Lipodystrophy is a rare lipid storage disorder that is characterized by a loss of adipose tissue. It can be inherited due to monogenic mutation or acquired by medication and autoimmune illness. Two primary forms of inherited lipodystrophy are congenital generalized lipodystrophy manifested as a near-complete loss of fat tissue since birth and familial partial lipodystrophy with progressive, partial loss of fat tissue during late childhood and puberty. Lipodystrophy results in severe metabolic conditions, including insulin resistance, type 2 diabetes, hepatosteatosis, polycystic ovary syndrome, acanthosis nigricans, and hypertension. This chapter summarizes the symptoms, causes, and treatments of inherited and acquired lipodystrophy.
- adipose tissue
- metabolic syndrome
- lipid disorders
- ectopic lipid
In order to survive and adapt to challenging environment, living organisms have equipped themselves with different mechanisms of energy storage that can be accessed when there is a shortage of food supply. In mammals, fat is mainly stored in adipose tissues . There are two types of adipose tissues: white adipose tissue that stores the majority of the body fat and also functions as an endocrine organ and brown adipose tissue that generates the body heat . In adipocytes, fat is stored in lipid droplets (LDs) in the form of neutral lipids, e.g., triacylglycerol (TAG) and cholesteryl ester (CE). White adipocytes contain unilocular LDs that occupy up to 90% of the cytoplasmic space, while brown adipocytes contain multilocular LDs. Obesity is characterized by both increase in the size and number of white adipocytes . Fat storage in white adipose tissue is essential for proper metabolic homeostasis . In contrast, when fat storage in white adipose tissue is compromised or overwhelmed, the ectopic fat accumulation in non-adipose tissues will result in severe metabolic disorders .
Lipodystrophy is an extreme fat storage condition, in which white adipose tissue is selectively lost . Partial or generalized loss of fat in this condition causes an array of complications including insulin resistance, type 2 diabetes and acanthosis nigricans, hypertriglyceridemia, hepatic steatosis, hypertension, polycystic ovarian syndrome, and proteinuric kidney disease [7, 8]. The severity of lipodystrophy depends on the level of adipocyte depletion in the body. Fat loss can occur in nearly the entire body known as congenital generalized lipodystrophy (CGL) or partial loss in small and discrete areas known as familial partial lipodystrophy (FPLD). While CGL is manifested early in life at birth or soon after, partial fat loss in FPLD occurs during late childhood and puberty. CGL can be determined by measurements of skinfold thickness with calipers or by whole-body magnetic resonance imaging (MRI) scan . Since lipodystrophy is a monogenetic disorder, it can also be diagnosed and confirmed by genotyping.
Lipodystrophy is a very rare genetic disease (1 in 10 million for CGL). Currently, there have been around 300–500 CGL cases and 1000 FPLD cases reported; however, the number of undiagnosed patients is suspected to be three times more . Nearly 20 loci for different subtypes of lipodystrophy have been identified. These genes are implicated in the regulation of either the development of white adipose tissue or the expansion of LDs in white adipocytes. In this chapter, we will outline these lipodystrophy-causative gene loci as well as describe in brief the acquired condition of lipodystrophy.
2. Genetics of congenital generalized lipodystrophy
There are four different genetic subtypes of CGL that result from different mutations.
2.1 Type 1 CGL (CGL1) and AGPAT2
Mutations that are responsible for CGL1 (Online Mendelian Inheritance in Man [OMIM] #608594) occur in the region of 1-acylglycerol-3-phosphate O-acyltransferase 2 (
AGPAT2 is a member of lysophosphatidic acid acyltransferases (LPAATs) including AGPAT family (AGPAT1–AGPAT11) and others such as CGI-58 and endophilin . In fact, AGPAT2 was identified with AGPAT1 by searching an EST database for human homologs of yeast LPAAT in 1997 . There are 11 isoforms of AGPATs that are involved in the de novo synthesis of phospholipids (PLs) and triacylglycerol from glycerol-3-phosphate (G3P).
