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Author ORCID Identifier

https://orcid.org/0000-0002-4593-7708

Date Available

6-17-2026

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Pharmacology

Faculty

Terry D. Hinds Jr.

Faculty

Olivier Thibault

Abstract

Glucocorticoids are vital steroid hormones that govern metabolism, stress responses, and immune functions through intricate, tissue-specific mechanisms, both genomic and non-genomic. These hormones bind to the glucocorticoid receptor (GR), which then acts as a transcription factor to modulate gene expression. Chronic elevation of glucocorticoid levels may lead to glucocorticoid resistance, resulting in adiposity, inflammation, and insulin resistance, thereby adversely affecting multiple metabolic tissues. Whether produced endogenously or administered exogenously, excessive, chronic glucocorticoid concentrations impair glucocorticoid signaling. Although there are two primary isoforms of the receptor, GR⍺ and GRβ, only GR⍺ interacts with glucocorticoids.Through the research conducted in this dissertation, we examined the mechanisms underlying glucocorticoid resistance, including a high GRβ-to-GRα ratio, as well as its associated physiological effects. The discussion initially emphasizes the influence of sex differences and signaling complexity on disease risk and treatment outcomes, highlighting the need for more precise glucocorticoid therapies. Then we discuss an investigation that examined how GRβ affects lipid metabolism and inflammatory signaling pathways in the liver. Building upon these findings, we explored how GRβ modifies glucocorticoid-responsive mechanisms through gene transcription, using RNA-sequencing, and advanced PamGene kinase signaling pathways. Collectively, these studies demonstrate that glucocorticoid resistance mediated by GRβ influences hepatic lipidome remodeling, alters insulin-signaling kinase pathways, and subsequently promotes inflammatory signaling, thereby modulating kinase-dependent glucocorticoid responsiveness.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.324

Archival?

Archival

Funding Information

This research was not supported by grant funding. However, grant from the American Heart Association 25PRE1374495, supported G.J.M salary 2025-2026.

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