Altering adipose tissue responses to glucocorticoids through genetic manipulation of the 11B-HSD1 gene

McCabe, Emma Louise (2016). Altering adipose tissue responses to glucocorticoids through genetic manipulation of the 11B-HSD1 gene. University of Birmingham. Ph.D.

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Abstract

Glucocorticoids (GC) are regulators of permissive and adaptive physiology. GC excess can lead to metabolic complications including type 2 diabetes and metabolic syndrome. Levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which reactivates GC. 11β-HSD1 activity is deregulated in a range metabolic disorders in which GC levels are normal. I hypothesise that 11β-HSD1 is a critical regulator of adipose tissue sensitivity to GC excess, and that through 11β-HSD1 depletion adipose tissue will be desensitised to GCs and resist metabolic deregulation.
Using 11β-HSD1 KO mice in a model of GC excess we demonstrate that 11β-HSD1 mediates the adverse metabolic effects of GC excess on a global scale.
I further investigated brown adipose tissue (BAT) with GC excess. I demonstrate that 11β-HSD1 regulates BAT activity and mitochondrial function, possibly suppressing BATs thermogenic potential. I extended my studies to examine the potential for white adipose tissue (WAT) to assume markers of thermogneic and mitochondrial function in the context of 11βHSD1 and GC excess. The data suggest 11β-HSD1 may suppress the potential of WAT to assume a ‘BAT-like’ profile.
These data show 11β-HSD1 loss of function confers a protective phenotype with GC excess and demonstrates it’s role in mediating the metabolic phenotype associated with GCs. These data support the idea that GCs can influence BAT and WAT thermogenic potential and may increase knowledge of metabolic dysregulation in humans suffering form GC excess. This therefore highlights 11β-HSD1 as an exciting potential target for the treatment for the metabolic disease associated with GC excess.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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