title: Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep.
abstract: OBJECTIVE
  Obesity hypoventilation and obstructive sleep apnea are common complications of obesity linked to defects in respiratory pump and upper airway neural control. Leptin-deficient ob/ob mice have impaired ventilatory control and inspiratory flow limitation during sleep, which are both reversed with leptin. We aimed to localize central nervous system (CNS) site(s) of leptin action on respiratory and upper airway neuroventilatory control.
  
  
  METHODS
  We localized the effect of leptin to medulla versus hypothalamus by administering intracerbroventricular leptin (10 μg/2 μL) versus vehicle to the lateral (n = 14) versus fourth ventricle (n = 11) of ob/ob mice followed by polysomnographic recording. Analyses were stratified for effects on respiratory (nonflow-limited breaths) and upper airway (inspiratory flow limitation) functions. CNS loci were identified by (1) leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and (2) projections of respiratory and upper airway motoneurons with a retrograde transsynaptic tracer (pseudorabies virus).
  
  
  RESULTS
  Both routes of leptin administration increased minute ventilation during nonflow-limited breathing in sleep. Phrenic motoneurons were synaptically coupled to the nucleus of the solitary tract, which also showed STAT3 phosphorylation, but not to the hypothalamus. Inspiratory flow limitation and obstructive hypopneas were attenuated by leptin administration to the lateral but not to the fourth cerebral ventricle. Upper airway motoneurons were synaptically coupled with the dorsomedial hypothalamus, which exhibited STAT3 phosphorylation.
  
  
  CONCLUSIONS
  Leptin relieves upper airway obstruction in sleep apnea by activating the forebrain, possibly in the dorsomedial hypothalamus. In contrast, leptin upregulates ventilatory control through hindbrain sites of action, possibly in the nucleus of the solitary tract.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Physiology; Preclinical School, Xinjiang Medical University, Xinjiang, China.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Huy
authors.initials: H
authors.lastname: Pho
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Jason
authors.initials: J
authors.lastname: Kirkness
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Ladenheim
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Sheng
authors.initials: S
authors.lastname: Bi
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.affiliation: Departments of Physical Therapy, University of Florida, Gainesville, FL.|McKnight Brain Institute, University of Florida, Gainesville, FL.
authors.forename: David D
authors.initials: DD
authors.lastname: Fuller
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schwartz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000818:Animals; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007040:Hypoventilation / Q000150:complications / Q000503:physiopathology; D020738:Leptin / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects; D009765:Obesity / Q000150:complications / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D017286:Polysomnography; D012119:Respiration / Q000187:drug effects*; D012137:Respiratory System / Q000187:drug effects* / Q000294:innervation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012890:Sleep / Q000187:drug effects* / Q000502:physiology*; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000503:physiopathology; D017552:Solitary Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology
chemical_list: D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: dorsomedial hypothalamus; nucleus of the solitary tract; ob/ob mouse; obesity hypoventilation syndrome; sleep apnea syndrome