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FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization

Author

Listed:
  • InSug O-Sullivan

    (Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine)

  • Wenwei Zhang

    (Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine)

  • David H. Wasserman

    (Vanderbilt Medical School)

  • Chong Wee Liew

    (University of Illinois at Chicago College of Medicine)

  • Jonathan Liu

    (Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine)

  • Jihye Paik

    (Dana Farber Cancer Institute)

  • Ronald A. DePinho

    (Dana Farber Cancer Institute)

  • Donna Beer Stolz

    (Center for Biologic Imaging, University of Pittsburgh)

  • C. Ronald Kahn

    (Joslin Diabetes Center, Harvard Medical School)

  • Michael W. Schwartz

    (Diabetes and Obesity Center of Excellence, University of Washington)

  • Terry G. Unterman

    (Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine
    Medical Service, Jesse Brown VA Medical Center, 820 South Damen Avenue, Chicago, Illinois 60612, USA, USA)

Abstract

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. 13C-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.

Suggested Citation

  • InSug O-Sullivan & Wenwei Zhang & David H. Wasserman & Chong Wee Liew & Jonathan Liu & Jihye Paik & Ronald A. DePinho & Donna Beer Stolz & C. Ronald Kahn & Michael W. Schwartz & Terry G. Unterman, 2015. "FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8079
    DOI: 10.1038/ncomms8079
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    Cited by:

    1. Randall H. Friedline & Hye Lim Noh & Sujin Suk & Mahaa Albusharif & Sezin Dagdeviren & Suchaorn Saengnipanthkul & Bukyung Kim & Allison M. Kim & Lauren H. Kim & Lauren A. Tauer & Natalie M. Baez Torre, 2024. "IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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