Genomic and Non-Genomic Actions of Glucocorticoids on Adipose Tissue Lipid Metabolism

Abstract

Glucocorticoids (GCs) are hormones that aid the body under stress by regulating glucose and free fatty acids. GCs maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). WAT stores energy as triglycerides, while BAT uses fatty acids for heat generation. The multiple genomic and non-genomic pathways in GC signaling vary with exposure duration, location (adipose tissue depot), and species. Genomic effects occur directly through the cytosolic GC receptor (GR), regulating the expression of proteins related to lipid metabolism, such as ATGL and HSL. Non-genomic effects act through mechanisms often independent of the cytosolic GR and happen shortly after GC exposure. Studying the effects of GCs on adipose tissue breakdown and generation (lipolysis and adipogenesis) leads to insights for treatment of adipose-related diseases, such as obesity, coronary disease, and cancer, but has led to controversy among researchers, largely due to the complexity of the process. This paper reviews the recent literature on the genomic and non-genomic effects of GCs on WAT and BAT lipolysis and proposes research to address the many gaps in knowledge related to GC activity and its effects on disease.

Keywords: adipose tissue; brown adipose tissue; corticosterone; dexamethasone; diabetes; genomic mechanism; glucocorticoid; glucocorticoid receptor; lipid metabolism; lipolysis; metabolic disorder; non-genomic mechanism; obesity; white adipose tissue.

Figure 1

Genomic effects of GCs on lipolysis in WAT. The genomic effects occur through the binding of GC to the GR and the movement of GC-GR to the nucleus, where they can regulate the transcription of genes related to lipid metabolism, including lipolytic enzymes ATGL and HSL. Other regulators of lipid metabolism, such as pioglitazone (peroxisome proliferator-activated receptor gamma ligand) and growth hormone (GH), have counterbalancing effects to glycerol release that alter the way GCs induce lipolysis.

Figure 2

Effects of GCs on lipid metabolism in BAT. The effects of GCs on lipolysis in BAT appear to be independent of UCP1 and the GR. Multiple potential mechanisms in BAT include the effects of the extracellular FA availability on GCs’ induced lipid accumulation.

Figure 3

Non-genomic effects of GCs on lipolysis in WAT. The non-genomic effects are independent of ATGL/HSL gene or protein expression. Multiple suggested non-genomic mechanisms include AKT-PDE3B pathway, the ANGPTL4-cAMP pathway, and the insulin-PI3K pathway. The ANGPTL4 is a GR target gene that may be classified as inducing possible non-genomic mechanisms through its activation in cAMP. The non-genomic pathways affect lipolysis by regulating activity of HSL/perilipin through affecting phosphorylation. 11β-HSD1: 11-β hydroxysteroid dehydrogenase type, AKT: Protein Kinase B, PDE3B: phosphodiesterase 3B, ANGPTL4: Angiopoietin-like protein 4, cAMP: Cyclic adenosine monophosphate, PI3K: Phosphatidylinositol 3-kinase, BA3R: Beta-3 adrenergic receptor.