HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity

In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and beta-cell dysfunction. In particular, beta-cells express antioxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, beta-cells exhibit increased glucose-stimulated insulin secretion in order to compensate for insulin resistance. This increase in beta-cell function under the condition of enhanced metabolic stress suggests that beta-cells possess a defense mechanism against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces beta-cell hypoxia inducible factor 2 alpha (HIF-2 alpha), which stimulates antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and subsequent mitochondrial damage. Knockdown of HIF-2 alpha in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and beta-cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible beta-cell HIF-2 alpha knockout mice developed more severe beta-cell dysfunction and glucose intolerance on a high-fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism through which beta-cells defend against increased metabolic stress to promote beta-cell compensation in obesity.