Background: The hypothalamus plays a role in regulating beta-cell function and glucose tolerance. Increased body iron status has been linked to increased risk for development of obesity, metabolic syndrome and diabetes. Hypoxia Inducible Factor 1α (HIF-1α) is a transcription factor known to be stabilised by iron depletion. We examined the role of hypothalamic HIF-1α and of iron chelation upon glucose tolerance in mice.
Methods/Results: Mice were fed a high-fat diet (HFD) ± oral iron chelator deferasirox (DFS). The arcuate nucleus in the hypothalamus integrates central and peripheral cues to regulate weight, food intake and energy expenditure. To investigate whether the effects of DFS were centrally mediated, hypothalamic arcuate nucleus specific HIF-1α-null mice were created by direct stereotaxic injection of adenoviral Cre recombinase, or adeno-GFP in controls. As expected, mice on HFD had poor glucose tolerance. However, mice lacking arcuate nucleus HIF-1α on HFD had significantly worse glucose tolerance than HFD GFP-controls (see Figure). DFS increased GLUT2 mRNA expression in the hypothalamus, and increased post-prandial hypothalamic ATP generation, consistent with improved nutrient sensing. Impaired neuronal glucose sensing has been linked to abnormal glucose tolerance. Interestingly, systemic DFS was able to prevent glucose tolerance deterioration in hypothalamic-HIF-1α mice. DFS does not improve glucose tolerance in mice lacking β-cell HIF-1α, suggesting that it is β-cell HIF-1α activity that mediates the overall improvement in the hypothalamic-HIF-1α mice. β-cell mass was increased in HFD-fed mice lacking hypothalamic HIF-1α, presumably in a failed attempt to correct glucose intolerance.
Discussion: Hypothalamic HIF-1α is important for nutrient sensing and glucose tolerance, and impaired hypothalamic HIF-1α may contribute to impaired glucose tolerance and diabetes.