The role of glucocorticoid receptor signaling in metabolic disease: a matter of time and sex

Li, S. (2025)

Doctoral Thesis

This dissertation explores how glucocorticoid signaling contributes to metabolic diseases, emphasizing the influence of sex differences and circadian rhythms. Chronic glucocorticoid elevation is linked to muscle atrophy, glucose intolerance, and obesity, particularly in patients using synthetic glucocorticoids for inflammatory conditions. We investigated sex differences in glucocorticoid-induced muscle atrophy utilizing a mouse model. While both sexes exhibit muscle mass loss, female mice experience more significant functional decline. In Chapter 3, we examine how timing of glucocorticoid treatment affects metabolic outcomes. Administration of glucocorticoids misaligning with rodents' circadian rhythm worsened insulin resistance, whereas the treatment with the natural glucocorticoid cycle reduces metabolic side effects. These findings suggest that chronotherapy aligning with natural circadian rhythm could minimizing adverse effects. In Chapter 4, we explore the role of glucocorticoid signaling in polycystic overay syndrome (PCOS), a condition characterized by androgen excess and metabolic dysfunction. Androgens enhance GR expression, worsening glucose intolerance. While preventive GR blockade mitigates metabolic issues, therapeutic intervention is less effective. This study highlights the overlap between androgen and glucocorticoid pathways, suggesting that early GR modulation may help manage PCOS-related metabolic dysfunction.

• Glucocorticoids
• Muscle atophy
• Glucose metabolism
• Circadian rhythm
• Sex difference
• Polycystic ovary syndrome
• Glucocorticoid receptor

• All authors: Li, S.
• Supervisor: Meijer, O.C.
• Co-supervisor: Kroon, J.
• Committee: Rensen, P.C.N.; Dubois, V.; Kervezee, L.; Boon, M.R.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2025-04-23
• ISBN (print): 9789465221120