The effects of glucocorticoids on brown fat : physiological and molecular studies

Sammanfattning: Brown adipose tissue (BAT) is the main site for non-shivering thermogenesis in most mammals. The BAT-specific uncoupling protein-1 (UCP1) uncouples substrate oxidation from ATP production and hereby decreases metabolic efficiency. Currently, the search is on for factors that decrease BAT activity and hereby contribute to the development of obesity and obesity-related diseases. Antagonizing these could thus provide therapeutic benefits.Glucocorticoids are a class of steroid hormones that signal through the nuclear glucocorticoid receptor (GR) and play a role in glucose homeostasis, lipid metabolism and the immune response. Various studies in lean rodents have reported that exogenously administrated glucocorticoids increase BAT weight, fat content and lipid droplet size, and reduce GDP-binding to BAT, NE turnover in BAT and total BAT UCP1 mRNA and protein. In genetically obese ob/ob mice and fa/fa rats that exhibit hypercortisolism, adrenalectomy improves BAT morphology and increases BAT activity. Human studies on the effects of glucocorticoids on BAT are scarce, but indicate a decrease in BAT activity after prolonged hypercortisolism.The mechanisms behind the suppressive effects of glucocorticoids on BAT remain unclear. Research in rodents has shown that glucocorticoids may decrease sympathetic output from the central nervous system to BAT in situations of eucortisolism, hereby reducing its thermogenic activity. On the other hand, in vitro experiments show cell autonomous effects of glucocorticoids on the β-adrenergic signalling pathway and a dose-dependent suppression of UCP1 transcription mediated by the GR.It remains to be determined in which physiological situations either of these two pathways mediate the suppressive effects of glucocorticoids on BAT. Moreover, more research is needed into the intracellular signalling of glucocorticoids in brown adipocytes.