Contribution of glucocorticoid–mineralocorticoid receptor pathway on the obesity-related adipocyte dysfunction
Highlights
► Glucocorticoids induced adipocytokine dysregulation and ROS in adipocytes. ► Such changes were rectified by MR blockade, not by GR antagonist. ► In human, adipose MR was increased in parallel with body mass index. ► Glucocorticoid-MR pathway may contribute to the obesity-related disorders.
Introduction
Accumulating clinical evidence indicates that excessive accumulation of visceral fat is closely associated with obesity-related metabolic disorders [1]. Our group demonstrated that overproduction of reactive oxygen species (ROS) in obese fat tissue leads to the dysregulation of adipocytokines and accelerates the development of metabolic disorder [2].
Several studies demonstrated that activation of MR promotes inflammation, proliferation, and fibrosis via ROS generation. As we and other group previously indicated [3], [4], mineralocorticoid receptor (MR) blockade by MR antagonist eplerenone (EP) ameliorated insulin resistance and adipocytokine dysregulation, and reduced ROS and macrophage infiltration in adipose tissue of obese mice. In adipocytes, MR activation caused the increase of ROS and the adipocytokine dysregulation, while MR blockade improved such changes [3]. Collectively, adipose MR may play an important role in metabolic disorder in the development of obesity.
The MR binds not only to aldosterone but also to glucocorticoid with equal affinity [5]. In addition, the affinities of glucocorticoids (cortisol in humans, corticosterone in rodents) for MR are 10-fold higher than those for glucocorticoid receptor (GR) [6]. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts cortisone (an inactive corticoid) into cortisol (an active corticoid), is highly expressed in adipocytes [7]. These evidences suggest that glucocorticoid action could be exhibited mainly through MR in adipocytes, but adipose glucocorticoid-MR pathway has not been fully elucidated. We here tested the glucocorticoid action in adipocytes by using antagonists for MR and GR. The effect of glucocorticoid on adipocytokines and adipose ROS was also examined. In addition, mRNA expressions for important proteins, including MR, GR, PPARγ2, NADPH oxidase subunit p22, adiponectin, and 11β-HSD1, were directly compared in subcutaneous and visceral fat of human subjects, according to their BMI.
Section snippets
Animals
Male BKS.Cg-m+/+Leprdb/J (db/db) obese mice were purchased from Charles River Laboratories (Charles River Japan Inc., Yokohama, Japan). Their respective lean control male db/m + heterozygous littermates were purchased from the same supplier. Mice were sacrificed at 10 weeks of age by intraperitoneous administration of 5% pentobarbital in one shot. The experimental protocol was approved by the Ethics Review Committee for Animal Experimentation of Osaka University School of Medicine. This study also
Expression of corticoid receptors and their target genes in obese model mice
The mRNA levels of corticoid receptors and their target genes were examined in white adipose tissue (WAT) of db/db and db/m + mice (Fig. 1). MR mRNA level of db/db mice was significantly higher than that of db/m + mice (Fig. 1A). In parallel with the change of MR, serum- and glucocorticoid-induced kinase 1 (Sgk1), a MR target gene [12], was also significantly increased in db/db mice (Fig. 1B). On the other hand, both GR and regulated in DNA damage and development 1 (REDD1), a GR target gene [13],
Discussion
The main findings of the present study were: (1) MR and its target gene mRNA levels were significantly increased in obese adipose tissues. (2) Physiological concentration of glucocorticoid caused the increase of adipose ROS and the adipocytokine dysregulation. (3) Glucocorticoid-induced ROS and adipocytokine dysregulation were significantly reversed by blockade of MR, not by GR antagonism. (4) In human visceral adipose tissue, MR mRNA level was increased as the BMI increased, while no apparent
Funding
This work was supported by Grants-in-Aid for Scientific Research (C) No. 22590979 (to N. M.), and Scientific Research on Innovative Areas No. 22126008 (to T. F.).
Acknowledgments
We are grateful to Pfizer Inc (New York, NY) for providing eplerenone. We thank Miyuki Nakamura for the excellent technical assistance. We also thank all members of the III laboratory (Adiposcience laboratory), Department of Metabolic Medicine, Osaka University for helpful discussions on the project.
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