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APPL1-mediated activation of STAT3 contributes to inhibitory effect of adiponectin on hepatic gluconeogenesis

Youming Ding1, Deling Zhang2, Bin Wang1

  • 1Department of Hepatobiliary & Laparoscopic Surgery, Wuhan University Renmin Hospital, Wuhan 430060, China.

Molecular and Cellular Endocrinology
|June 2, 2016
PubMed

Insights

Adiponectin suppresses liver glucose production via the APPL1-SirT1-STAT3 pathway. This study reveals how adiponectin signaling regulates gluconeogenesis in hepatocytes.

Area of Science:

  • Metabolism
  • Cell Signaling
  • Hormone Action

Background:

  • Adiponectin is known to inhibit hepatic gluconeogenesis.
  • The precise molecular mechanisms and signaling pathways involved are not fully understood.

Purpose of the Study:

  • To investigate the role of APPL1 (Adapter Protein Containing Pleckstrin Homology Domain, Clathrin-Binding Site, and Leucine Repeats) in mediating adiponectin's anti-gluconeogenic effects.
  • To elucidate the signaling cascade involving APPL1, SirT1, and STAT3 in adiponectin action.

Main Methods:

  • Primary hepatocytes were isolated from male C57BL/6 mice.
  • Western blot and RT-PCR were used to analyze protein and mRNA levels.
  • Immunoprecipitation and GST pull-down assays assessed protein-protein interactions.

Main Results:

  • APPL1 levels correlated inversely with gluconeogenic enzyme expression upon adiponectin stimulation.
  • APPL1 positively regulated adiponectin-induced STAT3 phosphorylation and acetylation, while SirT1 negatively regulated it.
  • Inhibition of STAT3 abolished adiponectin's effect on hepatic gluconeogenesis.
  • Adiponectin enhanced APPL1-SirT1 binding and reduced SirT1-STAT3 association.

Conclusions:

  • The APPL1-SirT1-STAT3 pathway is a key mediator of adiponectin signaling in primary hepatocytes.
  • This pathway provides a novel molecular mechanism for how adiponectin suppresses hepatic gluconeogenesis.
Keywords:
APPL1AdiponectinGluconeogenesisSTAT3SirT1

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