In adipose tissue, the synthesis of PLs and TAG begins with the acylation of G3P with FA-CoA by glycerol phosphate acyltransferase (GPAT) at the SN1 position to form 1-acylglycerol-3-phosphate or lysophosphatidic acid (LPA). Then AGPAT2 catalyzes the conversion of LPA into phosphatidic acid (PA) via an acylation reaction at the SN2 position. PA is a pivotal intracellular signaling lipid for it sits at the branching point of de novo PL and TAG synthesis pathway and acts as a precursor for the lipin-mediated production of diacylglycerol (DAG), followed by phosphatidylcholine (PC), phosphatidylethanolamine (PE), and TAG, and as the substrate for the cytidine diphosphate synthase (CDS)-mediated generation of cytidine diphosphate diacylglycerol (CDP-DAG), followed by phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin . PA is a cone-shaped lipid that has the capacity to alter the curvature of the membranes, and it has been shown to mediate membrane fusion in both soluble N-ethylmaleimide-sensitive factor attachment protein (NSF)-receptor (SNARE)-dependent and SNARE-independent fashions [22, 23]. It has been implicated in the fusion of multiple LDs to form a gigantic LD . In addition, PA is believed to be an endogenous antagonist of peroxisome proliferator-activated receptor gamma (PPARγ) that is the master transcription factor in adipocyte differentiation . The malfunctioned
In addition, these BAT-derived preadipocytes exhibit an increased expression of autophagy-related proteins but a decreased autophagic flux . In isolated muscle-derived multipotent cells (MDMCs) from CGL1 patients and 3T3-L1 preadipocyte cells with the knockdown of AGPAT2, cell death also proceeds during adipogenesis, which might be associated with defective Akt activation as a result of altered PI composition [36, 37]. The constitutively active Akt and PPARγ agonist pioglitazone partially rescued the adipogenic defect in the
2.2 Type 2 CGL (CGL2) and SEIPIN
In CGL2 (OMIM #269700), mutations happen in the
Unlike patients with CGL1, patients with CGL2 suffer a near-total loss of both metabolically active and mechanical adipose tissues . In addition, these patients have significantly low median serum levels of leptin (0.01 ng/ml) and adiponectin (3.3 μg/ml) as compared to normal healthy individuals who had median serum levels of 4.6 ng/ml and 7.8 μg/ml for leptin and adiponectin, respectively . Also, they suffer cardiomyopathy and mild mental retardation in a more prevalent way [7, 8, 43]. One single patient with CGL2 has been reported to have teratozoospermia, a condition characterized by sperm defects including abnormalities in sperm morphology and bundled sperm with two or more sperms joined together by large ectopic LDs . Additionally, three patients in a family from Pakistan with
SEIPIN is a 398 amino acid transmembrane protein in the endoplasmic reticulum (ER), which regulates the transport of macromolecules including proteins and lipids between the ER and the LD . Therefore, it plays a role as a docking protein to regulate LD biogenesis and adipogenesis [48, 49]. Seipin, an integral ER membrane, participates in lipid homeostasis via various complex mechanisms. One of them is to assist LD assembly and fusion as well as adipocyte differentiation . In fact, SEIPIN deficiency in mammals or its yeast ortholog Fld1p/Sei1p can lead to changes in LD morphology, manifested as clustering of multiple small LDs or supersized LDs . Recently, SEIPIN/Fld1p has been found to be stabilized to ER-LD contacts to assist the protein and lipid trafficking into growing LDs. SEIPIN strengthens the contact site between ER and LD to regulate the growth of immature LDs . The protein might also be involved in PL and TAG synthesis by its binding and interaction with phosphatidic acid phosphatase lipin-1 and AGPAT2 [52, 53].
2.3 Type 3 CGL (CGL3) and CAV1
CGL3 (OMIM #612526) is induced by mutations in the
Caveolin-1 is the scaffolding protein primarily constituting specialized vesicular invaginations of 50–100 nm called caveolae [1, 36]. It was discovered by Anderson Lab in 1992 [65, 66]. Its potential function in vesicle transport was reported by Glenney using cDNA encoding caveolin-1 from lungs . There are three caveolin isoforms: CAV1, CAV2, and CAV3. While CAV3 is muscle specific, CAV1 and CAV2 are predominantly expressed in adipose tissue, endothelial cells, and fibroblasts [68, 69]. As the main component of caveolae, caveolin-1 plays an essential role in the caveolae assembly alongside with other caveolar proteins, such as cavin1–cavin4, Pacsin2, and EH domain-containing 2 (EHD2) . In addition to its essential role in caveolae formation, caveolin-1 is also a key determinant of normal lipid homeostasis, vesicular trafficking, and signaling transduction . Caveolae plays a regulatory role in maintaining the integrity and function of the LDs as well as binding and transporting fatty acids and cholesterol by budding off the plasma membrane . Moreover, they serve as a platform for augmenting insulin and PKA signaling . In adipocyte cells, the expression of caveolin-1 is increased 10-fold during adipogenesis [73, 74]. The abundance level of caveolin-1 determines the PL and surface protein composition in LDs and the LD growth. In fact, the expression of
Similar to caveolin-1 deficiency, lacking another caveolar protein cavin-1 in humans also causes another type of congenital generalized lipodystrophy (type 4 CGL) [76, 77, 78]. Interestingly, subcutaneous injection of caveolin-1 overexpressed preadipocytes could form fat pads and larger adipocytes . Both caveolin-1 and cavin-1 are the strong indicators of adipogenic differentiation in human tumors and liposarcoma . Taken together, these data indicate the critical role of adipocyte caveolae in adipose tissue development.
