OBJECTIVE: Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a
recessive disorder featuring near complete absence of adipose tissue. Remarkably,
although 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 characterization
of BSCL2 expression in developing adipocytes, C3H10T1/2 mesenchymal stem cells
were generated in which BSCL2 expression was knocked down using short hairpin RNA
(shRNA). These cells were used to investigate whether BSCL2 is required for
adipogenesis. BSCL2 constructs harboring pathogenic mutations known to cause
lipodystrophy were also generated and characterized. 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 peroxisome proliferator-activated
receptor (PPAR)gamma and CAAT/enhancer-binding protein-alpha, was preserved in
cells lacking BSCL2. However, the expression of these critical factors was not
sustained, suggesting that the activity of PPARgamma 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 subcellular localization of BSCL2 may be critical to its function.
CONCLUSIONS: This study demonstrates that BSCL2 is an essential, cell-autonomous
regulator of adipogenesis