Master of Science (MS), Wright State University, 2017, Physiology and Neuroscience

The carotid bodies (CB), the primary peripheral chemoreceptors, respond to changes in blood gases with neurotransmitter release, thereby increasing carotid sinus nerve firing frequency and ultimately correcting the pattern of breathing. It has previously been demonstrated that acute application of the adipokine leptin caused perturbations of intracellular calcium and membrane ion movement in isolated CB Type I cells (Pye et al, 2015) and augmented the response of the intact CB to hypoxia (Pye et al, 2016). This study's aim was to examine, in-vivo, if elevated leptin modulated CB function and breathing. Rats were fed high-fat chow or control chow for 16-weeks. High-fat fed (HFF) animals gained significantly more weight compared to control fed (CF) animals (n=18; p<.001; 512.56 g ± 14.70 g vs. 444.11 g ± 7.09 g). HFF animals also had significantly higher serum leptin levels compared to CF (n=18; p<.0001; 3.05 ng/mL ± 0.24 ng/mL vs. 1.29 ng/mL ± 0.12 ng/mL). Whole-body plethysmography was used to test the acute hypoxic ventilatory response (HVR) in unrestrained, conscious animals. HFF animals had an attenuated 2nd-phase of the HVR when compared to CF (n=18; p<.05; 710.1 ± 41.9 mL kg-1 min-1 vs. 855.4 ± 44.05 mL kg-1 min-1). CB Type I cells were isolated and intracellular calcium measured; no significant differences in the cellular hypoxic responses between groups were observed. These data show differences in the 2nd-phase of the HVR caused by high fat feeding are unlikely to be caused by an action of leptin on the Type I cells. However the possibility remains that leptin may have in-vivo postsynaptic effects on the carotid sinus nerve; this remains to be investigated.

Committee: Christopher Wyatt Ph.D. (Advisor); Eric Bennett Ph.D. (Other); David Ladle Ph.D. (Committee Member); Mark Rich M.D./Ph.D. (Committee Member); Robert Fyffe Ph.D. (Other) Subjects: Biology; Cellular Biology; Neurosciences; Physiology

PhD, University of Cincinnati, 2011, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

The regulation of food intake involves the coordinated action of multiple mechanisms including energy balance and mechanisms independent of caloric needs. In the case of the latter, referred to as non-homeostatic regulation, hedonic value of palatable foods and the motivation to obtain them are an important component. The mesolimbic reward pathway, a major component of drug addiction neurobiology, is implicated in the control of reward-based feeding behaviors. The lateral hypothalamic orexin system modulates a variety of systems including arousal, food intake and reward-related behaviors. Due to its extensive projections to many brain regions and diverse roles in behavioral systems, orexin is a prime candidate for the regulation of mesolimbic function and reward-based feeding behaviors. Moreover, orexin is well positioned to serve as a feed-forward system to integrate metabolic and visceral signals from the basal hypothalamus with learned reward-stimulus associations to affect mesolimbic function. However, this possibility remains to be understood. In these studies, we hypothesized that orexin promotes reward-based feeding behaviors and does so by acting on the mesolimbic circuit. First, we assessed the hypothesis that orexin is a critical promoter of reward-based feeding in models of conditioned and unconditioned responding for palatable food using behavioral pharmacology in rats. These data demonstrate that orexin signaling is necessary for promoting reward-based feeding under conditioned and unconditioned responding paradigms independent of energy status. Conditioned expectation of both palatable food and drug reinforcers activates the hypothalamic orexin system and stimuli previously associated with palatable food intake induce overconsumption in rodents. We hypothesized that context dependent expectation of palatable food and chow-meal feeding differentially activate the orexin system and its target regions. We assessed cue induced neuronal activation in orexin (open full item for complete abstract)

Committee: Stephen Benoit (Committee Chair); James Herman (Committee Member); Randall Sakai (Committee Member); Matthias Tschoep (Committee Member); Stephen Woods (Committee Member) Subjects: Neurology

Doctor of Philosophy, Case Western Reserve University, 2008, Physiology and Biophysics

Lipid accumulation in non-adipose tissue may play a role in the pathophysiology of heart failure. Accumulation of myocardial lipids and ceramide is associated with decreased contractile function, mitochondrial oxidative phosphorylation, and electron transport chain (ETC) complex activities. We hypothesized that the progression of heart failure would be exacerbated by elevated myocardial lipids and a ceramide-induced inhibition of oxidative phosphorylation and ETC activities. Rats were fed a normal (14% kcal fat) or high fat diet (60% kcal fat) for two weeks. Heart failure was induced by coronary artery ligation. High fat feeding prior to ligation surgery increased surgical mortality, consequently the study was modified so that all rats remained on the normal diet prior to ligation surgery. Following ligation surgery, rats were fed a normal (HF) or high fat diet (HF+FAT) for eight weeks. Sham-operated animals were fed a normal diet. State 3 respiration and ETC complex activities were increased in subsarcolemmal mitochondria (SSM) of HF+FAT, despite elevated myocardial ceramide. No further progression of left ventricular dysfunction was evident in HF+FAT.We then investigated possible mechanisms by which high fat improved mitochondrial function in heart failure. We hypothesized that a high fat diet during heart failure would increase mitochondrial fatty acid oxidation and state 3 respiration by activating genes involved in fatty acid uptake and utilization. Rats underwent ligation or sham surgery and were fed a normal (SHAM, HF) or high fat diet (SHAM+FAT, HF+FAT) for eight weeks. State 3 respiration using lipid substrates was elevated in SSM of HF+FAT and correlated to increased activities of short-, medium- and long-chain acyl-CoA dehydrogenase. This was associated with improved myocardial contractility as assessed by LV +dP/dt max. Despite decreased medium-chain acyl-CoA dehydrogenase mRNA in HF and HF+FAT, protein content was unchanged. Though high fat improved myo (open full item for complete abstract)

Committee: Margaret Chandler PhD (Advisor); Nosek Thomas PhD (Committee Chair); Hoppel Charles MD (Committee Member); Fisher Steven MD (Committee Member); Romani Andrea PhD (Committee Member); Nagy Laura PhD (Committee Member); Kirwan John PhD (Committee Member) Subjects: Anatomy and Physiology