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Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance
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Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance

Published on: February 17, 2023

Mechanism of lipid induced insulin resistance: activated PKCε is a key regulator

Suman Dasgupta1, Sushmita Bhattacharya, Sudipta Maitra

  • 1Cellular and Molecular Endocrinology Laboratory, Department of Zoology, School of Life Science, Visva-Bharati University, Santiniketan 731235, India.

Biochimica Et Biophysica Acta
|January 18, 2011
PubMed

Insights

Fatty acids impair insulin signaling by phosphorylating PKCε, leading to reduced insulin receptor expression. This mechanism involves palmitoylation and nuclear translocation of PKCε, ultimately decreasing insulin sensitivity.

Area of Science:

  • Molecular Biology
  • Cellular Metabolism
  • Endocrinology

Background:

  • Fatty acids (FAs) are known to disrupt insulin signaling pathways in target cells.
  • The insulin receptor (IR) is a key site affected by FAs, but the precise mechanism remains elusive.
  • Elevated FAs in diabetic mice correlate with increased PKCε phosphorylation and decreased IR expression.

Purpose of the Study:

  • To elucidate the mechanism by which FAs impair insulin receptor signaling.
  • To investigate the role of Protein Kinase C epsilon (PKCε) in FA-induced insulin resistance.
  • To identify the molecular players involved in FA-mediated downregulation of the insulin receptor.

Main Methods:

  • Utilized kinase-dead mutants of PKCε to assess its role in FA-induced IRβ reduction.
  • Investigated FA-induced phosphorylation of PKCε through palmitoylation, including site-directed mutagenesis (C276, C474).
  • Examined the nuclear translocation of phosphorylated PKCε and its interaction with transcription regulators (HMGA1, Sp1) using insulin target cells.

Main Results:

  • Phosphorylation of PKCε by FAs is crucial for the downregulation of the insulin receptor beta subunit (IRβ).
  • FA-induced PKCε phosphorylation occurs independently of kinase activity via palmitoylation, involving Cys276 and Cys474.
  • Phosphorylated PKCε translocates to the nucleus, facilitated by F-actin, where it interacts with HMGA1 and Sp1, impairing HMGA1-driven IR transcription.

Conclusions:

  • Fatty acids induce insulin resistance by promoting PKCε palmitoylation and nuclear translocation.
  • This process leads to the downregulation of the insulin receptor, compromising insulin signaling and sensitivity.
  • PKCε acts as a critical mediator in the adverse effects of fatty acids on insulin receptor regulation.

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