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

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* Corresponding author 1 Institut du thorax Nantes 2 Service d-Endocrinologie Caen 3 CRCNA - Centre de Recherche en Cancérologie - Nantes - Angers 4 Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine

Abstract : 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. Berardinelli and Seip congenital lipodystrophy BSCL is a rare autosomal genetic disease characterized by an almost complete lack of white adipose tissue WAT 1,2. BSCL is associated with metabolic disturbances, including insulin resistance, hypertriglyceridaemia, and liver steatosis. The most severe form of BSCL is caused by bi-allelic mutations in BSCL2, which encodes seipin, an endoplasmic reticulum ER protein of unknown function 3. Seipin deficiency strongly impairs adipocyte differentiation in vitro 4,5. In yeast and in cultured human cells, seipin deficiency alters lipid droplet LD morphology, with either a few giant or multiple small LDs 6–9. Recently, seipin was reported to be essential for the initiation of LD formation in yeast 10. In accordance with a potential role in triglyc-eride TG synthesis pathway, seipin was shown to interact with 1-acylglycerol-3-phosphate O-acyltransferase 2 AGPAT2 and lipin 1 11,12. Finally, seipin has been shown to promote TG storage through an interaction with the calcium pump SERCA2 in drosophila 13. Nevertheless, the precise biological role of seipin and the exact pathways in which it is implicated remain unclear. A major breakthrough in the understanding of the pathophysiology of BSCL2 came with the generation of global knockout KO mice for Bscl2. 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 14–16. 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 1

Autor: L. Dollet - J. Magré - M. Joubert - C Le May - A Ayer - L Arnaud - C Pecqueur - V. Blouin - B Cariou - Xavier Prieur -



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