2.4 Type 4 CGL (CGL4) and PTRF
CGL4 (OMIM #613327) is an autosomal recessive condition caused by mutations in the
As mentioned before, cavin-1 interacts with caveolin proteins to form caveolae and to mediate cellular trafficking and lipid turnover [70, 85]. Cavin-1 can stabilize caveolae and caveolin proteins probably via its interactions with cytoskeleton . In agreement with this finding,
3. Familial partial dystrophy
3.1 Type 1 FPLD (FPLD1)
Type 1 FPLD (OMIM #608600), also known as Köbberling-type lipodystrophy, was first reported by Köbberling et al. in 1971 . The syndrome manifests loss of subcutaneous fat in the extremities and gluteus, with normal or increased fat deposition in the face, neck, and trunk . The ratio of skin thickness from the abdomen to the thigh is significantly higher in these subjects, which can be used as a diagnostic method . Diabetes and other metabolic complications including hypertension, insulin resistance, and severe hypertriglyceridemia develop during adulthood, with higher severity in women than men [98, 99]. Similar to other types of lipodystrophy, FPLD1 is an extremely rare genetic condition whose chance of occurrence is 1 in 15 million [6, 36]. Unfortunately, the causative loci for FPLD1 have not been identified to unravel the underlying genetic mechanism of the syndrome.
3.2 Type 2 FPLD (FPLD2) and LMNA
FPLD2 (OMIM #151660) is an autosomal dominant condition that is caused by heterozygous mutations in the
Most cases of FPLD2 are caused by mutations in the lamin A/lamin C (
Lamin A is maturated from pre-lamin A via multiple-step posttranslational modifications . This process involves a cleavage reaction carried out by an endoplasmic reticulum membrane protease full name ZMPSTE24 located on chromosome 1p34 . Mutations in ZMPSTE24 have been shown to cause mandibuloacral dysplasia type B and autosomal-dominant FPLD2, due to the lack of functional lamin A . Nonetheless, the question as to whether there is an accumulation of pre-lamin A remains controversial. On the one hand, using lamin A/lamin C antibodies and pre-lamin A-specific monoclonal antibodies, one recent study has shown that fibroblasts carrying lipodystrophy-related LMNA mutations (R482W, I299V, C591F, T528 M) do not exhibit an accumulation of pre-lamin A as compared with their WT counterpart . On the other hand, one prior study has demonstrated that the pre-lamin A level is upregulated in
3.3 Type 3 FPLD (FPLD3) and PPRAG
FPLD3 (OMIM #151660) is caused by mutations in the
FPLD3 patients with PPARγ-induced FPLD suffer metabolic disorders including hypertriglyceridemia, insulin resistance with raised serum triglyceride and cholesterol levels and raised aminotransferase, and γ-glutamyltranspeptidase activities as well as manifest the symptoms of FPLD including subcutaneous fat loss from the arms, muscular hypertrophy in the legs, and arterial hypertension while having the subcutaneous fat buildup in the face, chin, trunk, and abdomen .
3.4 Type 4 FPLD (FPLD4) and PLIN1
It has been reported that null mutations in the
3.5 Type 5 FPLD (FPLD5) and CIDEC
The rare FPLD5 (OMIM #615238) is caused by a homozygous nonsense mutation in the LD protein cell death-inducing Dffa-like effector C (
3.6 Type 6 FPLD (FPLD6) and LIPE
Exome sequencing has revealed another novel case of FPLD6 (OMIM #615980) that is caused by a homozygous nonsense mutation in the
3.7 Type 7 FPLD (FPLD7) and CAV1
FPLD7 (OMIM #606721) is also caused by the mutation in the
4. Acquired partial lipodystrophy (APL)
4.1 Barraquer-Simons syndrome
Barraquer-Simons syndrome (OMIM #608709) is named after Barraquer and Simons who first described the disease in the 1900s. Unlike other lipodystrophies, Barraquer-Simons syndrome occurs not due to inherited genetic mutations but normally derives from an acute viral transfection, such as measles . Barraquer-Simons syndrome is extremely rare, with approximately 250 cases that have been reported in the literature with a male-to-female ratio of 1:4 . The syndrome results in loss of subcutaneous fat mainly in the upper part of the body (face, neck, arms, and thorax) and upper abdomen; however, some adipose tissues are preserved in the gluteal regions and lower extremities . Fortunately, Barraquer-Simons syndrome does not normally induce other metabolic complications such as insulin resistance, diabetes, and hypertriglyceridemia .
