almorexant and Body-Weight

The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model.. The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated.. The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals.. In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities.

Topics: Acetamides; Animals; Body Weight; Bone Development; Eating; Ghrelin; Growth Disorders; Homeostasis; Isoquinolines; Leptin; Male; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Rats; Rats, Sprague-Dawley; Respiration; Sleep; Sleep Apnea Syndromes; Sleep, REM; Wakefulness

Chronic upper airway obstruction (UAO) elicits a cascade of complex endocrine derangements that affect growth, sleep, and energy metabolism. We hypothesized that elevated hypothalamic orexin has a role in maintaining ventilation during UAO, while at the same time altering sleep-wake activity and energy metabolism. Here, we sought to explore the UAO-induced changes in hypothalamic orexin and their role in sleep-wake balance, respiratory activity, and energy metabolism.. The tracheae of 22-day-old Sprague-Dawley rats were surgically narrowed; UAO and sham-operated control animals were monitored for 7 weeks. We measured food intake, body weight, temperature, locomotion, and sleep-wake activity. Magnetic resonance imaging was used to quantify subcutaneous and visceral fat tissue volumes. In week 7, the rats were sacrificed and levels of hypothalamic orexin, serum leptin, and corticosterone were determined. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and respiration was also explored.. UAO increased hypothalamic orexin mRNA and protein content by 64% and 65%, respectively. UAO led to 30% chronic sleep loss, excessive active phase sleepiness, decreased body temperature, increased food intake, reduction of abdominal and subcutaneous fat tissue volume, and growth retardation. Administration of almorexant normalized sleep but induced severe breathing difficulties in UAO rats, while it had no effect on sleep or on breathing of control animals.. In upper airway obstruction animals, enhanced orexin secretion, while crucially important for respiratory homeostasis maintenance, is also responsible for chronic partial sleep loss, as well as considerable impairment of energy metabolism and growth.

Topics: Acetamides; Airway Obstruction; Animals; Body Temperature; Body Weight; Corticosterone; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Intracellular Signaling Peptides and Proteins; Isoquinolines; Leptin; Locomotion; Male; Neuropeptides; Orexins; Rats; Rats, Sprague-Dawley; Respiration; Sleep; Sleep Stages; Subcutaneous Fat, Abdominal; Wakefulness