EPAS1 and obesity due to melanocortin 4 receptor deficiency: In obesity, metabolic stress induces β-cell HIF-2α, which upregulates antioxidant genes such as Sod2 and Cat, limits mitochondrial ROS, and preserves both mitochondrial mass and glucose-stimulated insulin secretion; conversely, β-cell-specific HIF-2α deletion worsens mitochondrial damage and glucose intolerance under a high-fat diet [42].