brl-37344 and Obesity

The ob gene product is known to control food intake and energy expenditure. To determine whether thermogenic agents directly control ob gene expression, the effects of beta-adrenoceptor agonists on the level of the ob gene messenger RNA (mRNA) and on leptin secretion have been studied in mouse brown adipocytes differentiated in culture. These cells highly expressed the beta 3-adrenoceptor, the uncoupling protein, and the ob gene mRNAs. The ob gene was expressed in mouse brown adipocytes earlier than in mouse white adipocytes under the same culture conditions and to a similar level. The beta 3-, beta L-, and beta 2-adrenoceptor agonists BRL 37344, dobutamine, and terbutaline inhibited ob gene expression in mouse brown adipocytes differentiated in culture with EC50 values of 0.3, 1.0, and 85 nM, respectively. Leptin secretion by the cells under basal conditions was 78 +/- 10 pg/microgram DNA-4 h and was decreased by exposure to the beta-adrenoceptor agonists. The ob gene mRNA half-life was 9.4 h and was decreased to 2.4 h by 1 nM BRL 37344, indicating that the inhibitory effect of the beta 3-agonist might be due to destabilization of ob gene mRNA. (Bu)2cAMP (10-100 microM) and forskolin (20 microM) mimicked the effect of the beta-adrenoceptor agonists. FFA (150-800 microM) had only a small inhibitory effect on ob gene mRNA expression. The results suggest the existence in brown adipose tissue of a retroregulatory pathway by which leptin production in inhibited when the sympathetic nervous system is stimulated.

Topics: Adipocytes; Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Bucladesine; Cell Differentiation; Cells, Cultured; Dobutamine; Ethanolamines; Gene Expression; Kinetics; Leptin; Mice; Mice, Inbred BALB C; Obesity; Proteins; Receptors, Adrenergic, beta; Receptors, Leptin; RNA, Messenger; Terbutaline

Heat production by isolated brown adipocytes, from hypothalamic obese rats and from older rats, was investigated by microcalorimetry. The obese and older rats were 12 and 40 weeks-old, respectively. The basal heat production by the brown adipocytes was significantly less in the obese and older rats than in control rats 12 weeks of age. Isoproterenol and a novel adrenergic beta 3-agonist, BRL37344, increased heat production in a concentration-dependent manner in all rats. The effects of isoproterenol were significantly less in the obese group than in the controls, while BRL37344 stimulated heat production in all rats almost identically. These results suggest that (1) the heat producing capacity of brown adipocytes is reduced by hypothalamic obesity and aging, and (2) BRL37344 might be useful as an anti-obesity drug.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Aging; Animals; Body Temperature Regulation; Calorimetry; Ethanolamines; Hypothalamus; In Vitro Techniques; Male; Obesity; Rats; Rats, Wistar

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Lipolysis; Male; Mice; Mice, Obese; Obesity; Substrate Specificity

The effect on food intake of adrenergic agonists administered into the third cerebral ventricle was studied in Zucker fatty and lean rats. The alpha 2 agonist, clonidine, produced a larger dose-related increase in food intake in lean rats than in the fatty rats. Dose-response curves show similar sensitivity, but decreased responsiveness in the lean animal. The beta 2 adrenergic agonist, salbutamol, produced similar food effect in obese and lean rats reducing food intake in the lean rats at the highest dose (300 nmol), and in the fatty rats at the two highest doses. The effects were small in both groups. The beta 3 agonist, BRL 37344, ([4-(2-((2-hydroxy-2-(3-chlorophenyl)ethyl)amino)-propyl)-phenoxy acetate]) produced a larger dose-related decrease in food intake in the fatty rat than in the lean rats. Dose-response curves showed that sensitivity of beta-receptors was similar, but the lean animals were less responsive. The beta-adrenergic blocking drug propranolol blocked the anorectic effect of BRL 37344 in the fatty rat. These studies suggest that in the fatty rat, the alpha 2 receptor system is tonically more active and the beta 3 receptor system tonically less active, a relationship that would explain the hyperphagia and development of obesity in these animals.

Topics: Adrenergic beta-Agonists; Albuterol; Animals; Clonidine; Dose-Response Relationship, Drug; Drug Interactions; Eating; Ethanolamines; Female; Injections, Intraventricular; Obesity; Propranolol; Rats; Rats, Zucker; Sympathomimetics