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

Intranasal leptin enhanced the hypercapnic ventilatory response, 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 projecting to hypoglossal motoneurons, indicating leptin acts through medullary raphe serotonergic pathways.

Last updated: Jul 15, 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 administered intranasally reaches medullary raphe serotonergic neurons
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Serotonergic neurons project to hypoglossal motoneurons (XII MN)
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Activation of XII MN increases genioglossus muscle activity
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Increased pharyngeal muscle tone attenuates upper airway obstruction and improves ventilation during sleep

Limitations

  • ⚠Animal model (mice) limits direct translation to human obesity hypoventilation syndrome
  • ⚠Sex-specific effect on arousal latency (males only) not fully explained
  • ⚠Specific leptin dose and route not detailed in abstract

Frequently Asked Questions

What is obesity hypoventilation syndrome (OHS)?▼

OHS is a condition in obese individuals characterized by inadequate breathing during sleep, leading to low oxygen and high carbon dioxide levels, often with upper airway obstruction.

How does leptin affect breathing in this study?▼

Intranasal leptin enhanced the hypercapnic ventilatory response, increased genioglossus muscle activity, reduced pharyngeal obstruction, and increased ventilation during sleep in obese mice.

Why were serotonergic neurons targeted?▼

Previous research showed leptin's respiratory effects are attenuated by serotonergic antagonists, and this study confirmed that medullary raphe serotonergic neurons projecting to hypoglossal motoneurons are necessary for leptin's benefits.

Are there any sex differences reported?▼

Yes, leptin increased arousal latency in male mice but not in females, suggesting a sex-specific effect.

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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.