Modulation in Wistar Rats of Blood Corticosterone Compartmentation by Sex and a Cafeteria Diet

María Del Mar Romero,José Antonio Fernández-López,Maria Del Mar Grasa,Fredrik Holmgren-Holm,Marià Alemany,Montserrat Esteve,Xavier Remesar

doi:10.1371/journal.pone.0057342

Abstract

In the metabolic syndrome, glucocorticoid activity is increased, but circulating levels show little change. Most of blood glucocorticoids are bound to corticosteroid-binding globulin (CBG), which liver expression and circulating levels are higher in females than in males. Since blood hormones are also bound to blood cells, and the size of this compartment is considerable for androgens and estrogens, we analyzed whether sex or eating a cafeteria diet altered the compartmentation of corticosterone in rat blood. The main corticosterone compartment in rat blood is that specifically bound to plasma proteins, with smaller compartments bound to blood cells or free. Cafeteria diet increased the expression of liver CBG gene, binding plasma capacity and the proportion of blood cell-bound corticosterone. There were marked sex differences in blood corticosterone compartmentation in rats, which were unrelated to testosterone. The use of a monoclonal antibody ELISA and a polyclonal Western blot for plasma CBG compared with both specific plasma binding of corticosterone and CBG gene expression suggested the existence of different forms of CBG, with varying affinities for corticosterone in males and females, since ELISA data showed higher plasma CBG for males, but binding and Western blot analyses (plus liver gene expression) and higher physiological effectiveness for females. Good cross- reactivity to the antigen for polyclonal CBG antibody suggests that in all cases we were measuring CBG.The different immunoreactivity and binding affinity may help explain the marked sex-related differences in plasma hormone binding as sex-linked different proportions of CBG forms.

Highlights

Glucocorticoids play a critical role in the development and maintenance of the metabolic syndrome [1]
Males weighed more than females independently of diet, and increased their body weights in a higher percentage than females, the differences being more marked in the animals treated with cafeteria diet, as expected
The establishment of relationships between circulating corticosteroids, pose a considerable problem because of their rhythms [34], variations in binding vs. free proportions [35], tissue interconversion between 17-hydroxy(active) or 17-keto forms of corticosteroids, and the intrinsic problems of evaluating steroid hormones. This question has become critical in the context of the study of inflammatory processes related with the metabolic syndrome

Summary

Introduction

Glucocorticoids play a critical role in the development and maintenance of the metabolic syndrome [1]. Glucocorticoids hamper the inflammatory immune response [2], induce insulin resistance [3,4], enhance overall lipogenesis and fat deposition [5], and increase the liver glucose output [6], usually at the expense of amino acids [7]. Glucocorticoids waste body protein [8] and minerals [9], and there is a generalized consensus that their activity is increased in the metabolic syndrome [10]. Glucocorticoid excretion is more related to stress and stress-related conditions [11] than to obesity and diabetes, which usually show normal circulating serum levels [12]. CBG levels or their affinity for glucocorticoids are decreased [22]; insulin resistance and inflammation contribute to decrease CBG levels [20,23]

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Conclusion