Greater replication and differentiation of preadipocytes in inherited corticosteroid-binding globulin deficiency

Abstract

Glucocorticoids are pivotal for adipose tissue development. Rodent studies suggest that corticosteroid-binding globulin (CBG) modulates glucocorticoid action in adipose tissue. In humans, both genetic CBG deficiency and suppressed CBG concentrations in hyperinsulinemic states are associated with obesity. We hypothesized that CBG deficiency in humans modulates the response of human preadipocytes to glucocorticoids, predisposing them to obesity. We compared normal preadipocytes with subcultured preadipocytes from an individual with the first ever described complete deficiency of CBG due to a homozygous null mutation. CBG-negative preadipocytes proliferated more rapidly and showed greater peroxisome proliferator-activated receptor-γ-mediated differentiation than normal preadipocytes. CBG was not expressed in normal human preadipocytes. Glucocorticoid receptor number and binding characteristics and 11β-hydroxysteroid dehydrogenase activity were similar for CBG-negative and normal preadipocytes. We propose that the increased proliferation and enhanced differentiation of CBG-negative preadipocytes may promote adipose tissue deposition and explain the obesity seen in individuals with genetic CBG deficiency. Furthermore, these observations may be relevant to obesity occurring with suppressed CBG concentrations associated with hyperinsulinemia.

Food-intake regulation during stress by the hypothalamo-pituitary-adrenal axis

“…Cushing's syndrome is the best evidence. A mutation of the corticosterone-binding globulin with increased free GC levels has been also associated with a higher waist-to-hip ratio and a higher risk on obesity development (Barat et al, 2005;Joyner et al, 2003). The abdominal obesity is specially important as obese with a more peripheral body fat distribution does not show health risk markers (Nieuwenhuizen and Rutters, 2008).…”

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“…This is especially important with respect to GC-stimulated differentiation of pre-adipocytes and insulin resistance of mature adipocytes, with the former effect increasing fat content and the latter reducing the tissue sensitivity to insulin. For instance, preadipocytes from an individual with CBG deficiency had increased proliferation and enhanced differentiation compared to normal cells [121], which may be responsible for the increased adiposity in CBG deficiency. This notion was observed in genetic models of obesity and insulin resistance.…”

Functional Implication of an Arg307Gly Substitution in Corticosteroid-Binding Globulin, a Candidate Gene for a Quantitative Trait Locus Associated With Cortisol Variability and Obesity in Pig

“…Total or partial deficiency of CBG detected in some patients is associated with obesity and leads to a compensatory response of the hypothalamus-pituitary-adrenal axis to balance plasma free-cortisol concentrations (Emptoz-Bonneton et al 2000;Torpy et al 2001). However, this feedback control does not compensate for the lack of CBG at the tissue level, especially in adipose tissue, as preadipocytes from CBG-deficient patients display increased proliferation and enhanced differentiation compared to control cells (Joyner et al 2003). Excess CBG leading to elevated total and free cortisol levels may also induce increased adiposity as reported in our previous study.…”