Antipsychotics differentially regulate insulin, energy sensing, and inflammation pathways in hypothalamic rat neurons

Area of Science:

• Neuroscience
• Endocrinology
• Pharmacology

Background:

• Second-generation antipsychotics (APs) are standard treatments for schizophrenia but cause significant metabolic side effects.
• The hypothalamus regulates energy balance, and its dysfunction is linked to insulin resistance and obesity.
• Understanding how APs affect hypothalamic function is crucial for mitigating metabolic risks.

Purpose of the Study:

• To investigate the direct effects of APs on energy sensing and inflammatory pathways in hypothalamic neurons.
• To elucidate the mechanisms underlying AP-induced metabolic dysregulation.

Main Methods:

• Cultured rat hypothalamic neurons (rHypoE-19) were treated with olanzapine, clozapine, or aripiprazole.
• Western blotting assessed protein levels of AMPK, AKT, GSK3β, ERK1/2, JNK, and p38.
• Quantitative real-time PCR measured mRNA expression of IL-6, IL-10, and BDNF.

Main Results:

• Olanzapine and clozapine increased MAPK pathway activation (pERK1/2, pJNK); aripiprazole increased pJNK.
• Clozapine and aripiprazole increased AMPK phosphorylation and inhibited insulin-induced AKT phosphorylation.
• Olanzapine increased IL-6, aripiprazole decreased IL-10, and both increased BDNF expression.

Conclusions:

• Antipsychotics directly modulate insulin, energy sensing, and inflammatory pathways in hypothalamic neurons.
• Observed effects suggest APs can induce pro-inflammatory responses and impair insulin signaling and energy sensing.
• Differential effects on BDNF indicate potential for varied metabolic outcomes among APs.