cl-316243 and Hypothyroidism

The effect of hypothyroidism on gastrointestinal beta(1)- and beta(3)-adrenoceptor function and expression was examined in rat ileal smooth muscle preparations. (-)-Isoprenaline and the selective beta(3) agonist disodium (R,R)-5-[2-[[2-3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316234) relaxed both control and hypothyroid tissues in a dose-dependent manner. Responses to isoprenaline were reduced in tissues from hypothyroid rats, as was the shift produced with the beta(3)-adrenoceptor antagonist, 3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate (SR 59230A). No change was seen in responses to CL 316243. Experiments with a selective beta(1)-adrenoceptor antagonist produced results suggesting that isoprenaline did not act at this receptor. Messenger RNA levels for both beta(1)- and beta(2)-adrenoceptors were not affected by hypothyroidism. These results show that, unlike in adipose tissues, ileal beta(1)- and beta(3)-adrenoceptors are not directly regulated by thyroid hormone and that beta(3)-adrenoceptor coupling to the relaxation response is reduced in a rat model of hypothyroidism.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Dioxoles; Hypothyroidism; Ileum; Imidazoles; Isoproterenol; Male; Muscle, Smooth; Propanolamines; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-3; RNA, Messenger

Leptin, the product of the obese gene, is produced by white adipocytes. The release of leptin, as well as leptin mRNA content, was enhanced in adipocytes isolated from hypothyroid rats. The administration of tri-iodothyronine (T3) 8 h before death inhibited leptin release by adipocytes incubated for 6 or 24 h. Direct addition of T3 to pieces of adipose tissue enhanced the loss of leptin mRNA seen over 24 h in the presence of dexamethasone plus the beta3-adrenergic agonist Cl 316,243. In contrast, if pieces of adipose tissue were incubated with dexamethasone plus insulin, enhanced the T3 accumulation of leptin mRNA. These results indicate that T3 enhances net adipocyte leptin mRNA accumulation in a condition that approximates the fed state (presence of insulin) but inhibits leptin mRNA accumulation in a condition that approximates the fasted state (absence of insulin).

Topics: Adipocytes; Adrenergic beta-Agonists; Animals; Dexamethasone; Dioxoles; Glyceraldehyde-3-Phosphate Dehydrogenases; Hypothyroidism; Insulin; Leptin; Lipolysis; Male; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Ribosomal, 18S; Triiodothyronine

The present studies were designed to examine the regulation of leptin release in primary cultures of adipocytes from fed hypothyroid rats incubated with hormones for 24 hours. Leptin release was increased in the presence of dexamethasone, while the decrease in leptin mRNA content over a 24-hour incubation was reduced by dexamethasone. Dexamethasone did not affect the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA or 18S RNA content of adipocytes. Insulin increased leptin release by adipocytes in both the absence and presence of dexamethasone. Although insulin also prevented the loss of leptin mRNA, this effect was less than that observed for GAPDH mRNA or 18S RNA content. In isolated adipocytes, the loss of almost half the 18S RNA content over a 24-hour incubation was prevented in the presence of insulin but not oxytocin or epidermal growth factor (EGF). The specific beta3 catecholamine agonist CI 316,243 inhibited the effects of dexamethasone on leptin release and leptin mRNA accumulation, as did EGF, without affecting 18S RNA content. Oxytocin inhibited the increase in leptin release due to dexamethasone without affecting leptin mRNA levels. These data indicate that although dexamethasone and insulin are positive regulators of leptin release, only dexamethasone specifically prevented the loss of leptin mRNA in cultured rat adipocytes. In contrast, insulin, but not dexamethasone, prevented the marked loss in 18S RNA observed over a 24-hour incubation of rat adipocytes.

Topics: Adipocytes; Adrenergic beta-Agonists; Animals; Colforsin; Dexamethasone; Dioxoles; Epidermal Growth Factor; Glyceraldehyde-3-Phosphate Dehydrogenases; Hypothyroidism; Insulin; Leptin; Male; Oxytocin; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Ribosomal, 18S; Tetradecanoylphorbol Acetate