Abstract
Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway due to the loss of upper airway muscle tone during sleep. OSA is highly prevalent, especially in obesity. There is no pharmacotherapy for OSA. Previous studies have demonstrated the role of leptin, an adipose-tissue-produced hormone, as a potent respiratory stimulant. Leptin signaling via a long functional isoform of leptin receptor, LEPRb, in the nucleus of the solitary tract (NTS), has been implicated in control of breathing. We hypothesized that leptin acts on LEPRb positive neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPRb positive neurons of the NTS of Leprb-Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep. J60 was a potent activator of LEPRb positive NTS neurons, but did not stimulate breathing or upper airway muscles during NREM and REM sleep. We conclude that, in DIO mice, the stimulating effects of leptin on breathing during sleep are independent of LEPRb signaling in the NTS.
Highlights
Obstructive sleep apnea (OSA) is a highly prevalent condition observed in approximately 9–45% of adult men and women [1,2], and in more than 50% of obese individuals [1,3,4,5,6]
LEPRb positive neurons were abundantly expressed in the nucleus of the solitary tract (NTS)
designer receptors exclusively activated by designer drugs (DREADD) were successfully deployed in these neurons 4–6 weeks after AAV8-hSyn-diet-induced obesity (DIO)-hM3D(Gq)-mCherry administration (Figure 1)
Summary
Obstructive sleep apnea (OSA) is a highly prevalent condition observed in approximately 9–45% of adult men and women [1,2], and in more than 50% of obese individuals [1,3,4,5,6]. OSA is defined as recurrent closure of the upper airway during sleep due to loss of upper airway muscle tone [7]. OSA is a major cause of morbidity and mortality in the Western World [8,9] and contributes significantly to the development and progression of neurocognitive, metabolic, cardiovascular, and oncologic diseases [10,11,12]. Up-regulation of oxygen-sensitive α-subunit of hypoxia-inducible factor 1 may contribute to metabolic disorders in OSA [12]. Continuous positive airway pressure is the first-line treatment modality for OSA, which improves clinical symptoms, quality of life, and gas exchange, but it is poorly tolerated by a large proportion of patients [13]. The absence of effective pharmacotherapy and adverse effects of traditional therapeutic approaches in OSA patients require rodent models to understand the neural mechanisms regulating the control of breathing and upper airway patency in OSA [14,15,16,17,18,19,20]
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