Intriguingly, pharmacological inhibition or genetic inactivation of ATGL could rescue adipocyte differentiation and lipodystrophy in Bscl2-/- cells and mice.
Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7.
PELD (Progressive Encephalopathy with or without Lipodystrophy or Celia's Encephalopathy) is a fatal and rare neurodegenerative syndrome associated with the BSCL2 mutation c.985C>T, that results in an aberrant transcript without the exon 7 (Celia seipin).
BSCL2-iPS cells that recapitulate the lipodystrophic phenotypes in vitro could provide valuable models with which to study the physiology of lipid accumulation and the pathology of human lipodystrophy.
Bscl2(-/-) mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis, and insulin resistance.
Treatment with thiazolidinediones (TZD) in Bscl2(-/-) mice increases adipose tissue mass and partially rescues the metabolic complications associated with BSCL, highlighting that lipoatrophy is the major cause of the BSCL phenotype.
Mutations affecting the N-glycosylation site in Berardinelli-Seip lipodystrophy (BSCL)-associated gene BSCL2/seipin lead to a dominantly inherited spastic paraplegia termed seipinopathy.
A number of proteins mutated in genetic lipodystrophies are involved in the control of triglyceride synthesis towards the lipid droplet (1-acylglycerol-3-phosphate-O-acyltransferase 2), or its functions (seipin, cell death-inducing DFF45-like effector C, perilipin, caveolin-1, cavin-1).
We conducted an open-label prospective study of patients with acquired forms of lipodystrophy and inherited forms of lipodystrophy secondary to mutations in the AGPAT2, SEIPIN (also known as BSCL2), LMNA and PPARgamma (also known as PPARG) genes.
Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2(AGPAT2).
Leptin and total and high-molecular-weight adiponectin were measured in plasma of 16 BSCL1/AGPAT2 and 19 BSCL2/seipin patients and compared with heterozygous (n = 22) or nonmutated relatives (controls, n = 30); patients with Dunnigan-type partial lipodystrophy due to lamin A/C mutations (n = 23), HIV-related lipodystrophy (n = 124), and insulin receptor dysfunctions caused by mutations or autoantibodies (n = 17).
Loss of Bscl2 function thus interferes with the normal transcriptional cascade of adipogenesis during fat cell differentiation, resulting in near total loss of fat or lipodystrophy.