Date of Award
Summer 2024
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Biological Sciences
First Advisor
Deanna Arble
Second Advisor
Michelle Mynlieff
Third Advisor
Chelsea Cook
Abstract
Obesity is a complex disease that is defined by an excess amount of body fat. Obesity can have physical, neurological, and endocrine effects and detrimental effects on health. Some obese co-morbid conditions, such as type 2 diabetes have known mechanisms, while others, such as sleep disordered breathing do not. Moreover, there are common respiratory diseases associated with obesity, such as obstructive sleep apnea and obesity hypoventilation syndrome. Furthermore, individuals with obesity or obstructive sleep apnea have a blunted hypercapnic ventilatory response (HCVR) (120), which is indicative of impaired chemosensitivity, as HCVR is a measure of how well an individual responds to CO2 challenges. Despite a multitude of risks, obese physiology and how its components contribute to respiratory disease have yet to be fully elucidated. Correlational studies with individuals with sleep disordered breathing indicate that those individuals have a preference for high fat foods (250, 261). These data suggest it could be either sleep disturbances or intermittent hypoxia (IH) that cause an increased preference for high fat foods. A key unanswered question is to what extent does IH affect macronutrient intake. To answer this question, we used a mouse model to investigate how the timing of IH exposure affects body weight, macronutrient selection, and metabolism, both during IH and post-IH (Chapter 2). Overall, our data suggest that the timing of IH, but not IH itself, may affect how an individual consumes macronutrients. Leptin, a hormone increased with obesity, is associated with cardiometabolic disease (271). It is unclear if it is leptin insensitivity or other aspects of obesity that make individuals more susceptible to cardiometabolic diseases when experiencing IH. To determine the relative involvement of leptin and/or obesity in the cardiometabolic outcomes of IH, we exposed lean WT mice, obese leptin-deficient ob/ob mice, and calorically restricted ob/ob mice to IH (Chapter 3). Overall, we found that caloric restriction protects ob/ob mice against IH-induced cardiac impairment independent of leptin signaling. Mounting evidence indicates that changes in the brain, coincident with obesity, play a significant role in the ventilatory response. To investigate the neuronal populations responsible for affecting the hypercapnic ventilatory response and breathing in the context of obesity, we used multiple genetic mouse models and DREADD (designer receptor exclusively activated by designer drugs) technology (Chapter 4). Overall, we found that obesity-related neuronal populations in both the arcuate nucleus and periaqueductal gray contributed to the HCVR. We propose that hypothalamic modulation of the midbrain periaqueductal gray results in obesity-related reductions in chemosensitivity. Understanding the neuronal underpinnings that account for the bidirectional link between obesity and breathing is expected to significantly expand our understanding of respiratory physiology and, in turn, has great potential to lead to novel therapeutic treatments for obesity-associated breathing disorders.