Introduction: Hypoxia inducible factors (HIFs) play a critical role in the response to hypoxia and in obesity and diabetes. However, the literature shows that increasing HIF1α can cause favourable outcomes and can cause exacerbation of diabetes. We created a novel mouse model with a mutation of HIF1α asparagine 813 to glutamine. We hypothesise that mice with this mutation (HIF1α-N813Q) will be protects from adverse consequences of high fat diet (HFD).
Methods: Male HIF1α-N813Q mutants (n=5) and wild-type (WT) littermates (n=8) were studied from 14 weeks of age. Mice underwent glucose tolerance test (GTT), insulin tolerance test (ITT), glucose-stimulated insulin secretion (GSIS) and metabolic cage studies (Promethion). They were then challenged with HFD (45% of calories from lipids) before repeat metabolic assessments.
Results: Baseline glucose tolerance tests were not significantly different. N813Q mice gained less weight over the study (final weight 28.2g in WT versus 26.8g in N813Q, p<0.001 by mixed model test).
Male HIF1α-N813Q mice tended to a smaller deterioration in GTT after HFD compared to their WT littermates (124mmol/L/120min versus 362mmol/L/120min) following 4 weeks of HFD. Interestingly, given their lower weight, N813Q mice tended to eat more and to do less voluntary wheel running.
Conclusions: This initial data suggests that the asparagine to glutamine mutation confers protective effects in mice challenged with an HFD.