Mice deficient in proglucagon-derived peptides exhibit glucose intolerance on a high-fat diet but are resistant to obesity

Yusuke Takagi, Keita Kinoshita, Nobuaki Ozaki, Yusuke Seino, Yoshiharu Murata, Yoshiharu Oshida, Yoshitaka Hayashi

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Homozygous glucagon-GFP knock-in mice (Gcggfp/gfp) lack proglucagon derived-peptides including glucagon and GLP-1, and are normoglycemic.We have previously shown that Gcggfp/gfp show improved glucose tolerance with enhanced insulin secretion. Here, we studied glucose and energy metabolism in Gcggfp/gfp mice fed a high-fat diet (HFD). Male Gcggfp/ gfp and Gcggfp/+ mice were fed either a normal chow diet (NCD) or an HFD for 15-20 weeks. Regardless of the genotype, mice on an HFD showed glucose intolerance, and Gcggfp/gfp mice on HFD exhibited impaired insulin secretion whereas Gcggfp/+ mice on HFD exhibited increased insulin secretion. A compensatory increase in β-cell mass was observed in Gcggfp/+mice on HFD, but not in Gcggfp/gfp mice on the same diet. Weight gain was significantly lower in Gcggfp/gfp mice than in Gcggfp/+mice. Oxygen consumption was enhanced in Gcggfp/gfp mice compared to Gcggfp/+ mice on an HFD. HFD feeding significantly increased uncoupling protein 1 mRNA expression in brown adipose and inguinal white adipose tissues of Gcggfp/gfp mice, but not of Gcggfp/+mice. Treatment with the glucagon-like peptide-1 receptor agonist liraglutide (200 mg/kg) improved glucose tolerance in Gcggfp/gfp mice and insulin content in Gcggfp/gfp and Gcggfp/+ mice was similar after liraglutide treatment. Our findings demonstrate that Gcggfp/gfp mice develop diabetes upon HFD-feeding in the absence of proglucagon- derived peptides, although they are resistant to diet-induced obesity.

Original languageEnglish
Article numberA1324
JournalPloS one
Volume10
Issue number9
DOIs
Publication statusPublished - 17-09-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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