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Obstructive sleep apnea syndrome (OSAS), a chronic respiratory disorder affecting as many as 1 in 5 adults, is associated with repetitive collapse of the upper airway during sleep and results in fragmented sleep and intermittent periods of hypoxia and hypercapnia. If left untreated, OSAS increases the risk for hypertension, insulin resistance, metabolic syndrome (MetS) in a manner that is independent of obesity in mid-adulthood. However, it is still unknown if evidence of these relationships is apparent in young adults with OSAS who are otherwise healthy and free of other chronic comorbidities. Objectives: To determine if functional and biochemical evidence of insulin resistance, MetS, and vascular endothelial dysfunction (VED) exists in young, overweight men with OSAS and if the combined effects of obesity and OSAS augments the evidence of chronic disease pathogenesis beyond the effects of obesity alone. Subjects: Subjects were 12 overweight men with OSAS (age = 22.8 ± 0.8; BMI = 32.4 ± 1.0; apnea-hypopnea index (AHI) = 25.4 ± 5.4), 17 overweight men without OSAS (age = 22.5 ± 0.7; BMI = 31.6 ± 1.1; AHI = 2.2 ± 0.3), and 18 normal weight men without OSAS (age = 21.1 ± 0.5; BMI = 22.4 ± 0.4; AHI = 1.9 ± 0.3). Methods: Subjects were evaluated for OSAS using an unsupervised, portable polysomnography test. Total fat and central abdominal fat (CAF) were assessed using dual energy x-ray absorptiometry (DEXA). Fasting blood samples were used to quantify biochemical markers for insulin resistance (glucose, insulin, adiponectin, IL-6, and TNF-á) and endothelial dysfunction (CRP, VEGF, and VEGFR2) using ELISA, RIA, and flow cytometry. MetS was defined according to Adult Treatment Panel III (ATP III) clinical standards. Triglycerides, HDL cholesterol, and glucose were measured using a commercial lipid panel. Resting blood pressure was obtained manually via auscultation. VED was measured via strain gauge plethysmography, with endothelium-dependent vasodilatation being assessed from forearm reactive hyperemia after a 5-minute period of upper arm occlusion. Statistics: One-way ANOVA was used to determine group differences in variables. Two-way ANOVA was used to evaluate group x time interactions during the 2-minute recovery period following upper arm occlusion. Pearson partial correlation was used to assess relationships between continuous variables, with analyses being controlled for CAF or OSAS severity. Spearman correlation was used to assess relationships between number of MetS components present and both indices of adiposity and OSAS severity. Stepwise multiple linear regression analysis was used to determine significant predictors of OSAS severity, insulin resistance, components of the MetS, and endothelial dysfunction. Results: Overweight subjects with OSAS had more CAF, higher fasting triglycerides, and lower serum adiponectin concentrations than both overweight and normal weight non-apneic controls. Furthermore, fasting triglycerides were directly correlated to OSAS severity, even after the influence of central abdominal fat was removed. OSAS severity was an independent predictor of triglyceride levels, and vice versa. Insulin resistance, leptin, insulin, and CRP were all higher in overweight subjects than controls, but no further differences were attributable to severity of OSAS. No differences in IL-6, TNF-á, ADMA, and expression of VEGFR2 were noted between any groups. No group or group x time interaction differences existed in regards to postocclusive reactive hyperemia responses. Conclusions: Young men with OSAS exhibit several unique anthropometric and biochemical abnormalities that may indicate early pathogenesis of or increased risk for future development for cardiovascular and metabolic disorders. Identification and treatment of OSAS at this age may be critical to prevent the onset and progression of these chronic disorders. / Ph. D.

Chronic diseases such as osteoporosis, type 2 diabetes, and cardiovascular disease are diseases of long duration, slow progression, and are by far the leading cause of death worldwide. A growing body of evidence links adverse exposures in early development with an increased risk of chronic diseases in adult life. The studies presented in this dissertation sought to exploit this phenomenon to determine the extent to which gestational and lactational exposure to a high fat diet predisposes the offspring to certain diseases in later life and if the eating habits of adult offspring would be able to mitigate or exacerbate these conditions.  In the study presented in Chapter III, dams fed an atherogenic high fat diet prior to conception and throughout gestation and lactation experienced excess hepatic lipid accumulation and poor birth outcome as characterized by smaller litter sizes and higher post-delivery mortality. In the offspring, gestational and lactational exposure to such a diet resulted in growth restriction and skeletal aberrations indicative of osteoporosis, despite being fed a standard rodent diet post-weaning. We propose that dietary-induced hyperlipidemia, along with pregnancy-associated factors, resulted in fatty liver and subsequently reduced litter sizes and increased early mortality, and that the skeletal aberrations seen in the mature offspring represent dietary-induced inhibition of osteogenesis in favor of adipogenesis. In the study presented in Chapter IV, early exposure to a high fat diet resulted in central obesity, elevated lipid levels, hyperglycemia, and additional markers used in the diagnosis of the metabolic syndrome. Altering the diets of the mature offspring demonstrated that the eating habits of adulthood have the potential to mitigate or exacerbate certain metabolic parameters established earlier in life. Mechanisms contributing to the observed metabolic aberrations could include developmental plasticity and mismatch, catch-up growth, and altered programming of the appetite regulatory network. Collectively, this research suggests that early exposure to a fat-rich diet can lead to metabolic and skeletal aberrations in the adult offspring and adds support to the developmental origins of health and disease hypothesis by finding that adverse nutritional exposures in early life can play a role in the chronic diseases of adulthood. / Ph. D.