Expression of seipin in adipose tissue rescues lipodystrophy, hepatic steatosis and insulin resistance in seipin null mice

Gao, Mingming; Wang, Mengyu; Guo, Xin; Qiu, Xu; Liu, Lu; Liao, Jiawei; Liu, Jinjiao; Lu, Guotao; Wang, Yuhui; Liu, George

doi:10.1016/j.bbrc.2015.02.147

Cited by 20 publications

(15 citation statements)

References 28 publications

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Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that the adipose tissue plays a major role in the establishment of hepatic steatosis in Bscl2 −/− mice [7,9,15]. Expressing Seipin in adipose tissue alone is sufficient to rescue lipodystrophy, hepatic steatosis and insulin resistance in Bscl2 −/− mice [15]. Chen and collaborators also reported that mice with a specific hepatic deletion of Seipin (Bscl2 Li−/− ) did not show increased lipid deposition in the liver on a standard chow diet [80].…”

Section: Discussionmentioning

confidence: 99%

“…Ectopic storage of lipids in the form of intracellular droplets within hepatocytes induces lipotoxicity, which is associated with severe pathological conditions, including insulin resistance, pancreatic β-cell failure, and non-alcoholic steatohepatitis (NASH), as well as hepatic inflammation [12][13][14]. In the absence of a functional Seipin protein, hepatic steatosis may be a consequence of a cell-intrinsic effect or a cellextrinsic effect such as the disappearance of adipose tissue [15]. Bscl2 deficiency also has an intriguing impact on insulin sensitivity.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic BSCL2 (Seipin) Deficiency Disrupts Lipid Droplet Homeostasis and Increases Lipid Metabolism via SCD1 Activity

Lounis

Lalonde

Rial

et al. 2016

Lipids

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Berardinelli-Seip congenital lipodystrophy (BSCL) is an autosomal recessive disorder. The more severe form, designated BSCL2, arises due to mutations in the BSCL2 gene. Patients with BSCL2, as well as Bscl2 mice, have a near total absence of body fat, an organomegaly, and develop metabolic disorders including insulin resistance and hepatic steatosis. The function of the Seipin (BSCL2) protein remains poorly understood. Several lines of evidence have indicated that Seipin may have distinct functions in adipose versus non-adipose cells. Here we present evidence that BSCL2/Bscl2 plays a role in lipid droplet (LD) biogenesis and homeostasis in primary and cultured hepatocytes. Our results show that decreasing BSCL2/Bscl2 expression in hepatocytes increases the number and size of LD, as well as the expression of genes implicated in their formation and stability. We also show that knocking down SCD1 expression reverses the phenotype associated with Seipin deficiency. Interestingly, BSCL2 knockdown induces SCD1 expression and activity, potentially leading to increased basal phosphorylation of proteins involved in the insulin signaling cascade, as well as further increasing fatty acid uptake and de novo lipogenesis. In conclusion, our results suggest that a hepatic BSCL2/Bscl2 deficiency induces the increase and expansion of LD, potentially via increased SCD1 activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatic BSCL2 (Seipin) Deficiency Disrupts Lipid Droplet Homeostasis and Increases Lipid Metabolism via SCD1 Activity

Lounis

Lalonde

Rial

et al. 2016

Lipids

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“…Nonetheless, lipodystrophy secondary effects have some importance for these results. Some authors observed that the specific seipin deficiency in mouse adipose tissue is mainly responsible for dyslipidemia, lipodystrophy, hepatic steatosis, and insulin resistance [ 94 ]. In such a way, metabolic dysfunction should not be expected in nonadipocyte-specific seipin deficiency.…”

Section: Seipin Loss-of-functionmentioning

confidence: 99%

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Sarmento

Medeiros

Agnez-Lima

et al. 2018

International Journal of Cell Biology

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Seipin is a nonenzymatic protein encoded by the BSCL2 gene. It is involved in lipodystrophy and seipinopathy diseases. Named in 2001, all seipin functions are still far from being understood. Therefore, we reviewed much of the research, trying to find a pattern that could explain commonly observed features of seipin expression disorders. Likewise, this review shows how this protein seems to have tissue-specific functions. In an integrative view, we conclude by proposing a theoretical model to explain how seipin might be involved in the triacylglycerol synthesis pathway.

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“…Bscl2 −/− mice display severe lipodystrophy, with at least a 90% decrease in WAT mass and the development of insulin resistance and hepatic steatosis, thus recapitulating the main features of the human BSCL phenotype 14 15 16 . Adipose-specific Bscl2 −/− mice exhibit progressive lipodystrophy associated with similar metabolic complications 17 , whereas the transgenic overexpression of Bscl2 in WAT from Bscl2 −/− mice is sufficient to rescue the phenotype 18 . Finally, thiazolidinedione (TZD) treatment in global or adipose-specific Bscl2 KO mice promotes an increase in WAT mass, leading to an improvement of the metabolic complications 16 17 .…”

mentioning

confidence: 99%

Seipin deficiency alters brown adipose tissue thermogenesis and insulin sensitivity in a non-cell autonomous mode

Dollet

Magré

Joubert

et al. 2016

Sci Rep

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Loss-of-function mutations in BSCL2 are responsible for Berardinelli-Seip congenital lipodystrophy, a rare disorder characterized by near absence of adipose tissue associated with insulin resistance. Seipin-deficient (Bscl2−/−) mice display an almost total loss of white adipose tissue (WAT) with residual brown adipose tissue (BAT). Previous cellular studies have shown that seipin deficiency alters white adipocyte differentiation. In this study, we aimed to decipher the consequences of seipin deficiency in BAT. Using a brown adipocyte cell-line, we show that seipin knockdown had very little effect on adipocyte differentiation without affecting insulin sensitivity and oxygen consumption. However, when submitted to cold acclimation or chronic β3 agonist treatment, Bscl2−/− mice displayed altered thermogenic capacity, despite several signs of BAT remodeling. Under cold activation, Bscl2−/− mice were able to maintain their body temperature when fed ad libitum, but not under short fasting. At control temperature (i.e. 21 °C), fasting worsened Bscl2−/− BAT properties. Finally, Bscl2−/− BAT displayed obvious signs of insulin resistance. Our results in these lipodystrophic mice strongly suggest that BAT activity relies on WAT as an energetic substrate provider and adipokine-producing organ. Therefore, the WAT/BAT dialogue is a key component of BAT integrity in guaranteeing its response to insulin and cold-activated adrenergic signals.

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Expression of seipin in adipose tissue rescues lipodystrophy, hepatic steatosis and insulin resistance in seipin null mice

Cited by 20 publications

References 28 publications

Hepatic BSCL2 (Seipin) Deficiency Disrupts Lipid Droplet Homeostasis and Increases Lipid Metabolism via SCD1 Activity

Hepatic BSCL2 (Seipin) Deficiency Disrupts Lipid Droplet Homeostasis and Increases Lipid Metabolism via SCD1 Activity

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Seipin deficiency alters brown adipose tissue thermogenesis and insulin sensitivity in a non-cell autonomous mode

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