Altered lipid partitioning and glucocorticoid availability in CBG‐deficient male mice with diet‐induced obesity

Abstract

Objective: To evaluate how deficiency in corticosteroid-binding globulin (CBG), the specific carrier of glucocorticoids, affects glucocorticoid availability and adipose tissue in obesity. Methods: C57BL/6 (WT) and CBG-deficient (KO) male mice were fed during 12 weeks with standard or hyperlipidic diet (HL). Glucocorticoid availability and metabolic parameters were assessed. Results: Body weight and food intake were increased in KO compared with WT mice fed a standard diet and were similar when fed a HL diet. Expression of CBG was found in white adipose tissue by immunochemistry, real-time PCR, and Western blot. In obesity, the subcutaneous depot developed less in KO mice compared with WT, which was associated with a minor adipocyte area and peroxisome proliferatoractivated receptor-c expression. Conversely, the epididymal depot displayed higher weight and adipocyte area in KO than in WT mice. CBG deficiency caused a fall of hepatic 11b-hydroxysteroid dehydrogenase type 2 expression and an increase in epidymal adipose tissue, particularly in HL mice. Conclusions: Deficiency in CBG drives lipid partitioning from subcutaneous to visceral adipose depot under a context of lipid excess and differentially modulates 11b-hydroxysteroid dehydrogenase type 2 expression.

Emerging Role of Corticosteroid-Binding Globulin in Glucocorticoid-Driven Metabolic Disorders

“…There is a discrepancy between our reports and those of Petersen et al (28) and Gulfo et al (29), on the levels of free GC measured after stress, when the rise in GC is important. The latter found either no significant differences in free GCs after stress between WT and Cbg KO or increased levels for Cbg KO, whereas we have shown that Cbg KO show a hypoglucocorticoid response to stress compared to WT (31, 32), including after chronic stress (33).…”

“…In our studies, total and free corticosterone levels were measured not only in the morning (9:00 a.m.) but also in the evening (9:00 p.m.) when the secretion of GC is at its peak (mice are nocturnal animals). In the morning, we found increased free GC levels in Cbg KO as in the study by Gulfo et al (29) or Petersen et al (28), but in the evening, this genotype difference was no longer present because the higher total GC levels in WT compensated the increased free GC percentage in Cbg KO. Thus, the lack of genotype effect on mRNA expression in basal conditions is expected since when free GC are high (at night), there are no genotype differences in their levels.…”

“…However, the weight loss, as well as liver gene expression estimated by gene arrays, was found equivalent between genotypes after 36 h of food deprivation. Using the same mouse model, a recent study examined the metabolic consequences of a 12-week-long very HFD (60 vs. 18% kcal fat for control diet) on body weight, white adipose tissue, and liver (29). Under the very HFD, total body weight gain and food intake were similar in both Cbg KO and WT groups.…”

“…To explain this paradox, they hypothesized that Cbg KO mice have become insensitive to high levels of free GC, but they did not provide data on the mechanism involved. On their side, Gulfo et al (29) found higher free GC levels in Cbg KO mice, both under normal and very HFD, associated with lower thymus and higher adrenals weight, thereby pleading in favor of chronically elevated free GC levels. Taken together, the data from the different groups are confusing regarding whether Cbg KO mice are a model of hyper- or hypocorticosteronism.…”

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

“…CBG-deficient mice show lower total corticosterone levels and higher free corticosterone and ACTH 15 , and greater adrenal gland size 16 , i.e., they have an altered response to the HPA axis. In addition, the sexual dimorphism that elicits increased levels of total corticosterone in females with respect to males is eliminated by CBG deficiency 17,18 .…”