Date of Award

Spring 2023

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Claudia Grillo

Abstract

Obesity has created a devastating public health crisis that severely affects both quality of life and exacerbates serious health conditions such as heart disease and diabetes. For this reason, better treatments are critical, yet there are very few. The systems that regulate our metabolism and food consumption are intricate, complex, and still poorly understood, as the brain integrates peripheral signals with central neural networks to control our energy balance. One of these peripheral signals, leptin, holds great promise as a way to treat obesity but has been ineffective in patients with obesity. Therefore, our goal is to better understand the mechanisms leptin utilizes to control food intake to develop better targets for appetite regulation. This study characterizes a novel, leptin-dependent pathway that begins in the dorsal raphe nucleus (DRN) and projects to the arcuate (ARC) nucleus of the hypothalamus, using serotonin (5-HT) to drive its anorectic effects. This novel pathway may hold significance in understanding the complete picture of how leptin affects the brain to control food intake. I conducted several studies to test the overarching hypothesis of this proposal that 5-HT released from the leptin receptor expressing neurons in the DRN works to reduce food intake through the ARC. First, neuroanatomical tracing tools were used to map projections from leptin receptor expressing 5-HT DRN neurons to the ARC. Second, pharmacology and optogenetics were used to activate these leptin receptor expressing DRN neurons to evaluate their effect on food intake. Third, the role of 5-HT was examined by in vivo microdialysis following leptin administration to the DRN, as well as using pharmacological depletion of 5-HT. Finally, a 5-HT2C receptor antagonist was administered to the ARC prior to leptin in the DRN to examine the role of these receptors in leptin’s anorectic effects. Examination of this neural pathway will ultimately lead to a stronger understanding of appetite regulation in the central nervous system, allowing for alternate targets for the treatment of obesity.

Available for download on Thursday, May 15, 2025

Share

COinS