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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat / methods
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism
  • Glucose Intolerance / metabolism*
  • Glucose Tolerance Test / methods
  • Insulin / metabolism
  • Insulin Resistance / physiology*
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism*
  • Peptides / metabolism*
  • Proglucagon / metabolism*
  • Weight Gain / physiology


  • Insulin
  • Peptides
  • Proglucagon
  • Glucagon-Like Peptide 1
  • Glucose

Grant support

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (22590974 to NO and 24659451 to YH), and by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (23122507 and 25122708 to YH).