A subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis

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, Ruth T. Yu, Carey N. Lumeng, Elif A. Oral, Michael Downes, Ronald M. Evans and Alan R. Saltiel ()
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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
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7047

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