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A subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis

Author

Listed:
  • Shannon M. Reilly

    (Life Sciences Institute, University of Michigan)

  • Maryam Ahmadian

    (Gene Expression Laboratory, Salk Institute for Biological Sciences)

  • Brian F. Zamarron

    (Program in Immunology, University of Michigan)

  • Louise Chang

    (Life Sciences Institute, University of Michigan)

  • Maeran Uhm

    (Life Sciences Institute, University of Michigan)

  • BreAnne Poirier

    (Life Sciences Institute, University of Michigan)

  • Xiaoling Peng

    (Life Sciences Institute, University of Michigan)

  • Danielle M. Krause

    (Life Sciences Institute, University of Michigan)

  • Evgenia Korytnaya

    (Metabolism, University of Michigan)

  • Adam Neidert

    (Metabolism, University of Michigan)

  • Christopher Liddle

    (Gene Expression Laboratory, Salk Institute for Biological Sciences
    Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital)

  • Ruth T. Yu

    (Gene Expression Laboratory, Salk Institute for Biological Sciences)

  • Carey N. Lumeng

    (University of Michigan)

  • Elif A. Oral

    (Metabolism, University of Michigan)

  • Michael Downes

    (Gene Expression Laboratory, Salk Institute for Biological Sciences)

  • Ronald M. Evans

    (Gene Expression Laboratory, Salk Institute for Biological Sciences)

  • Alan R. Saltiel

    (Life Sciences Institute, University of Michigan)

Abstract

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue–liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.

Suggested Citation

  • Shannon M. Reilly & Maryam Ahmadian & Brian F. Zamarron & Louise Chang & Maeran Uhm & BreAnne Poirier & Xiaoling Peng & Danielle M. Krause & Evgenia Korytnaya & Adam Neidert & Christopher Liddle & Rut, 2015. "A subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7047
    DOI: 10.1038/ncomms7047
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