Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep

Sleep. 2016 May 1;39(5):1097-106. doi: 10.5665/sleep.5762.


Study objectives: 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.

Keywords: dorsomedial hypothalamus; nucleus of the solitary tract; ob/ob mouse; obesity hypoventilation syndrome; sleep apnea syndrome.

MeSH terms

  • Animals
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / physiology
  • Hypoventilation / complications
  • Hypoventilation / physiopathology
  • Leptin / administration & dosage
  • Leptin / deficiency
  • Leptin / pharmacology*
  • Male
  • Mice
  • Motor Neurons / drug effects
  • Obesity / complications
  • Obesity / physiopathology
  • Phosphorylation / drug effects
  • Polysomnography
  • Respiration / drug effects*
  • Respiratory System / drug effects*
  • Respiratory System / innervation
  • STAT3 Transcription Factor / metabolism
  • Sleep / drug effects*
  • Sleep / physiology*
  • Sleep Apnea, Obstructive / complications
  • Sleep Apnea, Obstructive / physiopathology
  • Solitary Nucleus / cytology
  • Solitary Nucleus / drug effects
  • Solitary Nucleus / physiology


  • Leptin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse