Seipin ablation in mice results in severe generalized lipodystrophy

Cui, Xin; Wang, Yuhui; Tang, Yin; Liu, Yixiao; Zhao, Liping; Deng, Jingna; Gao, Xu; Peng, Xin‐Gui; Ju, Shenghong; Liu, George; Yang, Hongyuan

doi:10.1093/hmg/ddr205

Cited by 156 publications

(174 citation statements)

References 28 publications

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“…We and others have established an essential role of SEIPIN in adipogenesis both in vitro and in vivo (6)(7)(8)16,17). However, SEIPIN is highly expressed in mature adipocytes, where its function is completely unknown.…”

Section: Discussionmentioning

confidence: 97%

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Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

et al. 2014

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Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy, characterized by an almost complete loss of adipose tissue and severe insulin resistance. BSCL2 is caused by loss-of-function mutations in the BSCL2/SEIPIN gene, which is upregulated during adipogenesis and abundantly expressed in the adipose tissue. The physiological function of SEIPIN in mature adipocytes, however, remains to be elucidated. Here, we generated adipose-specific Seipin knockout (ASKO) mice, which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of white and brown adipose tissue, insulin resistance, and hepatic steatosis. Lipidomic and microarray analyses revealed accumulation/imbalance of lipid species, including ceramides, in ASKO adipose tissue as well as increased endoplasmic reticulum stress. Interestingly, the ASKO mice almost completely phenocopy the fat-specific peroxisome proliferator–activated receptor-γ (Pparγ) knockout (FKO-γ) mice. Rosiglitazone treatment significantly improved a number of metabolic parameters of the ASKO mice, including insulin sensitivity. Our results therefore demonstrate a critical role of SEIPIN in maintaining lipid homeostasis and function of adipocytes and reveal an intimate relationship between SEIPIN and PPAR-γ.

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Section: Discussionmentioning

confidence: 97%

“…Homozygous Seipin fl/fl mice were obtained as described (6). Adipose-specific deletion of Seipin exon 3 was induced by crossing Seipin fl/fl mice to transgenic mice expressing Cre recombinase driven by an aP2 promoter (18).…”

Section: Animalsmentioning

confidence: 99%

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

et al. 2014

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“…In contrast, the same group recently reported that pioglitazone was unable to fully restore the adipogenic programme in seipindeficient (Bscl2 −/− ) mouse embryonic fibroblast (MEF)-derived adipocytes [15]. A major breakthrough in the field of seipin came recently, with the demonstration by two independent groups that Bscl2 −/− mice develop severe lipodystrophy, validating the hypothesis that seipin has a critical role in adipocyte differentiation in vivo [15,16]. In these two models, Bscl2…”

Section: Introductionmentioning

confidence: 99%

“…In one study, Bscl2 −/− mice displayed normal plasma glucose concentrations in the random-fed state [16], while in the second, they were frankly hyperglycaemic [15]. In addition, lipid metabolism in these two models raises several questions.…”

Section: Introductionmentioning

confidence: 99%

“…Second, while these mice exhibit liver steatosis [15,16], the hepatic lipid metabolism has not been explored with in vivo functional studies and therefore remains poorly understood. The aim of the present study was to unravel how seipin deficiency leads to the metabolic complications associated with BSCL, with a special focus on liver steatosis and dyslipidaemia.…”

Section: Introductionmentioning

confidence: 99%

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Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Prieur¹,

Dollet²,

Takahashi³

et al. 2013

Diabetologia

135

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Aims/hypothesis Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Methods Bscl2−/− mice were generated and phenotyped. X. Prieur, L. Dollet and M. Takahashi contributed equally to this study.Electronic supplementary material The online version of this article

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BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism

Zhou

et al. 2022

Clinical & Translational Med

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Background Heart failure (HF) is one of the leading causes of death worldwide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli‐Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2 −/− mice exhibit hypertrophic cardiomyopathy with reduced cardiac steatosis. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Methods We generated mice with cardiomyocyte‐specific deletion of Bscl2 ( Bscl2 cKO ) and studied their cardiac substrate utilisation, bioenergetics, lipidomics and contractile function under baseline or after either a treatment regimen using fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ) or a prevention regimen with high‐fat diet (HFD) feeding. Mice with partial ATGL deletion and cardiac‐specific deletion of Bscl2 were also generated followed by cardiac phenotyping. Results Different from hypertrophic cardiomyopathy in Bscl2 −/− mice, mice with cardiac‐specific deletion of Bscl2 developed systolic dysfunction with dilation. Myocardial BSCL2 deletion led to elevated ATGL expression and FAO along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2 cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, cardiac dysfunction in Bscl2 cKO mice could be partially reversed by FAO inhibitor TMZ, or prevented by genetic abolishment of one ATGL allele or HFD feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2 cKO hearts, which were partially normalised by TMZ or HFD. Conclusions We identified a new form of cardiac dysfunction with excessive lipid utilisation which ultimately causes cardiac substrate depletion and bioenergetics failure. Our findings also uncover a crucial role of BSCL2 in controlling cardiac lipid catabolism and contractile function and provide novel insights into metabolically treating energy‐starved HF using FAO inhibitor or HFD.

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Seipin ablation in mice results in severe generalized lipodystrophy

Cited by 156 publications

References 28 publications

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism

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