Minireview: New Molecular Mediators of Glucocorticoid Receptor Activity in Metabolic Tissues

Abstract

The glucocorticoid receptor (GR) was one of the first nuclear hormone receptors cloned and represents one of the most effective drug targets available today for the treatment of severe inflammation. The physiologic consequences of endogenous or exogenous glucocorticoid excess are well established and include hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting. However, at the molecular and tissue-specific level, there are still many unknown protein mediators of glucocorticoid response and thus, much remains to be uncovered that will help determine whether activation of the GR can be tailored to improve therapeutic efficacy while minimizing unwanted side effects. This review summarizes recent discoveries of tissue-selective modulators of glucocorticoid signaling that are important in mediating the unwanted side effects of therapeutic glucocorticoid use, emphasizing the downstream molecular effects of GR activation in the liver, adipose tissue, muscle, and pancreas.

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

“…It remains to be established experimentally whether Dex may lead to selective induction of Foxa3 in fat tissue because of the unique accessibility of GR to binding elements present at the Foxa3 promoter though specific cofactors available in fat (13,17,46). It is conceivable that GR may rely on tissue-specific factors to activate Foxa3, given that GR previously has been shown to form distinct complexes in a tissueand agonist-selective manner, leading to differential geneexpression programs (1). Further ChIP analyses combined with biochemical studies will elucidate the specific components of the tissue-selective complexes bound at the GRE present at the Foxa3 promoter.…”

“…Foxa3 | GR signaling | dexamethasone | fat expansion | adipose tissue G lucocorticoids (GCs) are a class of steroid hormones that bind to the GC receptor (GR) and exert broad physiological functions (1). Unliganded GR has been shown to reside in the cytoplasm in association with chaperone complexes and to translocate into the nucleus upon binding of agonists to activate or transrepress gene expression at select promoters (2).…”

“…For example, GC treatment has been shown to increase hepatic gluconeogenesis and lipogenesis and to cause muscle atrophy (1,6). Specifically, in adipose tissues GCs have been shown to increase adiposity in human and rodents by promoting fat differentiation (7,8) and inhibiting energy expenditure by decreasing brown adipose tissue (BAT) thermogenesis (9,10) and by suppressing the browning of subcutaneous fat (11).…”

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

“…The main biological role of the natural GCs is to supply enough blood glucose into circulation to guarantee the central nervous system functions and compensatory responses of the organism during conditions of acute stress or reduced food intake [4] . For this, GCs promotes several systemic actions that include i) increase in the hepatic glucose production, ii) reduction in the peripheral glucose uptake into adipose tissue and skeletal muscles, iii) increase in the fat lipolysis and muscle proteolysis to provide enough substrates for gluconeogenesis, and iv) attenuation of the insulin secretion from pancreatic β cells [4] .…”

“…For this, GCs promotes several systemic actions that include i) increase in the hepatic glucose production, ii) reduction in the peripheral glucose uptake into adipose tissue and skeletal muscles, iii) increase in the fat lipolysis and muscle proteolysis to provide enough substrates for gluconeogenesis, and iv) attenuation of the insulin secretion from pancreatic β cells [4] .…”