Corticosteroid-Binding Globulin is expressed in the adrenal gland and its absence impairs corticosterone synthesis and secretion in a sex-dependent manner

Abstract

Corticosteroid-binding globulin (CBG) is synthesized by the liver and secreted into the bloodstream where binds to glucocorticoids. Thus CBG has the role of glucocorticoid transport and free hormone control. In addition, CBG has been detected in some extrahepatic tissues without a known role. CBG-deficient mice show decreased total corticosterone levels with missing of classical sexual dimorphism, increased free corticosterone, higher adrenal gland size and altered HPA axis response to stress. Our aim was to ascertain whether CBG deficiency could affect the endocrine synthetic activity of adrenal gland and if the adrenal gland produces CBG. We determined the expression in adrenal gland of proteins involved in the cholesterol uptake and its transport to mitochondria and the main enzymes involved in the corticosterone, aldosterone and catecholamine synthesis. The results showed that CBG is synthesized in the adrenal gland. CBG-deficiency reduced the expression of ACTH receptor, SRB1 and the main genes involved in the adrenal hormones synthesis, stronger in females resulting in the loss of sexual dimorphism in corticosteroid adrenal synthesis, despite corticosterone content in adrenal glands from CBG-deficient females was similar to wildtype ones. In conclusion, these results point to an unexplored and relevant role of CBG in the adrenal gland functionality related to corticosterone production and release.

Corticosteroid-binding-globulin (CBG)-deficient mice show high pY216-GSK3β and phosphorylated-Tau levels in the hippocampus

“…The knockout mouse model used in the present study exhibits reduced serum levels of total-CORT compared to those in cbg +/+ mice (90-175nM in cbg -/- vs. 200-300nM in cbg +/+ ) and higher amounts of free-CORT compared to cbg +/+ mice (10-30nM in cbg -/- vs. 3-5nM in cbg +/+ ) measured at the nadir of the circadian rhythm and under basal conditions as previously reported [ 26 , 28 , 30 , 31 ]. In contrast, we observed similar levels of total-CORT, but significantly higher free-CORT levels in the hippocampus of cbg -/- mice compared to those in cbg +/+ mice, which represented 93% of the total CORT.…”

“…Similar corticosterone levels have also been found in the adrenal gland of cbg -/- compared to cbg +/+ mice, particularly in females. This was found despite the downregulation in the expression of enzymes involved in CORT synthesis as a consequence of CBG deficiency, suggesting a role of CBG in mediating tissue CORT release [ 31 ]. We investigated whether cbg -/- mice hippocampi showed increased glucocorticoid activity.…”

“…Polymorphisms affecting FKBP5 affinity for CORT receptors have been associated with HPA axis disorders, such as anxiety or stress altered responses [ 21 , 58 , 59 ]. As noted above, CBG-deficient mice have an altered HPA axis with elevated ACTH plasma levels [ 26 ] and a diminished adrenal response that entails adrenal hyperplasia [ 28 , 31 ], with impairment of CORT synthesis and secretion [ 31 ]. Collectively, our current findings, in addition to those previously reported, reinforce the hypothesis that CBG has an unexplored role in CORT action and homeostatic regulation of the HPA axis.…”

“…In addition, CBG-deficient mice lose the usual sexual dimorphism of total-CORT circulating levels, and both sexes show similar values [ 29 , 30 ]. Adrenal gland functionality is altered in CBG-deficient mice with diminished expression of genes involved in CORT synthesis, in spite of the increased adrenal CORT concentration in females, indicating an active role of CBG in regulating CORT adrenal excretion [ 31 ]. In contrast, it has also been shown that CBG-deficient mice present a more inflamed white adipose tissue [ 32 ].…”

“…In contrast, it has also been shown that CBG-deficient mice present a more inflamed white adipose tissue [ 32 ]. We previously described the expression of CBG in the white adipose tissue, lung and adrenal gland [ 28 , 30 , 31 , 33 ]. Lung CBG expression in males is greater than that in females, in contrast to the expression observed in the liver [ 30 , 34 ].…”