Molecular and Cellular Bases of Lipodystrophy Syndromes

Abstract

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Keywords: adipose tissue; diabetes; genetics; immunity; insulin resistance; lipodystrophy; lipomatosis; senescence.

Figure 1

Cellular targets of the main molecular defects responsible for lipodystrophy syndromes. Adipocyte schematic representation with localization of the main proteins involved in the molecular pathophysiology of lipodystrophy syndromes (hatched symbols). AGPAT2, 1-acylglycerol-3-phosphate-O-acyltransferase 2; AKT2, serine/threonine-protein kinase 2; ATGL, adipose triglyceride lipase; BLM, Bloom syndrome protein; CAV1, caveolin-1; CAVIN1, cavin-1; CGI58, comparative gene identification-58, also known as α/β-hydrolase domain-containing 5 (ABHD5); DGAT, diacylglycerol acyltransferase; EPHX1, epoxide hydrolase 1; FA, fatty acid; FA-CoA, fatty acid-coenzyme A; FAS, fatty acid synthase; G3P, glycerol-3-phosphate; GLUT4, glucose transporter 4; GPAT, glycerol-3-phosphate acyltransferase; HSL, hormone-sensitive lipase; LMNA, lamin A/C; MFN2, mitofusin-2; NEFA, non-esterified fatty acids; NSMCE2, E3 SUMO-protein ligase NSE2; PAP, phosphatidic acid phosphatase; PLIN1, perilipin-1; POLD1, DNA polymerase delta 1, catalytic subunit; PPARγ, peroxisome proliferator-activated receptor gamma; RXR, retinoid X receptor; TAG, triacylglycerol; TCA cycle, tricarboxylic acid cycle; WRN, WRN RecQ like helicase.

Figure 2

Metabolic consequences of lipodystrophy leading to cellular lipotoxicity.

Figure 3

Phenotypic features of lipodystrophy syndromes. (A) Muscular hypertrophy and lipoatrophy of limbs in Type 2 Familial Partial Lipodystrophy (Dunnigan syndrome). (B, C) Cervical and axillary acanthosis nigricans in patients with lipodystrophy due to LMNA (B) or BSCL2 (C) pathogenic variants.

Figure 4

Imaging features in lipodystrophy syndromes. (A) Dual energy-ray absorptiometry (DEXA) in a 31 year-old patient with CGL1, showing a major decrease in total and segmental fat mass. (B) Abdominal computed tomodensitometry in a 12 year-old patient with acquired generalized lipodystrophy showing homogeneous hepatomegaly with low attenuation of the parenchyma (Hounsfield units: -13), and absence of subcutaneous adipose tissue.

Figure 5

Benefits of metreleptin replacement therapy in generalized lipodystrophies.