The human lipodystrophy gene BSCL2/Seipin may be essential for normal adipocyte differentiation

Victoria A. Payne, Neil Grimsey, Antoinette Tuthill, Sam Virtue, Sarah L. Gray, Edoardo Dalla Nora, Robert K. Semple, Stephen O'Rahilly, Justin J. Rochford

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    Abstract

    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/enhancerbinding protein-alpha, was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained, suggesting that the activity of PPAR gamma 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.

    Original languageEnglish
    Pages (from-to)2055-2060
    Number of pages6
    JournalDiabetes
    Volume57
    Issue number8
    Early online date5 May 2008
    DOIs
    Publication statusPublished - Aug 2008

    Keywords

    • vivo
    • in-vitro
    • protein
    • congenital generalized lipodystrophy
    • lipin
    • PPAR-gamma
    • mutation
    • expression
    • adipogenesis
    • seipin

    Cite this

    Payne, V. A., Grimsey, N., Tuthill, A., Virtue, S., Gray, S. L., Nora, E. D., ... Rochford, J. J. (2008). The human lipodystrophy gene BSCL2/Seipin may be essential for normal adipocyte differentiation. Diabetes, 57(8), 2055-2060. https://doi.org/10.2337/db08-0184

    The human lipodystrophy gene BSCL2/Seipin may be essential for normal adipocyte differentiation. / Payne, Victoria A.; Grimsey, Neil; Tuthill, Antoinette; Virtue, Sam; Gray, Sarah L.; Nora, Edoardo Dalla; Semple, Robert K.; O'Rahilly, Stephen; Rochford, Justin J.

    In: Diabetes, Vol. 57, No. 8, 08.2008, p. 2055-2060.

    Research output: Contribution to journalArticle

    Payne, VA, Grimsey, N, Tuthill, A, Virtue, S, Gray, SL, Nora, ED, Semple, RK, O'Rahilly, S & Rochford, JJ 2008, 'The human lipodystrophy gene BSCL2/Seipin may be essential for normal adipocyte differentiation' Diabetes, vol. 57, no. 8, pp. 2055-2060. https://doi.org/10.2337/db08-0184
    Payne VA, Grimsey N, Tuthill A, Virtue S, Gray SL, Nora ED et al. The human lipodystrophy gene BSCL2/Seipin may be essential for normal adipocyte differentiation. Diabetes. 2008 Aug;57(8):2055-2060. https://doi.org/10.2337/db08-0184
    Payne, Victoria A. ; Grimsey, Neil ; Tuthill, Antoinette ; Virtue, Sam ; Gray, Sarah L. ; Nora, Edoardo Dalla ; Semple, Robert K. ; O'Rahilly, Stephen ; Rochford, Justin J. / The human lipodystrophy gene BSCL2/Seipin may be essential for normal adipocyte differentiation. In: Diabetes. 2008 ; Vol. 57, No. 8. pp. 2055-2060.
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    abstract = "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/enhancerbinding protein-alpha, was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained, suggesting that the activity of PPAR gamma 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.",
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    TY - JOUR

    T1 - The human lipodystrophy gene BSCL2/Seipin may be essential for normal adipocyte differentiation

    AU - Payne, Victoria A.

    AU - Grimsey, Neil

    AU - Tuthill, Antoinette

    AU - Virtue, Sam

    AU - Gray, Sarah L.

    AU - Nora, Edoardo Dalla

    AU - Semple, Robert K.

    AU - O'Rahilly, Stephen

    AU - Rochford, Justin J.

    PY - 2008/8

    Y1 - 2008/8

    N2 - 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/enhancerbinding protein-alpha, was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained, suggesting that the activity of PPAR gamma 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.

    AB - 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/enhancerbinding protein-alpha, was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained, suggesting that the activity of PPAR gamma 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.

    KW - vivo

    KW - in-vitro

    KW - protein

    KW - congenital generalized lipodystrophy

    KW - lipin

    KW - PPAR-gamma

    KW - mutation

    KW - expression

    KW - adipogenesis

    KW - seipin

    U2 - 10.2337/db08-0184

    DO - 10.2337/db08-0184

    M3 - Article

    VL - 57

    SP - 2055

    EP - 2060

    JO - Diabetes

    JF - Diabetes

    SN - 0012-1797

    IS - 8

    ER -