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A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis

Shannon M Reilly1, Maryam Ahmadian2, Brian F Zamarron3

  • 1Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.

Nature Communications
|January 13, 2015
PubMed

Insights

Amlexanox treatment for obesity increases cAMP, promoting IL-6 secretion from fat cells. This improves glucose metabolism in obese mice by affecting the liver, suggesting a new therapeutic pathway for type 2 diabetes.

Area of Science:

  • Metabolic disease research
  • Molecular mechanisms of obesity
  • Diabetes therapeutics

Background:

  • Obesity and associated insulin resistance necessitate novel therapeutic strategies.
  • IKK-ε (inhibitor of κB kinase ε) and TBK1 (TANK-binding kinase 1) were previously identified as potential targets for obesity treatment.
  • Understanding the molecular pathways linking obesity, insulin resistance, and glucose metabolism is crucial.

Purpose of the Study:

  • To investigate the acute metabolic effects of amlexanox, an inhibitor of IKK-ε and TBK1, in obese mice.
  • To elucidate the role of amlexanox in modulating cAMP levels, cytokine secretion, and hepatic gene expression.
  • To explore the potential of targeting the adipose tissue-liver axis for treating metabolic dysfunction.

Main Methods:

  • Administration of amlexanox to obese mice to inhibit IKK-ε and TBK1.
  • Measurement of cyclic adenosine monophosphate (cAMP) levels in subcutaneous adipose tissue.
  • Assessment of interleukin-6 (IL-6) synthesis and secretion from adipocytes and preadipocytes.
  • Analysis of hepatic Stat3 phosphorylation and gene expression related to gluconeogenesis.
  • Preliminary analysis of similar metabolic effects in a cohort of obese patients.

Main Results:

  • Amlexanox treatment acutely increased cAMP levels in subcutaneous adipose depots of obese mice.
  • This increase in cAMP promoted the synthesis and secretion of IL-6 from adipocytes and preadipocytes.
  • IL-6 stimulated hepatic Stat3 phosphorylation, suppressing genes involved in gluconeogenesis.
  • These molecular events led to improved glucose handling in obese mice.
  • Preliminary human data suggested a similar association in obese patients.

Conclusions:

  • Amlexanox exerts acute metabolic benefits on glucose metabolism through a subcutaneous adipose tissue-liver axis.
  • The pathway involves amlexanox-induced increase in cAMP, IL-6 secretion, and subsequent hepatic gene regulation.
  • These findings highlight a novel therapeutic avenue for type 2 diabetes and obesity-related metabolic disorders.

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