A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis

Nat Commun. 2015 Jan 12;6:6047. doi: 10.1038/ncomms7047.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adult
  • Aged
  • Aminopyridines / pharmacology
  • Animals
  • Cyclic AMP / metabolism
  • Female
  • Gene Knockdown Techniques
  • Gluconeogenesis* / drug effects
  • Glucose-6-Phosphatase / metabolism
  • Humans
  • Inflammation / pathology
  • Insulin Resistance
  • Interleukin-6 / metabolism
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Receptors, Adrenergic, beta / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction* / drug effects
  • Subcutaneous Fat / drug effects
  • Subcutaneous Fat / metabolism*
  • Young Adult
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Aminopyridines
  • Interleukin-6
  • Receptors, Adrenergic, beta
  • STAT3 Transcription Factor
  • amlexanox
  • Cyclic AMP
  • p38 Mitogen-Activated Protein Kinases
  • Glucose-6-Phosphatase

Associated data

  • GEO/GSE57054