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

Abstract

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. Jianwei Xiong and Peng Sun contributed equally to this work.

Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes

“…Our findings also raise questions on the role of seipin in MAMs in non-adipocyte cells, especially in tissues where seipin is suspected to play a cell autonomous function. For instance, it would be interesting to study seipin function in MAM and calcium exchange in pancreatic b cells, where calcium handling plays a central role and heterozygous seipin deletion (Xiong et al, 2020) is sufficient to impair glucose-stimulated insulin secretion. Finally, this study leaves open whether the seipin-regulated mitochondrial calcium import described here is functionally connected to the known role of seipin in LD formation.…”

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

“…Intriguingly, whereas Bscl2 −/+ heterozygous mice are not lipodystrophic nor insulin resistant, one study revealed a decrease in insulin secretion in isolated islet ß-cells and in vivo in these animals [ 82 ]. Of note, neither lipotoxic nor glucotoxic hallmarks were reported in SKO mice islets ( Figure 2 ).…”

Not Enough Fat: Mouse Models of Inherited Lipodystrophy

“…Since AT transplantation and leptin replacement improve the renal function, the kidney phenotype is likely a consequence of the lipodystrophy and not a cell autonomous function of seipin. A recent study reported a pancreatic phenotype characterized by a beta-cell hypertrophy and an alteration of the insulin secretion profile in response to a glucose bolus (37). Intriguingly, this study showed that the heterozygous deletion of seipin is sufficient to lead to beta-cell dysfunction whereas it does not alter the AT mass, suggesting a cell autonomous action of seipin in beta-cells.…”