title: Predominately glucocorticoid agonist actions of RU-486 in young specific-pathogen-free Zucker rats.
abstract: Previous studies have demonstrated antiglucocorticoid actions for the progesterone receptor antagonist RU-486. In one study, daily administration of this drug for 2 wk decreased food intake (FI) and body weight gain (delta BW) in obese, but not lean, conventionally housed 5-wk-old female Zucker rats. We recently found that 2-wk administration of RU-486 attenuated delta BW in lean but not obese 12-wk-old male Zucker rats without affecting FI. To examine the actions of RU-486 and its effects on FI and delta BW in young (5 wk old) specific-pathogen-free (SPF) male and female Zucker rats, RU-486 was administered at 30 mg.kg-1.day-1 subcutaneously for 14 days. RU-486 did not affect FI in obese or lean male or female rats. RU-486 increased adrenal weight (P < 0.05) overall and in lean female rats and modestly decreased inguinal fat weight overall and in obese female rats (P < 0.01), suggesting some antiglucocorticoid activity in these animals. However, RU-486 also decreased thymus weight by 18-31% (P < 0.0001), increased plasma glucose by 10-16 mg/dl (P < 0.002), and increased plasma insulin by 47% in obese male rats (P < 0.028), demonstrating glucocorticoid agonist actions for the drug. Plasma corticosterone (B) and adrenocorticotropic hormone (ACTH) were elevated in vehicle-treated obese female and male rats by 150-360% (P < 0.0025) and 32-38% (P < 0.05), respectively, compared with lean rats. RU-486 treatment lowered the elevated plasma B and ACTH levels in obese female and male rats (both P < 0.02 vs. vehicle), a glucocorticoid agonist effect. We conclude that in young SPF Zucker rats 1) RU-486 administration does not alter FI or delta BW, 2) RU-486 has predominately glucocorticoid agonist actions in several tissues, 3) obese animals have increased hypothalamic-pituitary-adrenal (HPA) axis activity (plasma B and ACTH), and 4) RU-486 administration suppresses the HPA axis in obese rats.
authors.affiliation: Department of Nutrition, School of Veterinary Medicine, University of California, Davis 95616, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Havel
authors.forename: B L
authors.initials: BL
authors.lastname: Busch
authors.forename: D L
authors.initials: DL
authors.lastname: Curry
authors.forename: P R
authors.initials: PR
authors.lastname: Johnson
authors.forename: M F
authors.initials: MF
authors.lastname: Dallman
authors.forename: J S
authors.initials: JS
authors.lastname: Stern
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D005856:Germ-Free Life; D005938:Glucocorticoids / Q000819:agonists*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006728:Hormones / Q000097:blood; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D009765:Obesity / Q000473:pathology / Q000503:physiopathology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker / Q000254:growth & development*; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D005938:Glucocorticoids; D006727:Hormone Antagonists; D006728:Hormones; D015735:Mifepristone