Heterozygous deletion of Seipin in islet beta cells of male mice has an impact on insulin synthesis and secretion through reduced PPARγ expression

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.

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.

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.