Electronic Thesis and Dissertation Repository


Doctor of Philosophy




Dr. John Ciriello


Intermittent hypoxia (IH) is a major pathophysiological manifestation of obstructive sleep apnea (OSA). Previous studies have implicated IH in mediating many pathophysiological outcomes associated with OSA. Only few studies have examined IH-induced alterations to central signaling pathways important in cardiovascular and metabolic phenotypes associated with OSA. This thesis employed a rodent model of IH to examine changes to molecular neural pathways associated with metabolic and cardiovascular pathophysiological outcomes of OSA. Acute IH induces a specific negative body energy balance phenotype. This is concomitant to a reduction in body weight and food intake, with an elevation in food conversion efficiency. Increased plasma leptin concentrations also occur immediately following acute IH, which is mirrored by increased activation of leptin-signaling and satiety-inducing molecules within the arcuate nucleus of the hypothalamus (ARC). The effects observed on body energy balance following acute IH are attenuated in the homozygous leptin-deficient KILO rat, suggesting the importance of elevated leptin in mediating the body energy balance responses following acute IH. Over chronic IH exposure, rats have a complex metabolic phenotype, which includes a reduction in body weight and body fat mass. Throughout the chronic period of exposure, animals develop a resistance to the hormone leptin, the primary hallmark for the development of obesity. This is concomitant to increased food intake and fat-standardized plasma leptin concentrations. Within ARC, leptin-associated signaling pathways are not activated, and there is less protein content of satiety-inducing proteins. There is also more protein of a negative regulator of leptin signaling in ARC following chronic IH. Chronic IH also elevates resting blood pressure and reduces baroreceptor reflex gain, which are associated with reduced neuroplasticity markers within the nucleus of the solitary tract. Some of the changes observed over acute IH in these markers are leptin-dependent, as they are abolished in the leptin-deficient KILO rat. Leptin appears to interact at the major sensory site for IH, the carotid body, with the renin-angiotensin system, as blockers captopril and losartan inhibit IH-induced alterations to leptin signaling molecules. This thesis shows potential mechanisms by which IH can induce cardiovascular and metabolic phenotypes observed in OSA patients.