Altered Lipid Metabolism in Residual White Adipose Tissues of Bscl2 Deficient Mice

Weiqin Chen,Gavin E Reid,Todd A Lydic,Cassie J Fhaner,Bethany C Gross,Hongyi Zhou,Siyang Liu,Monika Oberer

doi:10.1371/journal.pone.0082526

Weiqin Chen, Gavin E Reid + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0082526

Copy DOI

Abstract

Mutations in BSCL2 underlie human congenital generalized lipodystrophy type 2 disease. We previously reported that Bscl2 −/− mice develop lipodystrophy of white adipose tissue (WAT) due to unbridled lipolysis. The residual epididymal WAT (EWAT) displays a browning phenotype with much smaller lipid droplets (LD) and higher expression of brown adipose tissue marker proteins. Here we used targeted lipidomics and gene expression profiling to analyze lipid profiles as well as genes involved in lipid metabolism in WAT of wild-type and Bscl2−/− mice. Analysis of total saponified fatty acids revealed that the residual EWAT of Bscl2−/− mice contained a much higher proportion of oleic18:1n9 acid concomitant with a lower proportion of palmitic16:0 acid, as well as increased n3- polyunsaturated fatty acids (PUFA) remodeling. The acyl chains in major species of triacylglyceride (TG) and diacylglyceride (DG) in the residual EWAT of Bscl2−/− mice were also enriched with dietary fatty acids. These changes could be reflected by upregulation of several fatty acid elongases and desaturases. Meanwhile, Bscl2−/− adipocytes from EWAT had increased gene expression in lipid uptake and TG synthesis but not de novo lipogenesis. Both mitochondria and peroxisomal β-oxidation genes were also markedly increased in Bscl2−/− adipocytes, highlighting that these machineries were accelerated to shunt the lipolysis liberated fatty acids through uncoupling to dissipate energy. The residual subcutaneous white adipose tissue (ScWAT) was not browning but displays similar changes in lipid metabolism. Overall, our data emphasize that, other than being essential for adipocyte differentiation, Bscl2 is also important in fatty acid remodeling and energy homeostasis.

Highlights

Adipose tissue plays a key role in whole body energy homeostasis
Our findings reveal a substantial modification of fatty acid compositions and glycerolipid species in residual browning Bscl22/2 epididymal WAT (EWAT)
Our data emphasize that the residual Bscl22/2 adipocytes are actively mobilizing dietary fatty acids through constant lipolysis despite the much reduced adipocyte size and depot, and suggest that the presence of these residual adipocytes may still be able to contribute to whole body energy balance in CGL2 patients

Summary

Introduction

Adipose tissue plays a key role in whole body energy homeostasis. Both obesity (excessive fat) and lipodystrophy (lack of fat) cause dysfunction of adipose tissues which leads to the development of similar metabolic complications including dyslipidemia, diabetes, hypertension and cardiovascular diseases. Congenital generalized lipodystrophy (CGL) is an autosomal recessive disease characterized by a near total absence of body fat from birth or infancy associated with earlier diabetes onset and debilitating metabolic complications [1,2,3]. We and two other groups have independently generated Bscl22/2 mice which display massive loss of white adipose tissues and recapitulate most metabolic disorders of human CGL2 [10,11,12]. Our in vitro data using isolated mouse embryonic fibroblasts (MEFs) or stromal vascular cells (SVCs) further revealed that Bscl is a novel cell autonomous regulator of cyclic AMP (cAMP)/protein kinase A (PKA) mediated lipolysis and essential for terminal fat cell differentiation [12]

Methods

Results

Conclusion