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Inhibition of γ-secretase in adipocytes leads to altered IL-6 secretion and adipose inflammation

David P Sparling1, Nile McCullough1, Utpal Pajvani2

  • 1Department of Pediatrics, University of Oklahoma Health Sciences Center , Oklahoma City, OK, USA.

Adipocyte
|July 1, 2020
PubMed

Insights

Inhibiting the gamma-secretase enzyme in fat cells reduces inflammatory markers like IL-6. This suggests gamma-secretase is a potential target for managing obesity and related inflammatory conditions.

Area of Science:

  • Biochemistry
  • Immunology
  • Metabolic Diseases

Background:

  • Adipocyte inflammation is implicated in obesity and Type 2 diabetes.
  • Novel therapeutic targets are needed to modulate inflammatory signaling in adipose tissue.
  • The gamma-secretase enzyme complex is involved in adipocyte function and immune regulation.

Purpose of the Study:

  • To investigate the role of adipocyte-specific gamma-secretase inhibition in altering adipose tissue inflammation.
  • To explore the mechanisms by which adipocytes influence macrophage inflammatory responses.

Main Methods:

  • Genetic blockade of gamma-secretase in adipocytes.
  • In vitro treatment of 3T3-L1 adipocytes with a gamma-secretase inhibitor and lipopolysaccharide (LPS).
  • Quantification of inflammatory gene expression (EMR1, IL6, ccl2) and macrophage activation markers.

Main Results:

  • Genetic gamma-secretase inhibition in adipocytes decreased EMR1 expression, a marker for macrophage presence.
  • In vitro, gamma-secretase inhibition significantly reduced IL-6 expression and secretion in adipocytes stimulated with LPS.
  • Media from inhibited adipocytes altered macrophage activation but not translocation.

Conclusions:

  • Adipocyte gamma-secretase activity influences inflammatory signaling pathways.
  • Gamma-secretase inhibition in adipocytes can modulate IL-6 signaling to macrophages.
  • Targeting gamma-secretase in adipocytes may offer a novel strategy for managing obesity-related inflammation.
Keywords:
AdipocyteIL-6gamma-secretaseinflammationmacrophage

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