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Insulin is an essential hormone with key roles in energy homeostasis and body composition. Mice and rats, unlike other mammals, have two insulin genes: the rodent-specific  Ins1  gene and the ancestral  Ins2  gene. The relationships between insulin gene dosage and obesity has previously been explored in male and female  Ins2  -/-  mice with full or reduced  Ins1  dosage, as well as in female  Ins1  -/-  mice with full or partial  Ins2  dosage. We report herein unexpected hyper-variability in  Ins1 -null male mice, with respect to their circulating insulin levels and to the physiological effects of modulating  Ins2  gene dosage. Two large cohorts of  Ins1  -/- : Ins2  +/-  mice and their  Ins1  -/- : Ins2  +/+  littermates were fed chow diet or high fat diet (HFD) from weaning, and housed in specific pathogen-free conditions. Cohort A and cohort B were studied one year apart. Contrary to female mice from the same litters, inactivating one  Ins2  allele on the complete  Ins1 -null background did not consistently cause a reduction of circulating insulin in male mice, on either diet. In cohort A, all HFD-fed males showed an equivalent degree of insulin hypersecretion and weight gain, regardless of  Ins2  dosage. In cohort B the effects of HFD appeared generally diminished, and cohort B  Ins1  -/- : Ins2  +/-  males showed decreased insulin levels and body mass compared to  Ins1  -/- : Ins2  +/+  littermates, on both diets. Although experimental conditions were consistent between cohorts, we found that HFD-fed  Ins1  -/- : Ins2  +/-  mice with lower insulin levels had increased corticosterone. Collectively, these observations highlight the phenotypic characteristics that change in association with differences in circulating insulin and  Ins2  gene dosage, particularly in male mice.

plos one

Hyper-Variability in Circulating Insulin, High Fat Feeding Outcomes, and Effects of Reducing Ins2 Dosage in Male Ins1-Null Mice in a Specific Pathogen-Free Facility