The TNF-α-FABP4-Dhhc7 Axis Mediates Olanzapine-Induced Insulin Resistance in Rats and Humans

Area of Science:

• Metabolic disorders
• Pharmacology
• Molecular biology

Background:

• Long-term olanzapine treatment is associated with increased insulin resistance (IR).
• Current methods to prevent olanzapine-induced IR are inefficient.
• The precise mechanism underlying olanzapine-induced IR requires elucidation.

Purpose of the Study:

• To investigate the molecular mechanism by which olanzapine induces insulin resistance.
• To identify key molecular players involved in olanzapine-induced IR.
• To explore potential therapeutic targets for mitigating olanzapine-induced IR.

Main Methods:

• Analysis of clinical data from 120 schizophrenia patients on long-term olanzapine treatment.
• Verification in a rat model and 3T3-L1 adipocytes.
• Western blotting and polymerase chain reaction to assess gene and protein expression.
• Investigation of glucose transporter 4 (GLUT4) membrane transport.
• Intervention using FABP4 adenovirus to improve olanzapine-induced IR.

Main Results:

• Olanzapine treatment increased circulating tumor necrosis factor-alpha (TNF-α) levels.
• Olanzapine exposure increased fatty acid binding protein 4 (FABP4) expression while decreasing Dhhc7 expression.
• Olanzapine inhibited glucose transporter 4 (GLUT4) membrane translocation.
• FABP4 adenovirus injection ameliorated olanzapine-induced insulin resistance.

Conclusions:

• Long-term olanzapine exposure induces insulin resistance via the TNF-α/FABP4/Dhhc7 signaling pathway.
• This pathway leads to reduced GLUT4 membrane translocation and impaired glucose metabolism.
• Targeting the TNF-α/FABP4/Dhhc7 axis may offer a strategy to prevent or treat olanzapine-induced insulin resistance.