Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats.

STUDY OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities.

Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats.

STUDY OBJECTIVES: 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. INTERVENTIONS: 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. MEASUREMENTS AND RESULTS: 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. CONCLUSIONS: 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.

Metabolite and mineral analyses of cotton near-isogenic lines introgressed with QTLs for productivity and drought-related traits.

Quantitative trait loci (QTLs) for yield and drought-related traits were exchanged via marker-assisted selection between elite cultivars of two cotton species, Gossypium barbadense (GB) cv. F-177 and Gossypium hirsutum (GH) cv. Siv'on. Three of the resultant near-isogenic lines (NILs), each introgressed with a different QTL region, expressed an advantage in osmotic adjustment (OA) and other drought-related traits relative to their recipient parents. These NILs and the parental genotypes were field-grown under well-watered and water-limited conditions, and characterized for their metabolic and mineral compositions. Comparisons were then made between (1) GB and GH genotypes, (2) the contrasting water regimes and (3) each NIL and its recipient parent. Hierarchical clustering analysis clearly distinguished between GB and GH genotypes based on either metabolite or mineral composition. Comparisons between well-watered and water-limited conditions in each of the genotypes showed differing trends in the various solutes. The greater concentrations of potassium, magnesium and calcium under water stress, when compared with well-watered conditions, may have enhanced OA or osmoprotection. All NILs exhibited significantly modified solute composition relative to their recipient parents. In particular, increased levels of alanine, aspartic acid, citric acid, malic acid, glycerol, myoinositol, threonic acid, potassium, magnesium and calcium were found under drought conditions in one or more of the NILs relative to their recipient parents. The increased values of these solutes could contribute to the superior capacity of these NILs to cope with drought.