Date of Award

12-10-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Dr. Bingzhong Xue

Second Advisor

Dr. Hang Shi

Third Advisor

Dr. Christoph Buettner

Abstract

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.

DOI

https://doi.org/10.57709/13395856

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