Glucocorticoid excess, the NAD\(^+\) metabolome and energy metabolism

Heaselgrave, Samuel Richard (2023). Glucocorticoid excess, the NAD\(^+\) metabolome and energy metabolism. University of Birmingham. Ph.D.

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Abstract

Glucocorticoids are crucial for healthy metabolic function and regulation of homeostasis. They can also be used as exogenous medical treatments to treat a plethora of conditions. However, sustained glucocorticoid excess is extremely detrimental to metabolic health and function, ultimately resulting in the condition, Cushing’s syndrome. These consequences are often dependent upon the presence of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Whether global markers of energy metabolism or the metabolically vital molecule nicotinamide adenine dinucleotide (NAD\(^+\)) are also affected by glucocorticoid excess, and whether 11β-HSD1 is required to mediate them, remains unclear. Additionally, it is unknown if NAD\(^+\) metabolome augmentation, through nicotinamide riboside (NR), is a viable therapeutic strategy to combat sustained glucocorticoid excess. Through in vivo investigation with male and female C57BL/6J (wild type, WT) and 11β-HSD1 knock out mice, this thesis identifies the existence of a 11β-HSD1 dependent mechanism by which glucocorticoid excess elevates markers of energy metabolism whilst also altering parts of the NAD\(^+\) metabolome, in a tissue specific and/or sex specific manner. However, NR treatment does not attenuate any of these effects. These findings show energy metabolism and NAD\(^+\) disruption are consequences of sustained glucocorticoid excess, however whether they contribute to other effects of glucocorticoid excess and the exact genomic or non-genomic mechanisms involved remains undetermined. Findings also provide further evidence supporting 11β-HSD1 inhibition to prevent the consequence of glucocorticoid excess whilst also questioning the viability of NAD\(^+\) metabolome augmentation as a treatment strategy.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):