Leptin alleviates obesity hypoventilation via serotonergic pathways

Area of Science:

• Neuroscience
• Respiratory Physiology
• Pharmacology

Background:

• Obesity hypoventilation syndrome (OHS) lacks effective drug treatments.
• Leptin shows promise in animal models by improving breathing and reducing airway obstruction.
• The role of serotonin pathways in mediating leptin's respiratory effects is unclear.

Purpose of the Study:

• To investigate if serotonergic innervation of hypoglossal motoneurons (XII MN) is essential for leptin's effects on OHS.
• To determine the specific neural pathways through which leptin influences respiratory control in OHS models.

Main Methods:

• Diet-induced obese (DIO) mice with selectively ablated serotonergic neurons innervating XII MN were used.
• Intranasal leptin's effects on hypercapnic ventilatory response (HCVR), sleep, arousal, breathing, and genioglossus muscle (GG) activity were assessed.
• A chemogenetic approach using Flp-on-inducible caspase was employed to ablate specific serotonergic neurons.

Main Results:

• Leptin enhanced HCVR and increased arousal latency in male mice, effects abolished by neuron ablation.
• Leptin increased GG muscle activity and minute ventilation during sleep, while attenuating airway obstruction.
• These leptin-induced improvements in breathing and airway function were eliminated when specific serotonergic neurons were ablated.

Conclusions:

• Leptin's therapeutic effects in OHS models are mediated by stimulating medullary raphe (MR) serotonergic neurons.
• These MR serotonergic neurons project to hypoglossal motoneurons (XII MN), activating pharyngeal muscles during sleep.
• Targeting this specific serotonergic pathway represents a potential therapeutic strategy for OHS.