Genetics of Lipodystrophies

Abstract

Human genetic lipodystrophic syndromes are rare conditions with total or partial body fat loss, severe lipid and glucose alterations and insulin resistance, leading to early diabetes, cardiovascular and hepatic complications. Most generalised forms, recessively inherited, result from mutations in four proteins, mainly 1‐acylglycerol‐3‐phosphate‐O‐acyltransferase‐2 (AGPAT2) involved in triglyceride synthesis, or seipin involved in the adipocyte lipid droplet formation/maintenance but also in caveolin‐1 and cavin‐1/polymerase I and transcript release factor, expressed in caveolae and at the lipid droplet surface. Partial lipodystrophic syndromes, generally dominantly inherited, mainly involve A‐type lamins (LMNA), forming the nuclear lamina, or the adipogenic transcription factor peroxisome proliferator‐activated‐receptor‐gamma. Less frequently Akt2, in the insulin signalling pathway, perilipin and cell‐death‐inducing‐DFF45‐like‐effector‐C, controlling adipocyte triglyceride storage, are affected. Insulin resistance and lipodystrophy can also be present in genetic syndromes of premature ageing as the Hutchinson–Gilford progeria or mandibuloacral dysplasia (LMNA or ZMPSTE24) and the Werner syndrome (affecting the helicase WRN). Patients’ management is difficult and recombinant human leptin treatment could be helpful.

Key Concepts:

  • Adipose tissue releases a number of factors and hormones and plays an important physiological role, only recently considered.

  • Genetic lipodystrophic syndromes are a heterogeneous group of diseases with lipoatrophy either generalised or partial.

  • The very limited fat expansion seen in lipodystrophies results in severe metabolic alterations and early complications as a result of fat overwhelming by nutriments.

  • Partial lipodystrophies due to a single gene mutation associate both fat hypertrophy and fat atrophy, stressing for the differential physiology of differently located fat depots.

  • A number of genetic lipodystrophies affect proteins involved in lipid droplet function, which stresses the underrecognised role of lipid droplet in adipocyte physiology.

  • The transcription factor PPARγ plays important roles in adipogenesis but also at the level of the vascular wall.

  • Mutations in the gene encoding lamin A/C result in a wide range of diseases collectively called laminopathies.

  • Human recombinant leptin can improve the metabolic alterations present in lipodystrophic patients with a low leptin level.

Keywords: adipose tissue; lipid droplets; adipogenesis; insulin resistance; diabetes; dyslipidaemia; metabolic complications

Figure 1.

Differentiation process of mesenchymal stem cells to mature adipocytes: involvement of proteins mutated in lipodystrophic syndromes. Preadipocytes arising from mesenchymal stem cells can differentiate into adipocytes. Some proteins mutated in human lipodystrophies are involved in the differentiation process, such as PPARγ, the major transcription factor of adipogenesis, or SREBP1‐c, which interacts with lamin A. Seipin and AGPAT2 are involved in the formation and maintenance of the lipid droplet. AGPAT2, 1‐acylglycerol‐3‐phosphate‐O‐acyltransferase 2; PPARγ, peroxisome proliferator‐activated receptor gamma; SREBP1‐c, sterol regulatory element‐binding protein 1c; ZMPSTE24, zinc metalloproteinase STE24 homologue.

Figure 2.

Adipocyte sublocalisation of the main proteins involved in genetic lipodystrophic syndromes. The proteins mutated in human genetic lipodystrophic act at the level of the nucleus (Lamin A/C and PPARγ), the ER (AGPAT2, seipin and ZMPSTE24), the lipid droplet surface (perilipin, CIDEC, caveolin1 and cavin 1) and/or the caveolae (caveolin 1 and cavin 1) or in the insulin signalling pathways (AKT2). AGPAT2, 1‐acylglycerol‐3‐phosphate‐O‐acyltransferase 2; AKT2, protein kinase B; CIDEC, cell death‐inducing DFF45‐like effector C; PPARγ, peroxisome proliferator‐activated receptor gamma and ZMPSTE24, zinc metalloprotease STE24 homologue.

Figure 3.

A 40 year‐old patient with a heterozygous PPARG mutation responsible for FPLD3. Note the subcutaneous lipoatrophy more prominent on the limbs, with muscular hypertrophy. The phenotype also included insulin‐resistant diabetes, major hypertriglyceridemia and severe hypertension.

Figure 4.

Hypothetical scheme of metabolic and cardiovascular alterations arising from human genetic lipodystrophies. Overwhelming of lipid storage in adipose tissue and oxidative stress result in adipocyte insulin resistance, inflammation and increased free fatty acids release. Ectopic fat depots in the liver, muscles, pancreas, heart and the blood vessels lead to lipotoxicity and insulin resistance, which increase the risk of type 2 diabetes and cardiovascular diseases. AGPAT2, 1‐acylglycerol‐3‐phosphate‐O‐acyltransferase 2; AKT2, protein kinase B; CIDEC, cell death‐inducing DFF45‐like effector C; NASH, nonalcoholic steatohepatitis; PPARγ, peroxisome proliferator‐activated receptor gamma and ZMPSTE24: zinc metalloproteinase STE24 homolog.

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Further Reading

Bastard JP and Fève B (2013) Physiology and Physiopathology of Adipose Tissue. France: Springer‐Verlag.

Garg A (2011) Lipodystrophies: genetic and acquired body fat disorders. Journal of Clinical Endocrinology and Metabolism 96(11): 3313–3325.

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Vigouroux, Corinne, Bidault, Guillaume, and Capeau, Jacqueline(Jun 2013) Genetics of Lipodystrophies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024915]