43 AGPAT2 mRNA expression is at least twice as high as that of AGPAT1 in human omental adipose tissue but is lower in the liver and far lower in the skeletal muscle.39 These observations suggest that the aberrant AGPAT2 enzyme may cause lipodystrophy by reducing the synthesis of triglycerides in adipose tissue, thus leading to adipocytes that are depleted of triglycerides, or by reducing the bioavailability of phosphatidic acid and phospholipids that are important for intracellular signaling and membrane functions.44 Affected patients lack metabolically active adipose tissue in most subcutaneous areas, intraabdominal and intrathoracic regions, and bone marrow, whereas mechanical adipose tissue, which fulfills a protective and cushioning function, such as in the joints, orbits, palms and soles, scalp, perineum, vulva, and pericalyceal regions of the kidneys, appears to be spared.45,46,47 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.
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.
Molecular Basis of Congenital Generalized Lipodystrophy Type 2
Magre and colleagues48 reported mutations in the seipin gene in patients from several large consanguineous pedigrees from Lebanon and Norway in which linkage to chromosome 11q13 had been noted. The seipin gene encodes a 398–amino-acid protein of unknown function; thus, the mechanisms causing lipodystrophy remain unclear. However, the fact that affected patients have high levels of expression of seipin mRNA in the brain yet weak expression in adipose tissue suggests that the central 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 lack both metabolically active and mechanical adipose tissue.47
Other Types of Congenital Generalized Lipodystrophy
Some patients with congenital generalized lipodystrophy (less than 20 percent) have neither mutations nor linkage to either the AGPAT2 or seipin gene, suggesting that additional loci49,50,51 and other distinct pathways are involved.
Dunnigan Variety of Familial Partial Lipodystrophy
Clinical Picture
Familial partial lipodystrophies are heterogeneous, autosomal dominant disorders with several distinct 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 (Figure 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.55,59,60,61,62,63
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 (Figure 4A and Figure 4B). The LMNA gene contains 12 exons and encodes lamins A and C (Figure 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 (Figure 4B).66
Figure 4. 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, nesprin-1, and lamina-associated polypeptide 1C and 2 (LAP1C and LAP2, respectively) interact with lamins A and C, whereas lamina-associated polypeptide 2 (LAP2), 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 nuclear-envelope 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 carboxy-terminal amino acids (indicated by the triangle) by a zinc metalloproteinase (ZMPSTE24). The lamins have an amino-terminal head, central -helical rod, and carboxy-terminal 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.
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 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 (Figure 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,61,62,63 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 PPAR Gene Mutations
Recently, my colleague and I described a heterozygous missense mutation — Arg397Cys — in the PPAR gene in a 64-year-old woman with diabetes, hypertriglyceridemia, hypertension, hirsutism, and marked loss of subcutaneous fat from her arms, legs, and face (Figure 2D and Figure 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 PPAR gene (either Pro467Leu or Val290Met) were recognized to have familial partial lipodystrophy (Figure 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.
Figure 5. The Structure of Peroxisome-Proliferator–Activated Receptor (PPAR) and Its Role in Adipogenesis.
Panel A shows the structure of PPAR 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 PPAR in adipogenesis. The activation of PPAR 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 PPAR, causing a conformational change. Synthetic thiazolidinedione compounds can also activate PPAR. A heterodimeric complex is then formed with retinoid X receptor (RXR). Various coregulators can further induce or repress the complex formed by PPAR 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 , , and (C/EBP, C/EBP, and C/EBP, 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.
The PPAR protein is a ligand-inducible nuclear transcription factor expressed at high levels in adipose tissue that has an essential role in adipogenesis (Figure 5B).72 The Arg397Cys mutation is predicted to disrupt the formation of a salt bridge between arginine at position 397 and glutamic acid at position 324 (Figure 5A). The other three mutant PPAR proteins were found to be transcriptionally impaired, had reduced ligand binding, and inhibited the action of coexpressed wild-type PPAR in a dominant negative manner.18,19,71 Thus, although mutations in the PPAR 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 PPAR 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, bird-like 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
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 post-translational proteolytic processing of prelamin A have been reported in a woman with severe mandibuloacral dysplasia, progeria, and generalized lipodystrophy 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
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 identified in a man with gradual onset of generalized lipodystrophy at puberty, cardiomyopathy, and depigmented skin papules.84
Mechanisms of Insulin Resistance and Metabolic Complications
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 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.
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 fat in nonlipodystrophic regions.
Improving Cosmetic Appearance
The loss of facial fat is becoming a special concern among HIV-infected patients with lipodystrophy. Various types of cosmetic surgery, including silicone and bovine-collagen implants, transplantation of fascia and fat from the thighs, reinjection of autologous fat, and the use of free flaps from the anterolateral thigh, anterior abdomen, or temporalis muscle, have been employed to improve the appearance of patients with lipodystrophy who have an extreme loss of facial fat.88,89 Transplantation of adipose tissue from the thigh or hip to the face is successful in only some patients with acquired partial lipodystrophy.
Weight loss can reduce excess deposits of fat in nonlipodystrophic regions. Nonetheless, excess fat deposits in the neck region in patients with familial partial lipodystrophy and in HIV-infected patients with lipodystrophy may require repeated surgical removal by liposuction or lipectomy.
Although the ability of thiazolidinediones to induce adipogenesis in lipodystrophic regions is limited,90 these drugs also improve glycemic control to some extent and may be a particularly attractive approach to the treatment of familial partial lipodystrophy resulting from PPAR mutations.19 However, thiazolidinediones may exacerbate the deposition of fat in nonlipodystrophic regions.
Management of Dyslipidemia
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 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.
Management of Hyperglycemia
The presence of hyperglycemia may necessitate the use of oral hypoglycemic drugs or insulin.37,39,91 Metformin, which may additionally reduce appetite, induce weight loss, and improve the polycystic ovary syndrome and hepatic steatosis, is a particularly attractive therapeutic choice.92,93 Highly concentrated insulin (500 U per milliliter) is indicated for patients who require more than 400 U of insulin per day. Aggressive glycemic control is pivotal for the prevention of the long-term complications of diabetes.
Additional Considerations for HIV-Infected Patients with Lipodystrophy
Switching HIV-infected patients with protease-inhibitor–induced lipodystrophy to alternative antiretroviral regimens may improve their serum lipid levels but may not reverse the loss of subcutaneous fat.94 Many statins, such as simvastatin, lovastatin, and atorvastatin, are metabolized by cytochrome P-450 isoform 3A4, which is inhibited by protease inhibitors95; therefore, pravastatin, ezetimibe, and plant stanols or sterols may be safer alternatives. Both nucleoside analogues and metformin can cause lactic acidosis, and thus metformin should be used with caution. Although recombinant human growth hormone may reduce the deposition of visceral fat, its ability to induce insulin resistance, hyperglycemia, and other adverse effects renders its use unwise.96
Other Therapeutic Options
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 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 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, R01-63656, 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 PPAR ribbon structure; and to Drs. Dolores Peterson, Margo A. Denke, and David Feinstein for referring patients.
Source Information
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.garg@utsouthwestern.edu.
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Acquired and Inherited Lipodystrophies
Walker U. A., Schott M., Scherbaum W. A., Bornstein S. R., Garg A.(Abhimanyu Garg, M.D.)