Hepatic Glucocorticoid Receptor Action and Glucose Homeostasis

One of the major metabolic functions of glucocorticoids (GC) is to maintain circulating glucose levels during stress, as glucose is the preferred energy source for the brain. Because of their potent anti-inflammatory and immune modulatory activities, GC are frequently used to treat inflammatory and autoimmune diseases. Chronic GC exposure, which can be a result of long-term GC pharmacotherapy and prolonged stress, however, causes undesired adverse effects that include hyperglycemia and insulin resistance. These adverse effects limit the application of GC therapy. GC act through an intracellular GC receptor (GR), a transcriptional regulator, to modulate the transcriptional rate of specific genes to exert physiological responses. The liver is a major target tissue of GC to modulate glucose homeostasis. In this review, we discuss the mechanisms of GR-activated transcription of genes involved in glucose metabolism and how hepatic GR primary target genes participate in the regulation of insulin sensitivity and glucose homeostasis. Transcriptional coregulators involved in GR-regulated transcription of glucose metabolism genes and signaling pathways specifically activated upon chronic GC exposure to induce glucose disorders are introduced. Metabolic profiles of liver-specific GR knockout mice are also reviewed. Finally, individual-specific GC responses and mechanisms underlying these phenomena are discussed. Overall, more extensive studies of the mechanisms of GR-regulated hepatic glucose homeostasis not only will expand our knowledge of the regulation of metabolic homeostasis but are also critical for developing improved GC pharmacotherapy and novel approaches to tackle metabolic disorders by targeting GR.