The Human Lipodystrophy Gene BSCL2/Seipin May Be Essential For Normal Adipocyte Differentiation

Abstract

Objective: Berardinelli-Seip Congenital Lipodystrophy type 2 (BSCL2) is a recessive disorder featuring near-complete absence of adipose tissue. Remarkably, whilst the causative gene, BSCL2, has been known for several years, its molecular function and its role in adipose tissue development have not been elucidated. Therefore, we examined whether BSCL2 is involved in the regulation of adipocyte differentiation, and the mechanism whereby pathogenic mutations in BSCL2 cause lipodystrophy.

Research design and methods: Following the characterisation of BSCL2 expression in developing adipocytes, C3H10T1/2 mesenchymal stem cells were generated in which BSCL2 expression was knocked down using shRNA. These cells were used to investigate whether BSCL2 is required for adipogenesis. BSCL2 constructs harbouring pathogenic mutations known to cause lipodystrophy were also generated and characterised.

Results: BSCL2 expression was strongly induced during adipocyte differentiation and the induction of BSCL2 expression was essential for adipogenesis to occur. The initial induction of key adipogenic transcription factors including PPARγ and C/EBPα was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained suggesting that the activity of PPARγ was impaired. Moreover, expression of key genes mediating triglyceride synthesis including AGPAT2, lipin-1 and DGAT2 was persistently reduced and lipid accumulation was inhibited. Analysis of pathogenic missense mutants of BSCL2 revealed that the amino acid substitution A212P causes aberrant targeting of BSCL2 within the cell, suggesting that sub-cellular localisation of BSCL2 may be critical to its function.

Conclusions: This study demonstrates that BSCL2 is an essential, cell autonomous regulator of adipogenesis.