Genetics of Lipodystrophies


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.



Agarwal AK, Arioglu E, De Almeida S et al. (2002) AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nature Genetics 31(1): 21–23.

Agarwal AK, Fryns JP, Auchus RJ and Garg A (2003) Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Human Molecular Genetics 12(16): 1995–2001.

Agarwal AK, Xing C, DeMartino GN et al. (2010) PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis‐induced lipodystrophy syndrome. American Journal of Human Genetics 87(6): 866–872.

Antuna‐Puente B, Boutet E, Vigouroux C et al. (2010) Higher adiponectin levels in patients with Berardinelli–Seip congenital lipodystrophy due to seipin as compared with 1‐acylglycerol‐3‐phosphate‐o‐acyltransferase‐2 deficiency. Journal of Clinical Endocrinology and Metabolism 95(3): 1463–1468.

Auclair M, Vigouroux C, Boccara F et al. (2013) Peroxisome proliferator‐activated receptor‐gamma mutations responsible for lipodystrophy with severe hypertension activate the cellular renin‐angiotensin system. Arteriosclerosis, Thrombosis, and Vascular Biology 33(4): 829–838.

Barroso I, Gurnell M, Crowley VE et al. (1999) Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402(6764): 880–883.

Bays HE (2011) Adiposopathy is ‘sick fat’ a cardiovascular disease? Journal of the American College of Cardiology 57(25): 2461–2473.

Béréziat V, Cervera P, Le Dour C et al. (2011) LMNA mutations induce a non‐inflammatory fibrosis and a brown fat‐like dystrophy of enlarged cervical adipose tissue. American Journal of Pathology 179(5): 2443–2453.

Blouin CM, Le Lay S, Eberl A et al. (2010) Lipid droplet analysis in caveolin‐deficient adipocytes: alterations in surface phospholipid composition and maturation defects. Journal of Lipid Research 51(5): 945–956.

Boutet E, El Mourabit H, Prot M et al. (2009) Seipin deficiency alters fatty acid Delta9 desaturation and lipid droplet formation in Berardinelli–Seip congenital lipodystrophy. Biochimie 91(6): 796–803.

Cao H, Alston L, Ruschman J and Hegele RA (2008) Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia. Lipids in Health and Disease 7: 3.

Cao H and Hegele RA (2000) Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan‐type familial partial lipodystrophy. Human Molecular Genetics 9(1): 109–112.

Capanni C, Mattioli E, Columbaro M et al. (2005) Altered pre‐lamin A processing is a common mechanism leading to lipodystrophy. Human Molecular Genetics 14(11): 1489–1502.

Caron M, Auclair M, Donadille B et al. (2007) Human lipodystrophies linked to mutations in A‐type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence. Cell Death and Differentiation 14(10): 1759–1767.

Caron‐Debarle M, Lagathu C, Boccara F, Vigouroux C and Capeau J (2010) HIV‐associated lipodystrophy: from fat injury to premature aging. Trends in Molecular Medicine 16(5): 218–229.

Cartwright BR and Goodman JM (2012) Seipin: from human disease to molecular mechanism. Journal of Lipid Research 53(6): 1042–1055.

Caux F, Dubosclard E, Lascols O et al. (2003) A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin‐resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. Journal of Clinical Endocrinology and Metabolism 88(3): 1006–1113.

De Sandre‐Giovannoli A, Bernard R, Cau P et al. (2003) Lamin A truncation in Hutchinson–Gilford progeria. Science 300(5628): 2055.

Decaudain A, Vantyghem MC, Guerci B et al. (2007) New metabolic phenotypes in laminopathies: LMNA mutations in patients with severe metabolic syndrome. Journal of Clinical Endocrinology and Metabolism 92(12): 4835–4844.

Eriksson M, Brown WT, Gordon LB et al. (2003) Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423(6937): 293–298.

Gale SE, Frolov A, Han X et al. (2006) A regulatory role for 1‐acylglycerol‐3‐phosphate‐O‐acyltransferase 2 in adipocyte differentiation. Journal of Biological Chemistry 281(16): 11082–11089.

Gandotra S, Le Dour C, Bottomley W et al. (2011a) Perilipin deficiency and autosomal dominant partial lipodystrophy. New England Journal of Medicine 364(8): 740–748.

Gandotra S, Lim K, Girousse A et al. (2011b) Human frame shift mutations affecting the carboxyl terminus of perilipin increase lipolysis by failing to sequester the adipose triglyceride lipase (ATGL) coactivator AB‐hydrolase‐containing 5 (ABHD5). Journal of Biological Chemistry 286(40): 34998–35006.

