GLP-2 prevents antipsychotics-induced metabolic dysfunction in mice

Area of Science:

• Neuroscience
• Endocrinology
• Pharmacology

Background:

• Antipsychotic medications can cause severe metabolic side effects, including hypothermia and weight gain.
• Current treatments for these side effects are lacking or ineffective for long-term management.

Purpose of the Study:

• To investigate the potential of a glucagon-like peptide 2 (GLP-2) analogue, teduglutide, in mitigating antipsychotic-induced metabolic side effects.
• To elucidate the underlying neural mechanisms of these side effects and teduglutide's therapeutic action.

Main Methods:

• Utilized a mouse model to assess the effects of olanzapine (an antipsychotic) and teduglutide.
• Investigated the role of ventromedial hypothalamus prodynorphin-expressing neurons (VMH^Pdyn neurons) using selective ablation and chemogenetics.
• Measured body temperature, weight gain, glucose tolerance, and insulin sensitivity.

Main Results:

• Teduglutide effectively prevented olanzapine-induced hypothermia and weight gain in mice.
• Teduglutide restored glucose tolerance and insulin sensitivity.
• Olanzapine suppressed VMH^Pdyn neurons, while teduglutide activated them; VMH^Pdyn neuron manipulation mimicked or reversed olanzapine's metabolic effects.

Conclusions:

• VMH^Pdyn neurons are critical mediators of antipsychotic-induced metabolic dysfunction.
• GLP-2 receptor agonism, via teduglutide, represents a promising therapeutic strategy to counteract acute and chronic metabolic side effects of antipsychotics.