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

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