Discovery of Glucocorticoid Receptor-β in Mice with a Role in Metabolism

Abstract

AbstractGlucocorticoid hormones control diverse physiological processes, including metabolism and immunity, by activating the major glucocorticoid receptor (GR) isoform, GRα. However, humans express an alternative isoform, human (h)GRβ, that acts as an inhibitor of hGRα to produce a state of glucocorticoid resistance. Indeed, evidence exists that hGRβ contributes to many diseases and resistance to glucocorticoid hormone therapy. However, rigorous testing of the GRβ contribution has not been possible, because rodents, especially mice, are not thought to express the β-isoform. Here, we report expression of GRβ mRNA and protein in the mouse. The mGRβ isoform arises from a distinct alternative splicing mechanism utilizing intron 8, rather than exon 9 as in humans. The splicing event produces a form of β that is similar in structure and functionality to hGRβ. Mouse (m)GRβ has a degenerate C-terminal region that is the same size as hGRβ. Using a variety of newly developed tools, such as a mGRβ-specific antibody and constructs for overexpression and short hairpin RNA knockdown, we demonstrate that mGRβ cannot bind dexamethasone agonist, is inhibitory of mGRα, and is up-regulated by inflammatory signals. These properties are the same as reported for hGRβ. Additionally, novel data is presented that mGRβ is involved in metabolism. When murine tissue culture cells are treated with insulin, no effect on mGRα expression was observed, but GRβ was elevated. In mice subjected to fasting-refeeding, a large increase of GRβ was seen in the liver, whereas mGRα was unchanged. This work uncovers the much-needed rodent model of GRβ for investigations of physiology and disease.