Inserm UMR_S1087, L'Institut du Thorax, IRS-UN, Nantes Cedex 1, France.
Diabetologia. 2013 Aug;56(8):1813-25. doi: 10.1007/s00125-013-2926-9. Epub 2013 May 17.
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.
Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation.
As observed in humans, Bscl2 (-/-) mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 (-/-) mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 (-/-) MEFs. In vivo treatment of Bscl2 (-/-) mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice.
CONCLUSIONS/INTERPRETATION: Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 (-/-) mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.
目的/假设：BSCL2/ seipin 基因突变导致伯-塞二氏先天性脂肪营养不良症（BSCL），这是一种罕见的隐性疾病，其特征为几乎没有脂肪组织和严重的胰岛素抵抗。我们旨在确定 seipin 缺乏如何改变葡萄糖和脂质稳态，以及噻唑烷二酮类药物是否可以挽救表型。
生成并表型分析 Bscl2（-/-）小鼠。使用小鼠胚胎成纤维细胞（MEFs）作为脂肪细胞分化的模型。
与人类观察到的情况一样，Bscl2（-/-）小鼠表现出早期脂肪组织耗竭，伴有胰岛素抵抗和严重的肝脂肪变性。然而，Bscl2（-/-）小鼠由于富含三酰甘油的脂蛋白（TRL）的清除增加和肝脏对脂肪酸的摄取，出现意外的低甘油三酯血症，基础能量消耗减少。MEFs 的体外实验表明，seipin 缺乏导致晚期脂肪细胞分化受损和基础脂肪分解增加。噻唑烷二酮类药物能够挽救脂肪生成受损，但不能改变 Bscl2（-/-）MEFs 中的脂肪分解。在 Bscl2（-/-）小鼠中用吡格列酮治疗 9 周可增加残余腹股沟和肠系膜脂肪垫以及血浆瘦素和脂联素浓度。吡格列酮治疗可增加这些小鼠的能量消耗，并改善胰岛素抵抗、低甘油三酯血症和肝脂肪变性。
结论/解释：seipin 在脂肪细胞的分化和储存能力中发挥关键作用，并影响葡萄糖和脂质稳态。在 Bscl2（-/-）小鼠中观察到的低甘油三酯血症与肝脏对 TRL 的摄取增加有关，为肝脂肪变性提供了一种新的模型。噻唑烷二酮类药物治疗可部分挽救与 BSCL 相关的代谢并发症，为 BSCL 患者提供了一个有趣的治疗前景。
