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Am J Respir Crit Care Med. 2019 Mar 15;199(6):773-783. doi: 10.1164/rccm.201805-0879OC.

Intranasal Leptin Relieves Sleep-disordered Breathing in Mice with Diet-induced Obesity.

Author information

1
1 Division of Pulmonary and Critical Care Medicine and.
2
2 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
3 Department of Molecular Biology and.
4
4 Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey; and.
5
5 Department of Pharmacology and Physiology, George Washington University, Washington, DC.

Abstract

RATIONALE:

Leptin treats upper airway obstruction and alveolar hypoventilation in leptin-deficient ob/ob mice. However, obese humans and mice with diet-induced obesity (DIO) are resistant to leptin because of poor permeability of the blood-brain barrier. We propose that intranasal leptin will bypass leptin resistance and treat sleep-disordered breathing in obesity.

OBJECTIVES:

To assess if intranasal leptin can treat obesity hypoventilation and upper airway obstruction during sleep in mice with DIO.

METHODS:

Male C57BL/6J mice were fed with a high-fat diet for 16 weeks. A single dose of leptin (0.4 mg/kg) or BSA (vehicle) were administered intranasally or intraperitoneally, followed by either sleep studies (n = 10) or energy expenditure measurements (n = 10). A subset of mice was treated with leptin daily for 14 days for metabolic outcomes (n = 20). In a separate experiment, retrograde viral tracers were used to examine connections between leptin receptors and respiratory motoneurons.

MEASUREMENTS AND MAIN RESULTS:

Acute intranasal, but not intraperitoneal, leptin decreased the number of oxygen desaturation events in REM sleep, and increased ventilation in non-REM and REM sleep, independently of metabolic effects. Chronic intranasal leptin decreased food intake and body weight, whereas intraperitoneal leptin had no effect. Intranasal leptin induced signal transducer and activator of transcription 3 phosphorylation in hypothalamic and medullary centers, whereas intraperitoneal leptin had no effect. Leptin receptor-positive cells were synaptically connected to respiratory motoneurons.

CONCLUSIONS:

In mice with DIO, intranasal leptin bypassed leptin resistance and significantly attenuated sleep-disordered breathing independently of body weight.

KEYWORDS:

hypoventilation; leptin; respiration; sleep apnea syndromes

PMID:
30309268
PMCID:
PMC6423095
[Available on 2020-03-15]
DOI:
10.1164/rccm.201805-0879OC

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