Dissertation
Body weight Regulation and the hypothalamus: RS1421085, IRX3, and bBeyond
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2025
DOI: 10.25820/etd.008203
Abstract
My thesis work has three main areas of inquiry: determining the metabolic impact of obesity-associated single nucleotide polymorphism (SNP) rs1421085, investigating tanycyte subtypes using computational analysis, and characterizing FGF21 sites of production and action. All these topics center on understanding the regulation of energy balance.
The SNP rs1421085 carries one of the highest associated risks with obesity in the genome. Using a novel mouse model harboring the risk-allele for rs1421085 (OA-SNPrs142/rs142), we examined its impact on energy balance and explored IRX3 as a potential mediator of the metabolic effects of rs1421085. OA-SNPrs142/rs142 mice are more susceptible to diet-induced obesity than mice lacking the risk-allele for rs1421085 (OA-SNP+/+) and have increased food intake and decreased energy expenditure under human obesogenic conditions. Additionally, OA-SNPrs142/rs142 mice have elevated Irx3 mRNA expression compared to OA-SNP+/+ mice in the brain with prominent expression in metabolically relevant regions such as the posterior hypothalamus (PH) and dorsal vagal complex (DVC). Increased IRX3 in the PH, but not the DVC, resulted in increased body weight and food intake. Finally, we found that increased expression of IRX3, specifically in IRX3+ neurons, decreases excitability and activity of IRX3+ neurons in the PH but not the DVC. Interestingly, inhibition of IRX3+ PH neurons led to increased body weight and food intake. These data demonstrate that OA-SNPrs142/rs142 mice recapitulate the body weight phenotype associated with rs1421085 in humans; and that increased IRX3 in the posterior hypothalamus, as seen in OA-SNPrs142/rs142 mice, is sufficient to drive some of the metabolic effects of the SNP.
The ability to maintain energy homeostasis is necessary for survival. Recently, a specialized ependymogial cell called tanycytes has been appreciated as a regulator of energy homeostasis. Tanycytes line the third ventricle and thus, are physically at the interface of brain communication with peripheral organs and have been proposed to mediate the transport of circulating hormones from the third ventricle into the parenchyma of the hypothalamus. Despite the important role tanycytes have been proposed to play in mediating communication from the periphery to the brain, we understand very little about the ontology and function of these cells due to their limited abundance and lack of ability to genetically target this cell population reliably. To overcome these hurdles, we integrated existing hypothalamic single cell RNA sequencing data, focusing on tanycytes, to allow for more in-depth characterization of tanycytic cell types and their putative functions.
Fibroblast growth factor 21 (FGF21) is an endocrine hormone that acts on tissues throughout the body to control metabolic processes. Both FGF21 and another endocrine FGF, FGF15/19, signal to sites of action by binding to the co-receptor β-klotho (KLB), which enables interaction between these different FGFs and their preferred FGF receptor. KLB is present in numerous tissues involved in metabolic regulation; however, the precise cell identities and spatial distribution of these cells has not been fully characterized. Furthermore, while circulating FGF21 is primarily produced by the liver, recent publications have indicated that brain-derived FGF21 impacts memory and learning. In this study, we utilize reporter mice to comprehensively determine the expression pattern of Klb and Fgf21 throughout the entire murine body. These findings represent a critical reference for future studies aimed at identifying major FGF targets in both peripheral and central tissues and to determine the significance of nonhepatic FGF21 production.
Details
- Title: Subtitle
- Body weight Regulation and the hypothalamus: RS1421085, IRX3, and bBeyond
- Creators
- Andrew I Sullivan
- Contributors
- Matthew J Potthoff (Advisor)Jon Resch (Committee Member)Deniz Atasoy (Committee Member)Jacob Michaelson (Committee Member)Kyle Flippo (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacology
- Date degree season
- Autumn 2025
- DOI
- 10.25820/etd.008203
- Publisher
- University of Iowa
- Number of pages
- xv, 166 pages
- Copyright
- Copyright 2025 Andrew I. Sullivan
- Language
- English
- Date submitted
- 09/16/2025
- Description illustrations
- illustrations, tables, graphs,
- Description bibliographic
- Includes bibliographical references (pages 148-166).
- Public Abstract (ETD)
- My thesis work has three main areas of inquiry: determining the impact of obesity-associated SNP rs1421085, investigating the subtypes of a specialized brain cell using large datasets, and determining where a metabolic protein (FGF21) is produced and where it can act. While covering a wide range of topics, all these inquiries center on understanding the regulation of energy balance (how much energy an organism takes in and expends). The single nucleotide polymorphism (SNP) rs1421085 carries one of the highest associated risks with obesity in the human genome. This SNP is proposed to alter body weight through a protein called IRX3. Using mice that have the obesity-associated allele of rs1421085, I investigated if rs1421085 causes obesity, if rs1421085 increases IRX3, and if increased IRX3 in the brain can cause obesity. While there are countless systems in the body that regulate energy balance, recent research has demonstrated that a unique and understudied cell population in the brain called tanycytes also contribute to energy balance. However, we understand very little about the subtypes of tanycytes because tanycytes are few and difficult to work with. To study tanycyte subtypes, we combined existing single cell sequencing datasets that contained tanycytes and investigated how each subtype was different. Fibroblast growth factor 21 (FGF21) is a hormone that acts throughout the body to control metabolic processes. FGF21 requires a receptor called KLB to act. Using unique mice that report where a gene is expressed, I determined where FGF21 and KLB are made throughout the body.
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985135148102771
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