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

TitleIntranasal Leptin Relieves Sleep-disordered Breathing in Mice with Diet-induced Obesity.
Publication TypeJournal Article
Year of Publication2019
AuthorsBerger, S, Pho, H, Fleury-Curado, T, Bevans-Fonti, S, Younas, H, Shin, M-K, Jun, JC, Anokye-Danso, F, Ahima, RS, Enquist, LW, Mendelowitz, D, Schwartz, AR, Polotsky, VY
JournalAm J Respir Crit Care Med
Volume199
Issue6
Pagination773-783
Date Published2019 03 15
ISSN1535-4970
KeywordsAnimals, Humans, Leptin, Mice, Mice, Inbred C57BL, Models, Animal, Nasal Absorption, Obesity, Sleep, Sleep Apnea Syndromes
Abstract

<p><b>RATIONALE: </b>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.</p><p><b>OBJECTIVES: </b>To assess if intranasal leptin can treat obesity hypoventilation and upper airway obstruction during sleep in mice with DIO.</p><p><b>METHODS: </b>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.</p><p><b>MEASUREMENTS AND MAIN RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>In mice with DIO, intranasal leptin bypassed leptin resistance and significantly attenuated sleep-disordered breathing independently of body weight.</p>

DOI10.1164/rccm.201805-0879OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID30309268
PubMed Central IDPMC6423095
Grant ListP50 ES018176 / ES / NIEHS NIH HHS / United States
R01 HL128970 / HL / NHLBI NIH HHS / United States
R01 HL133100 / HL / NHLBI NIH HHS / United States
R01 HL138932 / HL / NHLBI NIH HHS / United States