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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

Cyclin-dependent kinase-5 is a key molecule in tumor necrosis factor-α-induced insulin resistance

Atsushi Nohara1, Shuichi Okada, Kihachi Ohshima

  • 1Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Japan.

The Journal of Biological Chemistry
|August 5, 2011
PubMed

Insights

Tumor necrosis factor-alpha (TNF-α) causes insulin resistance by activating cyclin-dependent kinase-5 (CDK5) via a MEK/Erk pathway. This disrupts glucose transporter-4 (GLUT4) translocation in adipocytes.

Area of Science:

  • Cellular biology
  • Molecular endocrinology
  • Metabolic signaling

Background:

  • The precise mechanism by which tumor necrosis factor-alpha (TNF-α) induces insulin resistance is complex and debated.
  • Existing evidence suggests TNF-α affects insulin signaling through various pathways, including the downregulation of key effector targets or blockade of proximal and distal signaling events.
  • The specific molecular players and pathways involved can vary based on TNF-α dosage, treatment duration, and the cell type under investigation.

Purpose of the Study:

  • To elucidate the acute molecular mechanisms through which TNF-α triggers insulin resistance in differentiated 3T3L1 adipocytes.
  • To identify the specific signaling pathways and protein interactions responsible for TNF-α-induced impairment of insulin action.

Main Methods:

  • Differentiated 3T3L1 adipocytes were treated with TNF-α (20 ng/ml) for acute periods (5-15 min).
  • Investigated the effects of TNF-α on insulin signaling components, including IRS1-associated phosphatidylinositol 3-kinase, Erk pathway activation, cyclin-dependent kinase-5 (CDK5) phosphorylation, p35 expression, and TC10α activation.
  • Assessed changes in cortical F-actin depolymerization and insulin-stimulated glucose transporter-4 (GLUT4) translocation.
  • Utilized MEK inhibitor (PD98059), siRNA-mediated knockdown of CDK5 and p44/42 Erk to probe the identified pathways.

Main Results:

  • Acute TNF-α treatment did not significantly affect IRS1-associated phosphatidylinositol 3-kinase activity.
  • TNF-α promoted Erk-dependent phosphorylation of CDK5 at tyrosine 15 and increased p35 expression.
  • TNF-α stimulation led to TC10α phosphorylation and GTP loading, cortical F-actin depolymerization, and inhibition of insulin-stimulated GLUT4 translocation.
  • Inhibition of MEK/Erk or knockdown of CDK5/Erk restored insulin-stimulated GLUT4 translocation, reversing TNF-α-induced insulin resistance.

Conclusions:

  • These findings demonstrate that TNF-α induces insulin resistance in adipocytes via a MEK/Erk-dependent activation of CDK5.
  • This pathway leads to the disruption of cortical F-actin organization and subsequent inhibition of GLUT4 translocation, impairing glucose uptake.
  • Targeting the MEK/Erk/CDK5 axis presents a potential therapeutic strategy for combating TNF-α-mediated insulin resistance.

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