4.2 Highly active antiretroviral therapy (HAART)-induced lipodystrophy (LD-HIV)
LD-HIV can develop in some HIV-infected individuals who are undergoing antiretroviral therapy of more than 2 years . Several cases have been reported since 1998 . The toxicity of the treatment might result from HIV-1 protease inhibitors and nucleoside reverse-transcriptase inhibitors . The latter ones have been shown to disrupt lipid metabolism and mitochondrial functions . In patients with LD-HIV, subcutaneous fat loss occurs in the arms, legs, and face throughout the treatment course and does not cease after the therapy is discontinued . Fortunately, this type of APL does not result in diabetes and insulin resistance, but some individuals might experience some conditions such as hypertriglyceridemia and coronary heart disease .
Patients with lipodystrophy normally seek medical treatments toward the specific symptoms that they encounter. Since the disease affects its patients in multiple aspects, care and management require a multidisciplinary team involving pediatricians, surgeons, cardiologists, endocrinologists, nutritionists, and psychiatrists . Mental health supports should also be made to patients who suffer depressions from the diagnosis and anxieties about their appearance . In addition, special education might be necessary for those who have an intellectual disability . Furthermore, such cosmetic surgery as reconstructive facial surgery and bilateral gluteus maximus muscle flap advance might benefit the patients in improving their appearance and quality of life .
Dietary restriction is of paramount importance in the disease management. Particularly, those with CGL should follow a high-carb and low-fat diet, since it can raise very-low-density lipoprotein (VLDL) TAG levels while alleviating chylomicronemia . Sufficient energy supply along with regular exercise is highly important in children with CGL to ensure their normal growth . However, strenuous exercise is not recommended for CGL4 patients who can be treated with β-adrenergic blockers along with other antiarrhythmic medications to prevent catecholaminergic polymorphic ventricular tachycardia . Also, in this case, an implantable pacemaker or defibrillator can be quite beneficial . It remains unclear whether patients with CGL2 and cardiomyopathy should restrict exercise .
The first-line therapy for diabetes mellitus, such as metformin and sulphonylureas, can be prescribed to patients with CGL . The lack of subcutaneous fat in the abdomen and thighs might pose a potential barrier for insulin injection, and the patients might necessitate higher doses of insulin . Furthermore, kidney damage such as diabetic nephropathy and end-stage renal disease might occur in patients with long-standing diabetes as the result high blood glucose exposure. Treatments for such condition might involve hemodialysis and kidney transplantation .
Metreleptin can be a promising therapeutic drug in the near future as recent studies have shown its potency in improving metabolic complications involving diabetes mellitus, hypertriglyceridemia, and hepatic steatosis in CGL [146, 148, 149, 150, 151]. In fact, 63% reduction in circulating levels of TAG along with 30% increase in insulin sensitivity, and 20% reduction in liver volume are observed in seven patients treated with metreleptin over the period of 4 months . Three patients with CGL2 and two patients with CGL treated with recombinant leptin therapy in Japan during the treatment course of 36 months have shown ameliorated fasting glucose and TAG levels as well as increased insulin sensitivity . Metreleptin therapy can also reduce symptoms of other conditions such as macroalbuminuria, microalbuminuria, and hyperfiltration as well as improve the balance in sex hormone profile [151, 152]. Patients treated with metreleptin might suffer such adverse effects as hypoglycemia, headache, nausea, decreased weight, and abdominal pain [153, 154]. In addition, there is a rare possibility that antileptin antibodies might develop severe infections . Metreleptin therapy can reduce appetite signaled from the hypothalamus, as
Lipodystrophy is a rare genetic disease characterized by near-total loss or partial loss of body fat. The syndrome can result in an array of metabolic complications such as insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis. The disease is managed with dietary restriction and exercise programs in line with the leptin therapy.