Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Matthew R. Hayes

Abstract

With the high prevalence of overweight and obese people in the United States, understanding the endogenous systems that control energy balance is of clinical significance. Given that obesity is driven, in part, by excessive intake of calories, it is critical to understand how food intake is controlled, with the goal of improving pharmacotherapies to treat obesity. A variety of peripherally and centrally-derived neuroendocrine signals are released following ingestion and act in distributed nuclei throughout the brain to control energy balance. The contribution of particular nuclei and the specific cell types within those nuclei that impact energy balance control requires further investigation. This dissertation focuses on novel mechanisms of two anorexogenic hormones, glucagon-like peptide-1 (GLP-1) and amylin, for energy balance control. Given that glutamatergic signaling mediates the intake suppressive effects of GLP-1 and that astrocytes are key modulators of synaptic glutamate levels, I hypothesize that GLP-1 receptors (GLP-1R) are expressed on astrocytes within the nucleus tractus solitarius (NTS), a feeding relevant nucleus, and contribute to energy balance control. Furthermore, neurons within the NTS produce GLP-1 and project widely throughout the brain. Given that the lateral dorsal tegmental nucleus (LDTg), an understudied region in energy balance control, receives projections from the NTS and expresses the GLP-1R, I hypothesize that GLP-1R signaling in the LDTg regulates energy balance control. Traditionally believed to act in the area postrema, the hormone amylin has recently been shown to act in mesolimbic regions to control energy balance, findings that have broadened the perspectives of CNS amylin action. Given that the LDTg binds amylin and receives and send projections to mesolimbic sites, I hypothesized that the amylin receptor signaling in the LDTg modulates energy balance. Collectively, the data presented in this dissertation broaden our understanding of the central nervous system (CNS) action of neuroendocrine signals for energy balance control, in terms of both cell- and nuclei-specificity, providing greater insight into potential targets for the developing improved pharmacotherapies to treat obesity.

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