Role of Orexin in Abnormal Sleep and Growth Retardation Induced by Upper Airway Obstruction in Rats. Ariel Tarasiuk
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1 Role of Orexin in Abnormal Sleep and Growth Retardation Induced by Upper Airway Obstruction in Rats Ariel Tarasiuk Supported By The Israel Science Foundation (ISF), 164/2006, 160/2010, 31/2014 Sleep Disorders Center & Department of Physiology Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Israel
2 Pediatric Sleep disordered breathing (SDB) Upper airway obstruction (AO). 1) Sleep disorder. 2) Energy metabolism abnormalities. 3) Growth retardation. 4) Bone mass loss in adults. Neurobehavioral Cardiovascular
3 Little is known about the mechanisms leading to abnormal sleep, growth and energy metabolism in SDB. There is no unifying hypothesis explaining this phenomena.
4 Animal model UAO The juvenile Upper Airway Obstruction (UAO). UAO is induced by tracheal narrowing It lead to growth retardation, sleep disorder and energy metabolism abnormalities.
5 UAO lead to adaptive changes in the respiratory system: Increased respiratory muscle contractility. Changes in control of ventilation. These adaptations are essential Especially during sleep. Condition where respiratory muscle force is not sufficient to support ventilation. Tarasiuk et al J Apple Physiol 1991; Greenberg et al Am J Respir Crit Care Med 1995
6 Orexin (are hypothalamic neuropeptides OXA and OXB) Increase wakefulness, caloric intake and locomotion activity. Play primary role in control of ventilation (CO 2 response). Orexin acting peripherally through orexin receptor 1 (OX1R) play a role in bone metabolism/architecture by modulating local ghrelin levels. Wei et al Cell Metabolism 2014 OX1R modulate mesenchymal stem activity. Shift from cartilage to marrow adipocyte and vise versa
7 Hypotheses Upregulation of hypothalamic orexin play a role in maintaining ventilation, while at the same time altering sleep and energy metabolism in UAO. Upregulation of OX1R in the growth plate will lead to abnormal growth plate architecture/ metabolism.
8 Study protocol Animals - Juvenile male rats UAO surgery - Day 22 (Immediately post nursing). MRI Bone Micro CT Sleep recordings
9 Tarasiuk et al Sleep 2014 Orexin receptor antagonist (Oral gavage of)
10 Tarasiuk et al Sleep 2014 Arterial blood gas (behaving animals) Control UAO PO 2 (mm Hg) 88.6± ±3.2 PCO 2 (mm Hg) 38.8± ±3.1 ph (units) 7.4± ±0.01 HCO 3- (meq/l) 23.5± ±1.7 Hemoglobin (g/dl) 13.9± ±0.6
11 Hypothalamic orexin mrna Protein level 64% Sleep/Wake Activity Wake = +30% Slow wave sleep = -13% REM = -57% Sleep fragmentation & Partial sleep loss Dual Orexin Antagonist Almorexant (300 mg/kg) Wake = -30% Slow wave sleep = +25% REM = no change Tarasiuk et al Sleep 2014
12 Body weight & Food intake Tarasiuk et al Sleep 2014 Body weight -34% Body length -20% Intestine length/body length +22% +20% (Tarasiuk et al Sleep 2014)
13 Abdominal MRI Abdominal adiposities tissue Tarasiuk et al Sleep 2014
14 Daily Ghrelin, leptin & corticosterone levels Ghrelin - stimulate food intake and wakefulness. Leptin - suppress food intake and promote sleep.
15 Somatic growth and bone architecture Micro-CT (distal trabecular femur) Left tibia growth plate Masson trichrome Safranin O stain orange-red cartilage proteoglycans
16 Growth plate orexin 1 (OX1R) and ghrelin receptors (GHSR1a)
17 Early bone development markers
18 Dual Orexin Antagonist Improve Sleep and Growth Plate Width להוסיף תמונה
19 Conclusions Enhanced hypothalamic orexin secretion is crucially important for respiratory homeostasis maintenance in UAO. Elevation of orexin and OX1R lead to sleep disorder, impairment of energy metabolism and growth retardation. Abnormal sleep in UAO was associated with slower weight gain, despite elevated food intake, and increased plasma ghrelin and leptin level. Ultimately insufficient to compensate for inadequate sleep.
20 Collaborators Prof. Yeal segev Department of Microbiology and Immunology Graduated students Nilli Bardugo (PhD) Orit Porati (MSc) Avishag Levi (MsC) Ari Yahalom (MsC) Ariel Troib (PhD) Mohammad H. Assadi (PhD student)
21 GH acts directly and/or via IGF-1 on tissues. Hypothalamus The GHRH Slow Wave Sleep GHRH Pituitary GH Liver IGF-1 EGP
22 Stimulation of GHRH only partially restore growth This indicate that other pathways are involved in this growth retardation.
23 Growth Plate לוחית הגדילה
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