Partial Deletion of Perk Improved High-Fat Diet-Induced Glucose Intolerance in Mice

Abstract

Although pancreatic endoplasmic reticulum kinase (PERK) is indispensable to beta cells, low-dose PERK inhibitor improved glucose- stimulated insulin secretion (GSIS) and hyperglycemia in diabetic mice. Current study examined if partial deletion of <i>Perk</i> (<i>Perk</i>^+/-) recapitulated the effects of PERK inhibitor, on the contrary to the complete deletion. <i>Perk</i>^+/- mice and wild-type controls were fed with a high-fat diet (HFD) for 23 weeks. Glucose tolerance was evaluated along with serum insulin levels and islet morphology. <i>Perk</i>^+/- mice on normal chow were comparable to wild-type mice in various metabolic features. HFD-induced obesity was not influenced by <i>Perk</i> reduction; however, HFD-induced glucose intolerance was significantly improved since 15-week HFD. HFD-induced compromises in GSIS were relieved by <i>Perk</i> reduction, accompanied by reductions in phosphorylated PERK and activating transcription factor 4 (ATF4) in the islets. Meanwhile, HFD-induced islet expansion was not significantly affected. In summary, partial deletion of <i>Perk</i> improved glucose tolerance and GSIS impaired by diet-induced obesity, without changes in body weights or islet mass.