A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition

Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis(1,2). The liver possesses a rich sinusoidal capillary network with increased hypoxia and decreased gluconeogenesis in the perivenous zone(3). Here, diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in normal or diabetic db/db mice, potentiating hepatic insulin signaling, decreasing gluconeogenic gene expression, increasing glycogen storage and suppressing hepatic glucose production (HGP). VEGF inhibition induced hepatic hypoxia via sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia inducible factor-2α (HIF-2α) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling via direct and indirect induction of insulin receptor substrate 2 (IRS2), an essential insulin receptor adaptor protein(4–6). Further, liver IRS2 was both necessary and sufficient to mediate HIF-2α and VEGF inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between HIF-2α–mediated hypoxic signaling and hepatic insulin action via IRS2 induction, which can be co-opted by VEGF inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for HIF-1α, which promotes glycolysis(7–9), versus HIF-2α, which suppresses gluconeogenesis, and suggest novel treatment approaches for type 2 diabetes mellitus.