Leptin alleviates obesity hypoventilation via serotonergic pathways

Authors

Davaanyam, D., Alexis Ruiz, M., L de Deus, J., Shin, M. K., Winston, C. R., Wang, X., Amorim, M. R., Mendelowitz, D., Polotsky, V. Y.

Abstract

Rationale. There is no effective pharmacotherapy for obesity hypoventilation syndrome (OHS). Intranasal leptin augments the hypercapnic ventilatory response (HCVR), attenuates upper airway obstruction, and increases ventilation during sleep in diet-induced obese (DIO) mice. Respiratory effects of leptin can be attenuated by serotonergic antagonists. Objectives. To establish if serotonergic innervation of the hypoglossal motoneurons (XII MN) mediates effects of leptin on OHS. Methods. We examined effects of intranasal leptin on the HCVR, sleep architecture, arousal latency, flow limited (obstructed) and non-flow limited breathing, genioglossus muscle (GG) activity and metabolic rate across sleep/wake states in the presence and absence of serotonergic neurons innervating XII MN in DIO Sert-flp mice expressing FlpO recombinase in the serotonergic neurons. These mice were transfected into the XII MN with retrograde adeno-associated virus carrying either FlpO-dependent caspase or control yellow fluorescent protein (YFP). Measurements and Main Results. Control YFP virus was densely localized to the serotonergic neurons of the medullary raphe (MR), but not the dorsal raphe (DR), and these neurons were ablated by caspase. Leptin enhanced the HCVR, increased arousal latency in males, but not in females, and these effects were abolished by caspase. Neither leptin nor caspase affected sleep architecture or metabolic rate. Leptin increased GG activity awake and during NREM sleep, attenuated pharyngeal obstruction and increased minute ventilation in NREM and REM sleep. All effects of leptin were abolished by the FlpO-dependent caspase. Conclusions: Leptin treats OHS by stimulating MR serotonergic neurons, which project to XII MN and stimulate pharyngeal muscles during sleep.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Jun 2026.

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