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 lipogenesis1,2. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ3. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein4,5,6. 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 through 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 glycolysis7,8,9, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.

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Figure 1: Vegf inhibition improves hepatic insulin action.
Figure 2: Vegf inhibition induces hepatic vascular regression, liver hypoxia and HIF-2α stabilization to augment hepatic insulin signaling.
Figure 3: Activation of hepatic HIF-2α but not HIF-1α signaling is sufficient to improve liver insulin action.
Figure 4: HIF-2α regulates IRS2 through Srebp1c-dependent and Srebp1c-independent mechanisms.

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We thank R. DePinho, L. Harshman, B. Tam, C. Chartier, D. Suchet and members of the Kuo laboratory for insightful comments and C. Her, J. Kovalski, K. Thabet and D. Nandamundi for technical assistance. We thank G. Fuh (Genentech) for B20.4.1.1 antibody, C. Chartier (Stanford) for the human HIF1A allele lacking the inhibitory ODD (HIF-1αΔODD) and M. Montminy (Salk) for Ad-IRS2. Fellowship support was from the Stanford Medical Scientist Training Program (K.W. and L.M.M.), NIGMS US National Institutes of Health (NIH) GM-07365 training grant (K.W.), Stanford Cardiovascular Institute T32 training grant 1K12HL087746 (S.M.P.), Molecular and Cellular Immunobiology Program training grant 5T32AI07290 (L.M.M.), NIH American Recovery and Reinvestment Act Supplement 1R01HL074267 (L.M.M.), Radiological Society of North America Research Resident grants 1018 and 1111 (C.M.T.), NIH DK084206 (J.P.A.) and Molecular Endocrinology Training Program grant T32DK007563 (K.X.M.). This work was supported by P30 DK026743 (Cell Biology Core Facility, University of California–San Francisco Liver Center) to J.J.M., NIH RO1DK043748, P60 DK020593 and U24DK059637 to O.P.M., NIH CA67166 and the Sydney Frank Foundation to A.J.G. and a Stanford Developmental Cancer Research Award and NIH R01HL074267, R01NS064517 and R01CA158528 to C.J.K.

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K.W., S.M.P., L.M.M., C.M.T., S.J.W., K.A., M.V., C.W.-M.C. and K.X.M. designed and performed experiments, D.K. and J.Y. provided technical assistance, L.C.M., E.L., G.M., F.R., J.J.M. and M.C.S. provided reagents, J.P.A., O.P.M., G.T., A.J.G. and C.J.K. designed experiments, K.W., S.M.P., L.M.M., C.M.T., O.P.M. and C.J.K. wrote the manuscript.

Correspondence to Calvin J Kuo.

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S.W., K.A., L.M. and G.T. are employees of Regeneron Pharmaceuticals, which manufactures aflibercept.

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Wei, K., Piecewicz, S., McGinnis, L. et al. A liver Hif-2α–Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat Med 19, 1331–1337 (2013). https://doi.org/10.1038/nm.3295

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