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A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

  • Author(s): Reilly, Shannon M;
  • Ahmadian, Maryam;
  • Zamarron, Brian F;
  • Chang, Louise;
  • Uhm, Maeran;
  • Poirier, BreAnne;
  • Peng, Xiaoling;
  • Krause, Danielle M;
  • Korytnaya, Evgenia;
  • Neidert, Adam;
  • Liddle, Christopher;
  • Yu, Ruth T;
  • Lumeng, Carey N;
  • Oral, Elif A;
  • Downes, Michael;
  • Evans, Ronald M;
  • Saltiel, Alan R
  • et al.
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.

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