METABOLIC DYSFUNCTION IN CHRONIC INTERMITTENT HYPOXIA- ROLE OF HYPOTHALAMIC PEPTIDES

Date

2013-04-12

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Nedungadi, T.Prashant

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Purpose: Obstructive sleep apnea (OSA) is associated with an increase in cardiovascular risk factors that includes metabolic syndrome including hypertension. Our model of Chronic Intermittent Hypoxia (CIH) mimics the hypoxemia and the persistently elevated arterial pressure seen in OSA patients. Here we examine, if metabolic dysregulation associated with CIH is initiated through neuropeptides in central metabolic sites, arcuate nucleus (ARH) and paraventricular nucleus (PVN) of the hypothalamus. Methods: Body weight, daily food intake were measured. Biochemical assays were used for measuring hormonal levels. Metabolic studies to identify glucose tolerance, insulin tolerance and pre-disposal to diabetes were performed. Laser Capture Microdissection followed by real time RT-PCR were carried out for measurement of neuropeptide and receptor mRNA levels in the ARH and PVN along with immunohistochemical studies. Results: Body weight change was higher in the controls (CON) compared to CIH (CON: 25 ± 2.5; CIH: 16 ± 2.7). Food intake was significantly lower for CIH rats compared to controls (p < 0.03) Corticosterone (CORT) was elevated 6 fold during CIH. CIH caused reduction in fasting blood glucose levels, and improved glucose tolerance. Laser capture microdissection of ARH and PVN followed by RT-PCR showed significant increase in ΔFosB mRNA in both PVN and ARH (PVN CON: 1± 0.1 vs PVN CIH: 1.96 ± 0.14; ARH CON: 1 ± 0.18 vs ARH CIH: 2.5 ± 0.5). Neuropeptide Y mRNA levels was significantly decreased after CIH in ARH. However leptin levels were significantly higher in the PVN of CIH rats. Preliminary immunohistochemical observations suggest elevated FosB in both these regions. Conclusions: This is the first study to examine if metabolic dysfunction associated with CIH, characteristic feature of sleep apnea, is initiated through key metabolic sites in the brain. Metabolic dysregulation associated with CIH might be initiated centrally through peptides in the ARH-PVN hypothalamic circuitry.

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