Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells

Abstract

To examine the role of group VIA phospholipase A₂ (iPLA₂β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA₂β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA₂β-KO), or in insulin-secreting β-cells (β-Cell-iPLA₂β-KO), respectively. MØ-iPLA₂β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA₂β control mice after consuming a high-fat diet (HFD). MØ-iPLA₂β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA₂β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA₂β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA₂β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA₂β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA₂β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA₂β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD.