title: Mice Deficient in Proglucagon-Derived Peptides Exhibit Glucose Intolerance on a High-Fat Diet but Are Resistant to Obesity.
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.
authors.affiliation: 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.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takagi
authors.affiliation: 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.
authors.forename: Keita
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Metabolic Medicine, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Seino
authors.affiliation: Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Oshida
authors.affiliation: Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000379:methods; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test / Q000379:methods; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D052336:Proglucagon / Q000378:metabolism*; D015430:Weight Gain / Q000502:physiology
chemical_list: D007328:Insulin; D010455:Peptides; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D005947:Glucose