Gao J, Li Y, Fu X and Luo X (2012) A Chinese patient with acquired partial lipodystrophy caused by a novel mutation with LMNB2 gene. Journal of Pediatric Endocrinology and Metabolism 25(3–4): 375–377.

Garg A, Subramanyam L, Agarwal AK et al. (2009) Atypical progeroid syndrome due to heterozygous missense LMNA mutations. Journal of Clinical Endocrinology and Metabolism 94(12): 4971–4983.

George S, Rochford JJ, Wolfrum C et al. (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304(5675): 1325–1328.

Hayashi YK, Matsuda C, Ogawa M et al. (2009) Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. Journal of Clinical Investigation 119(9): 2623–2633.

Hegele RA, Cao H, Liu DM et al. (2006) Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. American Journal of Human Genetics 79(2): 383–389.

Holtta‐Vuori M, Salo VT, Ohsaki Y, Suster ML and Ikonen E (2013) Alleviation of seipinopathy‐related ER stress by triglyceride storage. Human Molecular Genetics 22(6): 1157–1166.

Jeninga EH, Gurnell M and Kalkhoven E (2009) Functional implications of genetic variation in human PPARgamma. Trends in Endocrinology and Metabolism 20(8): 380–387.

Kim C, Delépine M, Boutet E et al. (2008) Association of a homozygous nonsense Caveolin‐1 mutation with Berardinelli–Seip Congenital Lipodystrophy. Journal of Clinical Endocrinology and Metabolism 93(4): 1129–1134.

Le Dour C, Schneebeli S, Bakiri F et al. (2011) A homozygous mutation of prelamin‐A preventing its farnesylation and maturation leads to a severe lipodystrophic phenotype: new insights into the pathogenicity of nonfarnesylated prelamin‐A. Journal of Clinical Endocrinology and Metabolism 96(5): E856–E862.

Le Lay S, Briand N, Blouin CM et al. (2010) The lipoatrophic caveolin‐1 deficient mouse model reveals autophagy in mature adipocytes. Autophagy 6(6): 754–763.

Magré J, Delépine M, Khallouf E et al. (2001) Identification of the gene altered in Berardinelli–Seip congenital lipodystrophy on chromosome 11q13. Nature Genetics 28(4): 365–370.

Novelli G, Muchir A, Sangiuolo F et al. (2002) Mandibuloacral dysplasia is caused by a mutation in LMNA‐encoding lamin A/C. American Journal of Human Genetics 71(2): 426–431.

Oral EA, Simha V, Ruiz E et al. (2002) Leptin‐replacement therapy for lipodystrophy. New England Journal of Medicine 346(8): 570–578.

Parker VE, Savage DB, O'Rahilly S and Semple RK (2011) Mechanistic insights into insulin resistance in the genetic era. Diabetic Medicine 28(12): 1476–1486.

Rubio‐Cabezas O, Puri V, Murano I et al. (2009) Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Molecular Medicine 1(5): 280–287.

Semple RK, Cochran EK, Soos MA et al. (2008) Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance. Diabetes Care 31(5): 977–979.

Shackleton S, Lloyd DJ, Jackson SN et al. (2000) LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nature Genetics 24(2): 153–156.

Simha V and Garg A (2003) Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or Seipin genes. Journal of Clinical Endocrinology and Metabolism 88(11): 5433–5437.

Szymanski KM, Binns D, Bartz R et al. (2007) The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proceedings of the National Academy of Sciences of the USA 104(52): 20890–20895.

Tan K, Kimber WA, Luan J et al. (2007) Analysis of genetic variation in Akt2/PKB‐beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes. Diabetes 56(3): 714–719.

Van Maldergem L, Magré J, Khallouf TE et al. (2002) Genotype‐phenotype relationships in Berardinelli–Seip congenital lipodystrophy. Journal of Medical Genetics 39(10): 722–733.

Vigouroux C, Caron‐Debarle M, Le Dour C, Magré J and Capeau J (2011) Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity. International Journal of Biochemistry and Cell Biology 43(6): 862–876.

Vigouroux C, Magré J, Vantyghem MC et al. (2000) Lamin A/C gene: sex‐determined expression of mutations in Dunnigan‐type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy. Diabetes 49(11): 1958–1962.

Virtue S and Vidal‐Puig A (2010) Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome – an allostatic perspective. Biochimica et Biophysica Acta 1801(3): 338–349.

Wiltshire KM, Hegele RA, Innes AM and Brownell AK (2013) Homozygous Lamin A/C familial lipodystrophy R482Q mutation in autosomal recessive Emery Dreifuss muscular dystrophy. Neuromuscular Disorders 23(3): 265–268.

Young J, Morbois‐Trabut L, Couzinet B et al. (2005) Type A insulin resistance syndrome revealing a novel lamin A mutation. Diabetes 54(6): 1873–1878.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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