Role of FKBP51 and FKBP52 in Glucocorticoid Receptor Regulated Metabolism
Glucocorticoids (GCs) are important regulators of carbohydrate and lipid metabolism, serving to antagonize the actions of insulin. As such, GC antagonists have held promise in the treatment of diabetes and metabolic syndrome. Yet, widespread and potent side effects have precluded such usage. To identify new and selective targets of GC action, we tested the roles of FKBP51 and FKBP52 in glucocorticoid receptor (GR)-controlled metabolism using FKBP - ablated mice. FKBP51 and FKBP52 serve as GR co-chaperones and we show that loss of FKBP51 increases GR transcriptional activity, while FKBP52 loss decreases it. Using high fat diet (HF) as a metabolic stress, we have observed the following. In response to HF, no differences between WT and FKBP52 (+/–) animals occurred in body weight and visceral adiposity. However, high fat fed FKBP52 (+/–) mice became hyperglycemic, hyperinsulinemic and showed increased lipid accumulation in the liver. They also had reduced expression of GR - regulated gluconeogenic enzymes. We hypothesize that impairment of GR liver activity due to loss of FKBP52 decreases the expression of gluconeogenic enzymes, leading to substrate redistribution of pyruvate to de novo lipid synthesis and lipid accumulation. Increased lipid accumulation in the liver causes reduced insulin clearance and, ultimately, insulin resistance. In contrast, FKBP51 (–/–) animals fed HF did not become hyperglycemic. Instead, they were resistant to diet-induced obesity, with greatly reduced visceral adiposity under HF diet conditions. No difference was noted in the hepatic lipid accumulation of FKBP51 (–/–) mice on high fat diet. They had normal blood glucose and insulin levels with all diets, but did show low plasma triglyceride and free fatty acid levels under these conditions. Consistent with the phenotype, analysis of genes involved in the muscle lipid metabolism revealed elevated expression of CPT-1 and PDK4. Based on the results obtained so far, we are currently investigating the hypothesis that ablation of FKBP51 leads to over-activation of GR in the muscle, thereby increasing the expression of genes regulating lipid oxidation and/or energy expenditure. Our results are the first demonstration that FKBP proteins selectively control metabolic processes.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:glucocorticoid steroid immunophilins metabolism diabetes obesity
Date of Publication:01/01/2008