# Treatment of Sleep Apnea by Targeting Leptin Signaling

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2023 · $935,579

## Abstract

Obstructive sleep apnea (OSA) is recurrent upper airway obstruction caused by a loss of upper airway muscle
tone during sleep. There is no pharmacotherapy for OSA. There is an urgent need for therapeutics that reverse
neuromuscular defects in upper airway function. Our efforts have focused on leptin, an adipocyte-produced
hormone, which suppresses appetite, increases metabolic rate, and up-regulates control of breathing. We have
previously reported that obese mice develop OSA, which was treated by leptin. Our preliminary results show
that (1) leptin receptor (LepRb) deficient db/db mice develop OSA, which was abolished by
intracerebroventricular (ICV) leptin after expression of LepRb in the dorsomedial hypothalamus (db/db-LepRb-
DMH mice); (2) OSA improved in diet induced obese (DIO) LepRb-Cre mice upon activation of excitatory
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in LepRb+ neurons of the
nucleus of the solitary tract (NTS); (3) hypoglossal motoneurons do not express LepRb, but LepRb+ neurons
project to the hypoglossal nucleus and photogenetic stimulation of LepRb+ synapses increased hypoglossal
motoneuron activity in LepRb-ChR2 mice; (4) LepRb+ neurons in DMH and NTS are melanocortin 4 receptor
(MCR4) positive. Our hypothesis is that leptin acts on LepRb+ neurons in DMH and NTS to maintain upper
airway patency during sleep. Specific Aim 1 will test the hypothesis that activation of LepRb+ neurons in the
DMH alleviates upper airway obstruction and OSA. We propose that (A) selective stimulation of LepRb+ DMH
neurons by ICV leptin in db/db-LepRb-DMH mice and by activation of excitatory DREADDs in DIO LepRb-Cre
mice will improve upper airway patency and treat OSA; (B) knockout of LepRb+ in DMH neurons by Cre
recombinase in DIO LepRb flox/flox mice and inhibition of these neurons in DIO LepRb-Cre mice expressing
inhibitory DREADDs will decrease upper airway patency and aggravate OSA; (C) effects of leptin on OSA in
db/db-LepRb-DMH mice will be attenuated by MC4R blockers. Specific Aim 2 will examine mechanisms of
leptin’s action in the NTS on OSA in vivo and will be designed as SA1 A-C with exception that our interventions
will target NTS. Specific Aim 3 will examine synaptic connections between LepRb+ neurons, originating from
both the DMH and NTS, that project to and synapse upon hypoglossal motoneurons. We propose that both
DMH and NTS LepRb+ neurons connect to hypoglossal motoneurons and that optogenetic stimulation of (A)
DMH- and (B) NTS LepRb-channelrhodopsin (ChR2) expressing neurons and fibers activates hypoglossal
motoneurons. In SA1-2, we will employ a full arrays of physiological measurements developed in our laboratory
including polysomnograms, dynamic MR imaging, and pharyngeal collapsibility measurements in obese male
and female mice. In SA3, selective expression of optogenetic tools in targeted LepRb neuronal populations will
be employed in combination with patch clamp electrophysiology in bra...

## Key facts

- **NIH application ID:** 10783228
- **Project number:** 7R01HL128970-08
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** David Mendelowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $935,579
- **Award type:** 7
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783228

## Citation

> US National Institutes of Health, RePORTER application 10783228, Treatment of Sleep Apnea by Targeting Leptin Signaling (7R01HL128970-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10783228. Licensed CC0.

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