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Parlow, Julia Noel Charlene (Toews)

University of British Columbia

Produced by the liver, plasma corticosteroid-binding globulin (CBG) binds glucocorticoids in the blood and regulates their access to target tissues. Glucocorticoids exert sexually dimorphic effects on development, metabolism, stress, and inflammation, but precisely how CBG modulates these actions remains unclear. Here, we examined how disrupting the SerpinA6 gene encoding CBG affects glucocorticoid actions in male and female rats. Initial observations in wild-type animals indicated that females display pubertal increases in adrenal weight in tandem with increases in plasma CBG, whereas no such changes were observed in males. Interestingly, adrenal weight gain was blunted in female rats lacking CBG, such that adrenal growth trajectories became similar between sexes. Loss of CBG also altered the expression of ~4,600 adrenal genes in adult females, but not males, including those related to steroidogenesis and growth. To understand the mechanisms underlying the deficit in adrenal growth associated with CBG deficiency, we then characterized the capacity of female CBG-knockout rats to show compensatory adrenal growth induced by unilateral adrenalectomy. The results of these experiments suggest that CBG normally enhances the proliferation and transdifferentiation of the glucocorticoid-producing region (zona fasciculata) of the adrenal gland, as these responses were blunted in rats without CBG. Because glucocorticoids control liver development and metabolic activities, hepatic transcriptomic profiling revealed a sex-specific effect of CBG ablation to alter the expression of genes related to cholesterol biosynthesis, inflammation, and metabolism in adult females. These studies suggest that the emergence of sex differences in CBG levels during puberty promotes the sexual dimorphism of both liver and adrenal function. Characterization of inflammatory and hypothalamic-pituitary-adrenal (HPA) axis responses to acute lipopolysaccharide and restraint stress continued to underscore how CBG calibrates the HPA axis and glucocorticoid actions in each sex. Interestingly, CBG-deficient males rather than females were particularly sensitive to immune challenge. These studies reveal that CBG shapes the sexual dimorphism of the adrenal and liver as well as responses to stress and inflammation, providing insight into how CBG deficiencies are linked to sex differences in glucocorticoid-dependent diseases.

Text

2024-01-08

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87146

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/