O-Sullivan InSug, Zhang Wenwei, Wasserman David H, Liew Chong Wee, Liu Jonathan, Paik Jihye, DePinho Ronald A, Stolz Donna Beer, Kahn C Ronald, Schwartz Michael W, Unterman Terry G
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt Medical School, Nashville, Tennesse 37232, USA.
Nat Commun. 2015 May 12;6:7079. doi: 10.1038/ncomms8079.
FoxO proteins are major targets of insulin action. To better define the role of FoxO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FoxO1 reverses these effects. (13)C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is disrupted.
FoxO蛋白是胰岛素作用的主要靶点。为了更好地界定FoxO1在介导肝脏胰岛素效应中的作用，我们构建了肝脏特异性胰岛素受体敲除（LIRKO）小鼠和IR/FoxO1双敲除（LIRFKO）小鼠。在此我们表明，基于血糖、胰岛素和C肽水平以及葡萄糖和胰岛素耐量试验，LIRKO小鼠存在严重的胰岛素抵抗，而肝脏中FoxO1的基因缺失可逆转这些效应。¹³C-葡萄糖和胰岛素钳夹研究表明，LIRKO小鼠的肝脏葡萄糖生成（HGP）和葡萄糖利用的调节均受损，并且在LIRFKO小鼠中这些缺陷也随着基因表达的变化而恢复。我们得出结论：（1）抑制FoxO1对于胰岛素对HGP和利用的直接（肝脏）和间接效应均至关重要；（2）当肝脏FoxO1活性被破坏时，胰岛素的肝外效应足以维持正常的全身和肝脏葡萄糖代谢。
