While the mechanism of HIF-2α upregulation by obesity and gastrectomy is not clear, the induction of HIF-1α and HIF-2α by gut-specific von Hippel-Lindau deletion improves glucose tolerance [235], whereas HIF-2α is dispensable for the metabolic improvement by gastrectomy [235]. The gene discussed is EPAS1; the disease is obesity due to melanocortin 4 receptor deficiency.