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PLoS One. 2015 Sep 17;10(9):e0138322. doi: 10.1371/journal.pone.0138322. eCollection 2015.

Mice Deficient in Proglucagon-Derived Peptides Exhibit Glucose Intolerance on a High-Fat Diet but Are Resistant to Obesity.

Author information

1
Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan; Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
2
Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan.
3
Department of Metabolic Medicine, Nagoya University School of Medicine, Nagoya, Japan.
4
Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

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.

PMID:
26378455
PMCID:
PMC4574859
DOI:
10.1371/journal.pone.0138322
[Indexed for MEDLINE]
Free PMC Article

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