Abnormal Regulation of Hepatic Glucocorticoid Receptor mRNA and Receptor Protein Distribution in the Obese Zucker Rat

Abstract

JENSON, MICHELLE, GAIL KILROY, DAVID YORK AND DOUGLAS BRAYMER. Abnormal regulation of hepatic glucocorticoid receptor mRNA and receptor proteinn distribution in the obese Zucker rat. Obes Res. 1996;4:133-143. This study examines the cellular distribution of glucocorticoid receptor (GR) protein and transcriptional activity of the GR gene in the liver of Zucker obese (fa/fa) rats. Immunoabsorption and Western blotting showed an increase in nuclear GR protein level but a decrease in cytosolic GR levels in the liver of 5-week old male obese rats (fa/fa) compared to their lean Iittermates (Fa/-). These changes were confirmed by receptor-ligand binding assays with [3H]-dexamethasone which showed a sixfold increase in average obese nuclear GR binding and a twofold reduction in cytosolic GR binding. HSP90, but not HSP70, levels were reduced in hepatic cytosol and increased in hepatic nuclei prepared from obese rats. Using Northern blot analysis of hepatic RNA, we demonstrated a twofold increase in hepatic mRNAs for GR, malic enzyme (ME), tyrosine aminotransferase (TAT), and glyceraldehyde 3-P04-dehydrogenase in the obese rat. Increased transcription of GR and ME mRNAs in obese nuclei was indicated in nuclear run-on assays. These data suggest that there is increased nuclear localization of GR in the liver of obese rats and suggests that increased transcription

Effect of hyperlipidemia on 11β-hydroxysteroid-dehydrogenase, glucocorticoid receptor, and leptin expression in insulin-sensitive tissues of cats

“…This is in accordance with results from rats, in which high-fat diets led to significantly elevated serum leptin concentrations and significant changes in body mass [38,45]. Feeding a high-fat diet to cats induced a moderate but not significant elevation in leptin levels [26].…”

“…The importance of the GC receptor in the pathogenesis of insulin resistance, obesity and HC is emphasized by several rodent studies: in diabetic db/db mice and obese Zucker rats increased hepatic GC receptor mRNA expression caused hyperglycemia and insulin resistance. Conversely, selective inactivation of GC receptor improved insulin resistance and obesity in diabetic animals and patients with hypercortisolism [37][38][39][40]. Therefore, one could argue that the decreased GC receptor expression seen in this study exhibits a self protecting mechanism of the tissue against the increased tissue cortisol.…”

Glucocorticoids, metabolism and metabolic diseases

“…Indeed, liver-specific GR antagonism by antisense oligonucleotides or synthetic compounds is sufficient to cause substantial improvement of hyperglycemia and dyslipidemia in animal models of type II diabetes [51][52][53][54]. Also, the GR itself has been found to be over-expressed in hepatocytes of diabetic rodent models, in particular in its nuclear, active fraction [55,56], further substantiating the notion that the GC-GR axis plays a critical role in determining hepatic glucose output via its regulatory function for the promoter activity of gluconeogenic enzyme genes. Consistently, inhibition of GR expression by agonists for nuclear receptor liver X receptor (LXR) results in an amelioration of the diabetic phenotype in obese, db/db mice [57].…”

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

“…The GR belongs to a cytoplasmic nuclear hormone receptor that is a steroid ligand-activated transcription factor (Carson-Jurica et al 1990, Rosen & Miner 2005. In rodents, increased hepatic GR mRNA induces activation of the key hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) leading to hyperglycemia and insulin resistance in diabetic db/db mice and obese Zucker rats (Jenson et al 1996, Stafford et al 2001, Liu et al 2005. Pharmacological evidence further validates that selective inactivation of GR improves insulin resistance and obesity in these diabetic animals and patients with Cushing's syndrome (Okada et al 1992, Sartor & Cutler 1996, Watts et al 2005.…”