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The obesity epidemic is a major health and economic burden in the United States with approximately 35% of the population classified as overweight or obese, and annual medical costs for obese persons is approximately 150% more relative to lean persons. Obesity can develop when energy intake exceeds energy expenditure, and the stomach-derived orexigenic hormone ghrelin has emerged as a key mediator of this balance in humans due to its increased circulating concentrations in obese persons and involvement in regulating ingestive behaviors and numerous metabolic processes. We and others have previously shown ghrelin is sufficient to drive both appetitive (i.e. the searching for and storage of food) and consummatory (i.e. the consumption of food) ingestive behaviors and metabolic processes such as gut motility, nutrient partitioning, glycemia, and body temperature. The ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR), is widely expressed in the brain and on gastrointestinal vagal sensory neurons, and neuronal GHSR knockout affords protection against diet-induced obesity and glycemic dysregulation. Hence, the absence of ghrelin signaling results in a profoundly beneficial metabolic profile and elucidating the mechanisms through which ghrelin mediates ingestive behaviors and metabolic processes may provide novel obesity treatment options. Targeted central/peripheral ghrelin injections or neuronal-specific GHSR restoration in otherwise GHSR-null mice has provided mounting evidence for discrete neuroanatomical mechanisms regulating ghrelin’s behavioral and metabolic effects, yet a thorough interrogation of these distributed signaling pathways in the context of ghrelin-mediated ingestive behaviors or metabolism has yet to be conducted. Here, we utilize two rodent models (Siberian hamsters and mice) to examine the mechanisms through which ghrelin regulates ingestive behaviors and overall metabolic homeostasis. We find that central ghrelin signaling is necessary and sufficient to drive appetitive and consummatory ingestive behaviors and that hypothalamic agouti-related peptide is critical for ghrelin-induced appetitive, but not consummatory, behaviors. In addition, we identify a novel, peripheral sensory neuron ghrelin signaling pathway that is critical for regulating energy expenditure and metabolic homeostasis. Thus, this dissertation provides a significant step forward for our understanding of ghrelin signaling and the discrete mechanisms through which it mediates behaviors and metabolic processes.

During the past few decades, obesity has risen significantly in the United States with recent estimates showing that 65% of Americans are overweight and 30% are obese. This increase is a major cause for concern because obesity is linked to many secondary health consequences that include type II diabetes, heart disease, and cancer. Current approaches to the obesity problem primarily have focused on controls of food intake and have been largely unsuccessful. Food, however, almost always has to be acquired (foraging) and frequently is stored for later consumption (hoarding). Therefore, a more comprehensive approach that includes studying the underlying mechanisms in human foraging and food hoarding behaviors could provide an additional target for pharmaceutical or behavioral manipulations in the treatment and possibly prevention of obesity. Neuropeptide Y (NPY) is a particular peptide that provides a potent orexigenic drive to alter foraging, food hoarding (appetitive ingestive behaviors) and food intake (consummatory ingestive behaviors) in variety of species. NPY is predominantly produced in the arcuate nucleus of the hypothalamus (ARC) and has extensive efferent projections throughout the brain. Two target nuclei of ARC-NPY, the paraventricular nucleus of the hypothalamus (PVH) and perifornical area (PFA), have been shown to mediate the effect of NPY on food intake in laboratory rats and mice, but nothing is known about the effect of ARC-NPY on foraging and food hoarding. In addition, the action of specific NPY receptor subtypes within these two nuclei for these behaviors is unknown. Even though ARC-NPY is one of the main sources of input into the PVH and PFA, it is not known if this NPY fiber projection mediates alterations in appetitive and consummatory ingestive behaviors. Therefore, the purpose of this dissertation is to test 1) if NPY within the PVH or PFA controls appetitive, as well as, consummatory ingestive behaviors, 2) if NPY Y1 receptors within the PVH or PFA differentially control appetitive or consummatory ingestive behaviors, and 3) if NPY from the ARC is necessary for the control of appetitive and consummatory ingestive behaviors.