AIMS/HYPOTHESIS Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function mutations in the Seipin gene (also known as Bscl2). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of Seipin on islet beta cell function. METHODS We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor γ (PPARγ), levels of Pdx-1, Nkx6.1, Glut2 (also known as Slc2a2) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female Seipin-knockout homozygous (Seipin-/-) and heterozygous (Seipin+/-) mice. RESULTS Male and female Seipin-/- mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female Seipin+/- mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPARγ was reduced in male Seipin-/- and Seipin+/- mice but not in female Seipin-/- or Seipin+/- mice. Treatment of male Seipin+/- mice with rosiglitazone corrected the glucose intolerance. Male Seipin+/- mice displayed a decrease in islet insulin concentration and GSIS with low expression of Pdx-1, Nkx6.1, Glut2 and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male Seipin-/- mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female Seipin+/- mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPARγ level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone. CONCLUSIONS/INTERPRETATION Heterozygous deletion of Seipin in islet beta cells impacts on insulin synthesis and secretion through reduced PPARγ expression. This leads to glucose intolerance and is relieved by oestradiol, which rescues PPARγ expression.

中文翻译：

---

雄性小鼠胰岛β细胞中Seipin的杂合缺失会通过降低PPARγ表达来影响胰岛素的合成和分泌。

目的/假说Berardinelli-Seip型先天性脂肪营养不良2型（BSCL2）是一种常染色体隐性遗传疾病，其特征在于脂肪营养不良和胰岛素抵抗。BSCL2由Seipin基因（也称为Bscl2）中的功能丧失突变引起。小鼠中该基因的缺失引起胰岛素抵抗，葡萄糖耐受不良和脂肪组织损失。这项研究评估了Seipin基因缺失对胰岛β细胞功能的影响。方法我们检查了胰岛细胞中seipin的表达并测量了葡萄糖谱，胰岛素合成，葡萄糖刺激的胰岛素分泌（GSIS），过氧化物酶体增殖物激活受体γ（PPARγ）的胰岛表达，Pdx-1，Nkx6.1，Glut2（也称为Slc2a2）和胰岛素原mRNA，胰十二指肠同源盒1（PDX-1）的核转运，胰岛编号，和雌性Seipin基因敲除纯合子（Seipin-/-）和杂合子（Seipin +/-）小鼠的β细胞质量和增殖。结果雄性和雌性Seipin-/-小鼠表现出葡萄糖耐量低，胰岛素抵抗，高胰岛素血症和脂肪组织缺乏。相比之下，雄性而非雌性Seipin +/-小鼠表现出葡萄糖耐受不良，而没有脂肪组织损失或胰岛素抵抗。脂蛋白在野生型小鼠的胰岛β细胞中高表达。胰岛PPARγ的表达在雄性Seipin-/-和Seipin +/-小鼠中降低，但在雌性Seipin-/-或Seipin +/-小鼠中未降低。用罗格列酮治疗雄性Seipin +/-小鼠可纠正葡萄糖耐受不良。雄性Seipin +/-小鼠的胰岛胰岛素浓度和GSIS降低，Pdx-1，Nkx6.1，Glut2和胰岛素原的表达低，而PDX-1核易位降低。这些变化通过罗格列酮给药得以挽救。雄性Seipin //-小鼠显示出明显但对罗格列酮敏感的胰岛胰岛素浓度，胰岛数量和β细胞量及增殖增加，但GSIS明显下降。去卵巢的雌性Seipin +/-小鼠表现出葡萄糖耐量低下，胰岛素合成和分泌不足，胰岛PPARγ水平下降。通过服用雌二醇或罗格列酮可逆转这些有害作用。结论/解释胰岛β细胞中Seipin的杂合缺失通过降低PPARγ表达影响胰岛素合成和分泌。这导致葡萄糖不耐症，并被雌二醇缓解，后者可以拯救PPARγ表达。但对罗格列酮敏感的人会增加胰岛胰岛素浓度，胰岛数量和β细胞的数量以及增殖，而GSIS则明显下降。去卵巢的雌性Seipin +/-小鼠表现出葡萄糖耐量低下，胰岛素合成和分泌不足，胰岛PPARγ水平下降。通过服用雌二醇或罗格列酮可逆转这些有害作用。结论/解释胰岛β细胞中Seipin的杂合缺失通过降低PPARγ表达影响胰岛素合成和分泌。这导致葡萄糖不耐症，并被雌二醇缓解，后者可以拯救PPARγ表达。但对罗格列酮敏感的人会增加胰岛胰岛素浓度，胰岛数量和β细胞的数量以及增殖，而GSIS则明显下降。去卵巢的雌性Seipin +/-小鼠表现出葡萄糖耐受不良，胰岛素合成和分泌不足，胰岛PPARγ水平下降；通过服用雌二醇或罗格列酮可逆转这些有害作用。结论/解释胰岛β细胞中Seipin的杂合缺失通过降低PPARγ表达影响胰岛素合成和分泌。这导致葡萄糖不耐症，并被雌二醇缓解，后者可以拯救PPARγ表达。去卵巢的雌性Seipin +/-小鼠表现出葡萄糖耐受不良，胰岛素合成和分泌不足，胰岛PPARγ水平下降；通过服用雌二醇或罗格列酮可逆转这些有害作用。结论/解释胰岛β细胞中Seipin的杂合缺失通过降低PPARγ表达影响胰岛素合成和分泌。这导致葡萄糖不耐症，并被雌二醇缓解，后者可以拯救PPARγ表达。去卵巢的雌性Seipin +/-小鼠表现出葡萄糖耐受不良，胰岛素合成和分泌不足，胰岛PPARγ水平下降；通过服用雌二醇或罗格列酮可逆转这些有害作用。结论/解释胰岛β细胞中Seipin的杂合缺失通过降低PPARγ的表达影响胰岛素的合成和分泌。这导致葡萄糖不耐症，并被雌二醇缓解，后者可以拯救PPARγ表达。