Congenital generalized lipodystrophies--new insights into metabolic dysfunction

Abstract

Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes. The predominant cause of metabolic complications in CGL is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue. Profound hypoleptinaemia further exacerbates metabolic derangements by inducing a voracious appetite. Patients require psychological support, a low-fat diet, increased physical activity and cosmetic surgery. Aside from conventional therapy for hyperlipidaemia and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with CGL. In this Review, we discuss the molecular genetic basis of CGL, the pathogenesis of the disease's metabolic complications and therapeutic options for patients with CGL.

Figure 1 |

Clinical features of patients with CGL. a | Lateral view of a 34-year-old female with type 1 CGL owing to a homozygous mutation c.589–2A>G (p.Val197Glufs*32) in AGPAT2. This patient has a generalized lack of body fat, extreme muscularity, umbilical prominence and acanthosis nigricans in the axillae and neck. b | Anterior view of an 8-year-old male with type 2 CGL owing to compound heterozygous mutations c.193delCinsGGA (p.Pro65Glyfs*28) and c.325_326insA (p.Thr109Asnfs*5) in BSCL2. This patient has a generalized lack of fat and extreme muscularity. c | Lateral view of an 11-year-old male with type 4 CGL owing to homozygous mutation c.135delG (p.Lys45Asnfs*5) in PTRF This patient has generalized lipodystrophy, prominent muscularity, acromegalic features such as large hands and feet and protuberant abdomen. d | The left palm of a patient with type 1 CGL (the patient in panel a) showing normal subcutaneous fat. e | The sole of the right foot of the patient in panel a with type 1 CGL showing normal subcutaneous fat. f | The left palm of the patient with type 2 CGL in panel b showing loss of subcutaneous fat. g | The right sole of the patient in panel b showing loss of subcutaneous fat. h | Arrow points to percussion-induced muscle mounding on the biceps of the patient shown in panel c. Images are not to the same scale. Abbreviation: CGL, congenital generalized lipodystrophy. Written consent for publication of panel a was obtained from the patient. Written consent for publication of panels b and c was obtained from the patient’s responsible relative. Panel h reproduced with permission from Wiley © Shastry, S. et al. Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations. Am. J. Med. Genet. A 152A, 2245–2253 (2010).

Figure 2 |

Lipid droplet formation in adipocytes. Lipid droplets are organelles that store triglycerides within the cell. They form as budding vesicles at the endoplasmic reticulum that fuse in adipocytes to form a single large lipid droplet. Many proteins, such as CIDEC, seipin and perilipin 1 are present on the lipid droplet membrane. CIDEC and seipin might be involved in the fusion of lipid droplets to form a larger droplet, whereas perilipin 1 is essential for lipid storage and hormone-mediated lipolysis. Caveolae are formed from lipid rafts on the cell surface, which include cholesterol, glycosphingolipids and caveolin 1. Endocytosis of caveolae forms caveolin vesicles that might directly merge with lipid droplets and translocate fatty acids to the lipid droplets. In the adipose tissue, triglyceride synthesis requires glycerol-3-phosphate as the initial substrate (classic pathway), whereas in the small intestine, triglyceride synthesis can occur via an alternative pathway using monoacylglycerol as the initial substrate. Acylation of glycerol-3-phosphate using FA-CoA at the sn-1 position is catalysed by GPAT, which results in the formation of 1-acylglycerol-3-phosphate or LPA. LPA is then acylated at the sn-2 position by AGPATs to yield phosphatidic acid. Removal of a phosphate group from phosphatidic acid by PAP produces DAG. Further acylation of DAG at the sn-3 position by DGAT finally produces triglyceride. In the alternative pathway, MAG is acylated to DAG by MGAT, which is then further converted to triglyceride. Abbreviations: AGPAT, 1-acyl-sn-glycerol-3-phosphate acyltransferase; CIDEC, cell death activator CIDE-3; CoA, coenzyme A; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; FA-CoA, fatty acyl coenzyme A; GPAT, glycerol-3-phosphate acyltransferase; LPA, lysophosphatidic acid; MGAT, monoacylglycerol acyltransferase; P, phosphate; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; TG, triglyceride. Reproduced with permission from Endocrine Society © Garg, A. Lipodystrophies: genetic and acquired body fat disorders. J. Clin. Endocrinol. Metab. 96, 3313–3325 (2011).

Figure 3 |

Mechanism of developing metabolic complications in obesity and CGL. a | Under normal conditions, dietary TGs are carried in chylomicrons and provide a source of FFA to the adipose tissue, liver and muscle for further storage and metabolism. Normally, adipocytes have plenty of capacity to store excess dietary TG and thus fewer TGs are directed to the liver and skeletal muscles. Skeletal muscles utilize FA for energy production (β-oxidation). During energy deprivation, the stored TGs are released from the adipocytes to deliver FA to the liver, skeletal muscle and other organs. b | In individuals with generalized or regional adiposity, adipocyte size enlarges and owing to the limited capacity to store more TG, dietary TG might be stored in sites such as the liver and skeletal muscles. Furthermore, lipolysis of excess TG stored in the adipocytes can also contribute to increased FA flux, which can contribute to TG storage in ectopic sites. Uptake of FFA and glucose depends on insulin action, thus in insulin resistance, uptake of FFA and glucose in these tissues is reduced, which might induce hypertriglyceridaemia, hyperglycaemia and hepatic steatosis. c | Patients with CGL lack adipocytes that can store TGs, which limits the disposal of excess dietary TG in the remaining adipocytes and consequently TGs are stored in ectopic sites such as the liver and skeletal muscles. This ectopic storage leads to severe insulin resistance and its complications. A lack of leptin induces hyperphagia, which further exacerbates ectopic storage of TG. Abbreviations: CGL, congenital generalized lipodystrophy; FA, fatty acid; FFA, free fatty acid; TG, triglyceride.