Intranasal Leptin Relieves Sleep-disordered Breathing in Mice with Diet-induced Obesity
| Autor: | Huy Pho, Alan R. Schwartz, Rexford S. Ahima, Haris Younas, Frederick Anokye-Danso, Thomaz Fleury-Curado, Slava Berger, Shannon Bevans-Fonti, Mi Kyung Shin, Lynn W. Enquist, Vsevolod Y. Polotsky, Jonathan C. Jun, David Mendelowitz |
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| Rok vydání: | 2019 |
| Předmět: |
Leptin
Pulmonary and Respiratory Medicine medicine.medical_specialty Critical Care and Intensive Care Medicine Alveolar hypoventilation Mice Sleep Apnea Syndromes Internal medicine Respiration medicine Animals Humans Obesity business.industry digestive oral and skin physiology Editorials Original Articles respiratory system Airway obstruction medicine.disease Diet Hypoventilation Mice Inbred C57BL Endocrinology Models Animal Sleep disordered breathing Receptors Leptin Nasal administration Nasal Absorption medicine.symptom Sleep business hormones hormone substitutes and hormone antagonists |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine |
| ISSN: | 1535-4970 1073-449X |
| DOI: | 10.1164/rccm.201805-0879oc |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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