Endocrinol Metab.  2023 Dec;38(6):782-787. 10.3803/EnM.2023.1738.

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

• Lee J
• Kim MJ
• Moon S
• Lim JY
• Park KS
• Jung HS

• KMID: 2549271
• DOI: http://doi.org/10.3803/EnM.2023.1738

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 Perk (Perk^+/-) recapitulated the effects of PERK inhibitor, on the contrary to the complete deletion. Perk^+/- 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. Perk^+/- mice on normal chow were comparable to wild-type mice in various metabolic features. HFD-induced obesity was not influenced by Perk reduction; however, HFD-induced glucose intolerance was significantly improved since 15-week HFD. HFD-induced compromises in GSIS were relieved by Perk 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 Perk improved glucose tolerance and GSIS impaired by diet-induced obesity, without changes in body weights or islet mass.

Keyword

PERK; High-fat diet; Glucose intolerance; Insulin secretion

Figure

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  Fig. 1. Metabolic phenotypes and islet morphology of pancreatic endoplasmic reticulum kinase (Perk)+/- mice. Adult male Perk+/- mice and male wild-type littermates were compared after confirmation of the genotypes and Perk expression. Intraperitoneal glucose tolerance test (1 g/kg weight) and insulin tolerance test (regular insulin 0.5 U/kg weight) were performed after overnight fasting at 20 weeks old. (A) Pictures of reverse transcription-polymerase chain reaction (left) and Western blotting (right) using isolated islets. (B) Body weights. (C) Fed blood glucose levels. (D) Glucose tolerance test. (E) Insulin tolerance test. (F) Serum insulin levels before and after glucose loading. (G) Pancreas weights. (H) Representative pancreatic sections of hematoxylin and eosin staining. For (B-E), two-way repeated-measures analysis of variance was used. Paired t test for (F) and Student’s t test for (G) were applied. No statistical differences were found. Animal numbers=10 to 16 for each genotype. Gapdh, glyceraldehyde-3-phosphate dehydrogenase.

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  Fig. 2. Changes in the metabolic phenotypes and islet morphology by high-fat diet (HFD) in pancreatic endoplasmic reticulum kinase (Perk)+/- mice. Mice of either genotype were given a HFD at age 5 weeks for 23 weeks, and compared to wild-type (WT) mice on chow-diet. Body weights (A) and random blood glucose levels (B) were monitored. After 5 and 15 weeks of HFD, intraperitoneal glucose tolerance tests were performed (1 g/kg weight) (C, D). Serum insulin levels were measured before and 15 minutes after the glucose loading after 15-week HFD (E), and were subject to assess insulin secretion by adjustment with glucose levels (F). Insulin resistance was estimated by multiplying fasting insulin and glucose levels (G). Representative pictures of immunohistochemical stains in the pancreas (islets marked by broken lines) extracted after 23-week HFD or normal chow (H), pooled analysis for average islet sizes (I), islet numbers on each section adjusted by the pancreas area (J), islet size distribution after pooling the islets in each group (K), and relative islet area adjusted by the pancreas area (L). For (A-D), two-way repeated-measures analysis of variance (ANOVA) and Bonferroni posttests were performed. For the others, one-way ANOVA and Bonferroni posttests were applied, except for (K) where qui-square test was applied. Animal numbers, 7 to 17 for each group; pancreas area, 37.7±2.5 mm2/section; islet numbers, median 35/section from a mouse. IPGTT, intraperitoneal glucose tolerance test; NS, no significant difference; LN, logarithmus naturalis; P-PERK, phosphorylated PERK; c-CAS3, cleaved caspase-3; ATF4, activating transcription factor 4. aP<0.05; bP<0.01; cP<0.001 between the indications.

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