title: Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?
abstract: OBJECTIVE
  Glucocorticoids may contribute to the association between retarded growth in utero and insulin resistance in adulthood. Administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring, which develop glucose intolerance, hyperinsulinaemia and hypercorticosteronaemia. This may be explained by tIssue-specific differences in expression of glucocorticoid receptors (GR) in adult offspring: GR is increased in visceral fat and liver, and decreased in hippocampus and soleus muscle. However, cause and effect between altered GR expression, hypercorticosteronaemia, and hyperinsulinaemia remains to be established.
  
  
  METHODS
  Rats were treated with dex (100 microg/kg per day) or saline during the third week of pregnancy. In 5-8-Month-old male offspring, GR expression in insulin target tIssues was quantified by RNase protection assay in rats that were adrenalectomised (ADX group), sham operated (SHAM group), or adrenalectomised with supra-physiological corticosterone replacement (CORT group) (n=7-8 per group), and in rats treated orally with vehicle, metformin (43 mg/kg per day) or rosiglitazone (1 mg/kg per day), after 3 weeks.
  
  
  RESULTS
  Manipulation of corticosterone concentration did not affect GR mRNA in skeletal muscle or adipose. In liver, sham-operated animals showed lower GR mRNA, but there was no difference between adrenalectomised and hypercorticosteronaemic animals (SHAM 0.11+/-0.01 ratio to beta-actin, vs ADX 0.22+/-0.02, CORT 0.23+/-0.02, (values expressed as means+/-s.e.m.), P<0.001). Rosiglitazone reduced GR mRNA by approximately 30% in liver of dex- and saline-treated offspring (P<0.05), but had no effect on GR in adipose and skeletal muscle. Metformin abolished the 38% up-regulation of liver GR mRNA induced by antenatal dex and also reduced GR mRNA preferentially in muscle of dex-treated animals (0.14+/-0.01 vs 0.10+/-0.01; P=0.03).
  
  
  CONCLUSIONS
  We conclude that neither hypercorticosteronaemia nor hyperinsulinaemia are sufficient to cause the changes in GR expression in dex-programmed rats, implying that these changes may be primary in determining the programmed insulin resistant phenotype. Normalisation of GR expression by metformin may be important in the mode of action of this anti-diabetic agent and may be especially useful to reverse-programmed up-regulation of GR.
authors.affiliation: Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cleasby
authors.forename: Dawn E W
authors.initials: DE
authors.lastname: Livingstone
authors.forename: Moffat J
authors.initials: MJ
authors.lastname: Nyirenda
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D000818:Animals; D001066:Appetite; D001835:Body Weight; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006946:Hyperinsulinism / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008687:Metformin / Q000494:pharmacology; D009929:Organ Size; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones
chemical_list: D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D003907:Dexamethasone; D008687:Metformin; D003345:Corticosterone