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Intranasal leptin alleviates obesity hypoventilation syndrome via serotonergic pathways in diet-induced obese mice

Intranasal leptin enhanced the hypercapnic ventilatory response, increased arousal latency in males, increased genioglossus muscle activity during wake and NREM sleep, attenuated pharyngeal obstruction, and increased minute ventilation during NREM and REM sleep in diet-induced obese mice. These effects were abolished by ablation of serotonergic neurons innervating the hypoglossal motoneurons, indicating leptin acts through medullary raphe serotonergic pathways.

Last updated: Jul 16, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score24/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Leptin alleviates obesity hypoventilation via serotonergic pathways.

observational

Davaanyam D, Ruiz MA, de Deus JL, Shin MK, Winston CR, Wang X, Amorim MR, Mendelowitz D, Polotsky VY · bioRxiv : the preprint server for biology (2026)

Participants: N/A
Duration: N/A
Intervention: Intranasal leptin administration in diet-induced obese Sert-flp mice with or without FlpO-dependent caspase ablation of serotonergic neurons projecting to hypoglossal motoneurons
Outcome: Hypercapnic ventilatory response (HCVR), arousal latency, sleep architecture, flow-limited and non-flow-limited breathing, genioglossus muscle activity, minute ventilation, metabolic rate
Effect Size: N/A
Population: Diet-induced obese (DIO) Sert-flp mice expressing FlpO recombinase in serotonergic neurons

Result:

PubMed: 42427597DOI: 10.64898/2026.06.23.734005

Mechanism Graph

Leptin stimulates medullary raphe serotonergic neurons
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These serotonergic neurons project to hypoglossal motoneurons (XII MN)
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Activation of XII MN increases genioglossus muscle activity
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Enhanced pharyngeal muscle tone attenuates upper airway obstruction and increases ventilation during sleep

Limitations

  • ⚠Study conducted in an animal model (mice), not in humans
  • ⚠Sex-specific effect on arousal latency observed only in males, limiting generalizability
  • ⚠Dose of intranasal leptin not specified in abstract

Frequently Asked Questions

What is obesity hypoventilation syndrome (OHS)?▼

OHS is a breathing disorder in obese individuals characterized by inadequate ventilation during sleep, leading to low oxygen and high carbon dioxide levels.

How does leptin affect breathing during sleep?▼

Leptin enhances the hypercapnic ventilatory response, increases genioglossus muscle activity, reduces pharyngeal obstruction, and increases minute ventilation during NREM and REM sleep.

Why were serotonergic neurons targeted in this study?▼

Previous research showed that respiratory effects of leptin can be attenuated by serotonergic antagonists, suggesting serotonin pathways mediate leptin's effects on breathing.

Is intranasal leptin a potential treatment for OHS in humans?▼

This study suggests intranasal leptin may be a promising pharmacotherapy for OHS, but human trials are needed to confirm efficacy and safety.

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References

  1. 1.Davaanyam D, Ruiz MA, de Deus JL, Shin MK, Winston CR, Wang X, Amorim MR, Mendelowitz D, Polotsky VY. "Leptin alleviates obesity hypoventilation via serotonergic pathways.." bioRxiv : the preprint server for biology, 2026. PMID: 42427597 DOI: 10.64898/2026.06.23.734005
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.