Hypoxia suppresses the activity of the prolyl hydroxylase family of enzymes (PHD1, PHD2, and PHD3), thereby preventing the degradation of hypoxia-inducible factor (HIF)–1α and HIF-2α and enabling the accumulation of these transcription factors. Taniguchi et al. created mice in which either single-PHD isoforms or combinations of PHD isoforms could be acutely and specifically deleted in hepatocytes. Mice lacking Phd3 in the liver (either by itself or in combination with other PHD isoforms) showed increased abundance of HIF-2α, decreased fasting glucose and insulin concentrations, and increased glucose and insulin tolerance. In addition, mice lacking Phd2 and Phd3 or all three isoforms in the liver developed hepatic steatosis, which the authors speculated could be caused by altered expression patterns of genes involved in gluconeogenesis, lipid metabolism, and cellular glucose uptake. Mice lacking Phd3 showed increased abundance of the mRNA and protein for insulin receptor substrate 2 (IRS2), which correlated with increased phosphorylation and activation of the kinase Akt and the Akt target FoxO1 in response to insulin. The promoter for IRS2 contained a binding site for HIF-2α. Acute deletion of Phd3 in mice fed a high-fat diet showed decreased fasting blood glucose and serum insulin and restored glucose tolerance compared with counterparts that retained Phd3. These effects of Phd3 deletion required HIF-2α and IRS2. Thus, PHD3 could be targeted to treat diabetes.
In the accompanying paper, Wei et al. investigated the role of the family of vascular endothelial growth factors (VEGFs), which are encoded by genes targeted by HIF-2α and which bind to VEGF receptors (VEGFRs). Inhibition of VEGF-A in diabetic db/db mice—either by injection with adenoviruses encoding the soluble extracellular ligand-binding domain of mouse VEGFR-1 (Ad-sFlt1) or of VEGFR-2 (Ad-Flk1) or by treatment with aflibercept (a recombinant fusion of human VEGFR-1 and VEGFR-2 that sequesters VEGF-A)—resulted in improved glucose or insulin tolerance (or both). Ad-sFlt1 or aflibercept treatment induced insulin signaling (as indicated by increased phosphorylation of Akt and GSK-3β), increased the abundance of IRS2, and decreased the abundance of two key gluconeogenic enzymes. Ad-sFlt1, Ad-sFlk1, or aflibercept treatment caused regression of hepatic vasculature, induced hypoxia in the liver, or reduced hepatic perfusion. Ad-sFlt1 treatment enhanced the protein abundance of HIF-2α and the expression of various hypoxia-inducible genes, and the ability of Ad-sFlt1 to improve glucose tolerance, increase phosphorylation of Akt and GSK-3β, and increase the abundance of IRS2 required HIF-2α. Mice expressing in a hepatic-specific manner forms of HIF-2α that could not be prolyl hydroxylated (Ad-HIF-2αPN) or that could not be degraded in the presence of oxygen showed improved glucose tolerance and insulin sensitivity, increased IRS2 abundance, increased markers of insulin signaling, and decreased expression of gluconeogenic enzyme-encoding genes. In db/db mice, the ability of Ad-HIF-2αPN expression or Ad-sFlt1 to improve metabolic measures or enhance insulin signaling required IRS2. The transcription factor SREBP-1c represses the transcription of Irs2, and expression of Ad-HIF-2αPN reduced the expression of Srebp-1 in insulin-stimulated hepatocytes and in fed mice. Furthermore, the ability of Ad-HIF-2αPN expression to increase IRS2 abundance in hepatocytes and fed mice was attenuated by expression of an active form of SREBP1c. Thus, VEGF inhibition enhances insulin signaling through a HIF-2α–dependent effect on Irs2 expression, which is partially mediated through repression of Srebp-1.
C. M. Taniguchi, E. C. Finger, A. J. Krieg, C. Wu, A. N. Diep, E. L. LaGory, K. Wei, L. M. McGinnis, J. Yuan, C. J. Kuo, A. J. Giaccia, Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nat. Med. 19, 1325–1330 (2013). [PubMed]
K. Wei, S. M. Piecewicz, L. M. McGinnis, C. M. Taniguchi, S. J. Wiegand, K. Anderson, C. W.-M. Chan, K. X. Mulligan, D. Kuo, J. Yuan, M. Vallon, L. C. Morton, E. Lefai, M. C. Simon, J. J. Maher, G. Mithieux, F. Rajas, J. P. Annes, O. P. McGuinness, G. Thurston, A. J. Giaccia, C. J. Kuo, A liver Hif-2α–Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat. Med. 19, 1331–1337 (2013). [PubMed]