Abstract
Mutations in BSCL2/SEIPIN cause Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), but the mechanisms whereby Bscl2 regulates adipose tissue function are unclear. Here, we generated adipose tissue (mature) Bscl2 knockout (Ad-mKO) mice, in which Bscl2 was specifically ablated in adipocytes of adult animals, to investigate the impact of acquired Bscl2 deletion on adipose tissue function and energy balance. Ad-mKO mice displayed reduced adiposity and were protected against high fat diet-induced obesity, but not insulin resistance or hepatic steatosis. Gene expression profiling and biochemical assays revealed increased lipolysis and fatty acid oxidation in white adipose tissue (WAT) and brown adipose tissue , as well as browning of WAT, owing to induction of cAMP/protein kinase A signaling upon Bscl2 deletion. Interestingly, Bscl2 deletion reduced food intake and downregulated adipose β3-adrenergic receptor (ADRB3) expression. Impaired ADRB3 signaling partially offsets upregulated browning-induced energy expenditure and thermogenesis in Ad-mKO mice housed at ambient temperature. However, this counter-regulatory response was abrogated under thermoneutral conditions, resulting in even greater body mass loss in Ad-mKO mice. These findings suggest that Bscl2 regulates adipocyte lipolysis and β-adrenergic signaling to produce complex effects on adipose tissues and whole-body energy balance.
Highlights
Mutations in BSCL2/SEIPIN cause BerardinelliSeip congenital lipodystrophy type 2 (BSCL2), but the mechanisms whereby Bscl2 regulates adipose tissue function are unclear
Histological analysis demonstrated an unusual pattern of adipocyte size changes in epididymal white adipose tissue (WAT) (eWAT) of AdmKO mice evidenced by increased proportions of both smaller and larger adipocytes (Fig. 1H, I), which was confirmed by immunofluorescent staining of PLIN1 (Fig. 1I)
Utilizing a novel mouse model in which Bscl2 is inducibly deleted in adipocytes of adult animals, we have characterized the impact of acquired deficiency of Bscl2 in mature adipose tissues
Summary
Mutations in BSCL2/SEIPIN cause BerardinelliSeip congenital lipodystrophy type 2 (BSCL2), but the mechanisms whereby Bscl regulates adipose tissue function are unclear. We generated adipose tissue (mature) Bscl knockout (Ad-mKO) mice, in which Bscl was ablated in adipocytes of adult animals, to investigate the impact of acquired Bscl deletion on adipose tissue function and energy balance. Impaired ADRB3 signaling partially offsets upregulated browning-induced energy expenditure and thermogenesis in Ad-mKO mice housed at ambient temperature. This counterregulatory response was abrogated under thermoneutral conditions, resulting in even greater body mass loss in AdmKO mice. These findings suggest that Bscl regulates adipocyte lipolysis and -adrenergic signaling to produce complex effects on adipose tissues and whole-body energy balance.—Zhou, H., X. Whether these or other pathways are directly responsible for the failure of adipogenesis in mammalian Bscl2-deficient cells remains to be determined
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