brl-26830a and Body-Weight

beta(3)-Adrenoceptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. beta(3)-Adrenoceptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, beta(3)-adrenoceptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify beta(3)-adrenoceptor agonist drugs because the pharmacology of both beta(3)- and beta(1)-adrenoceptors can vary; near absolute selectivity is needed to avoid beta(1/2)-adrenoceptor-mediated side effects and selective agonists tend to have poor oral bioavailability. All weight loss is lipid and lean may actually increase, so reducing weight loss relative to energy loss. beta(3)-adrenoceptor agonists have a more rapid insulin-sensitising than anti-obesity effect, possibly because stimulation of lipid oxidation rapidly lowers intracellular long-chain fatty acyl CoA and diacylglycerol levels. This may deactivate those protein kinase C isoenzymes that inhibit insulin signalling.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Anti-Obesity Agents; Body Weight; Dioxoles; Energy Metabolism; Ethanolamines; Humans; Obesity; Receptors, Adrenergic, beta-3

A double blind placebo controlled study was carried out in 40 subjects newly referred for treatment for obesity to determine the effects of the new thermogenic beta adrenoceptor agonist BRL 26830A. The subjects were randomised to receive either BRL 26830A, 200 mg daily for two weeks then 400 mg daily, or placebo for 18 weeks, and all were instructed to follow a 3.35 MJ diet that was low in fat and high in fibre. Weight loss was 15.4 (SD 6.6) kg in subjects given BRL 26830A compared with 10.0 (5.9) kg in those given placebo (p = 0.02). The relative weight loss was 0.93 (0.39%) a week with BRL 26830A and 0.61 (0.38)% with placebo (p = 0.02). Urinary excretion of nitrogen was similar in both groups, whereas measurements of skinfold thickness indicated a 4.1 kg difference in the amount of fat lost, suggesting that weight loss with BRL 26830A was mainly from adipose and not lean tissue. BRL 26830A had no effect on resting pulse rate or pressor effects on either diastolic or systolic blood pressure. No significant differences were found between the two groups in serum cholesterol concentration, percentage of high density lipoprotein cholesterol, plasma concentrations of glucose and insulin, the ratio of glucose to insulin, serum concentrations of triiodothyronine and thyroxine, and creatinine clearance. Short term administration of BRL 26830A to six subjects who had taken the drug for 18 weeks showed that the expenditure of energy increased by 11.6% during the second hour after administration, which suggests that BRL 26830A may enhance weight loss thermogenically. BRL 26830A may be a useful drug in the treatment of obesity.

Topics: Adrenergic beta-Agonists; Adult; Basal Metabolism; Body Weight; Clinical Trials as Topic; Diet, Reducing; Double-Blind Method; Ethanolamines; Female; Humans; Male; Middle Aged; Obesity; Skinfold Thickness; Time Factors

Changes in food intake, serum adipsin, and obesity were evaluated in the MSG-treated mouse. In Experiment 1, mice treated with MSG had 50% lower serum adipsin and over 2-fold higher percentage of body fat than the lean controls. Both feeding caffeine and restricting intake normalized serum adipsin and caused weight loss, but did not normalize the percentage of body fat. No additional effect was gained by feeding isoproterenol or ephedrine in combination with caffeine. In Experiment 2, we separated the direct effect of caffeine from the associated depression in intake using a paired feeding design, and also determined the effects of selected adrenergic agents and somatotropin (S). Somatotropin increased weight gain and reduced the percentage of body fat in healthy and obese mice, and tended to lower serum adipsin. Caffeine clearly depressed intake, caused weight loss, and increased serum adipsin, but similar results were achieved by restricting intake. None of the adrenergic drugs tested changed serum adipsin. Ephedrine depressed food intake and caused weight loss, but reduced the percentage of body fat only at the highest dietary concentration (2000 mg per kg of diet). Phenylephrine reduced weight gain without a concomitant effect on the percentage of body fat, and isoproterenol did not influence weight gain or body fat.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Animals; Body Composition; Body Weight; Caffeine; Central Nervous System Stimulants; Complement Factor D; Eating; Ephedrine; Ethanolamines; Female; Growth Hormone; Isoproterenol; Lactation; Mice; Phenylephrine; Serine Endopeptidases; Sodium Glutamate

Topics: Adrenergic beta-Agonists; Body Weight; Ethanolamines; Female; Humans; Male; Obesity

BRL 26830, (R*,R*)-(+/-)-methyl-4-(2-[(2-hydroxy-2-phenylethyl)amino]propyl)-benzoa te, is a new type of beta-adrenoceptor receptor agonist that combines antihyperglycemic and thermogenic properties. In C57Bl/KsJ db/db mice, treatment with BRL 26830 (50 mg of the hemifumarate salt/kg diet) decreased blood glucose concentration and normalized water intake. As judged by the normalization of polydipsia, BRL 26830 was effective within 2 days and the effect was maintained throughout a treatment period of up to 11 wk. Treatment of db/db mice with BRL 26830 resulted in an increase in both plasma and pancreatic insulin concentrations and a partial restoration of first-phase insulin secretion by the isolated, perfused pancreas in response to a high (16.7 mM) glucose pulse. Given acutely, BRL 26830 increased energy expenditure in both fed and fasted db/db mice. When given chronically, BRL 26830 increased significantly the dietary and thermoregulatory component of metabolic rate. It is suggested that the antidiabetic and thermogenic properties of BRL 26830 are linked and that blood glucose acts either directly or indirectly as a substrate for thermogenesis.

Topics: Adrenergic beta-Agonists; Animals; Blood Glucose; Body Weight; Chemical Phenomena; Chemistry; Circadian Rhythm; Energy Metabolism; Ethanolamines; Female; Glucose; Glyburide; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Obese; Rats; Rats, Zucker

BRL 26830A, (R*, R*)-(+/-)-methyl 4-[2-[(2-hydroxy-2-phenylethyl) amino] propyl]-benzoate, (E)-2-butenedioate (2:1) salt, is a new antihyperglycemic agent orally active in obese-hyperglycemic animal models. In C57Bl/6 ob/ob mice, BRL 26830A (1 mg/kg) given daily for periods of 14 d-6 weeks produced a marked improvement in glucose tolerance and a reduction in the fasting plasma insulin concentration. Adipocytes prepared from treated mice showed improved insulin responsiveness. In Zucker fa/fa rats, treatment with BRL 26830A (2.9 mg/kg/d for 23 d) produced improvements in both glucose tolerance and whole animal insulin sensitivity, as assessed by rate of fall of blood glucose in response to an intravenous dose of insulin. In C57Bl/KSJ db/db mice, BRL 26830A (admixed with food at 50 mg/kg diet) decreased blood glucose to values similar to those in lean mice. At the end of a 10-week treatment, BRL 26830A-treated mice had a higher plasma and pancreatic insulin content than the untreated db/db mice. In normoglycaemic rats and mice, BRL 26830A increases the plasma insulin concentration and increases glucose disposal. However, in most circumstances, there is a counteracting increase in endogenous glucose synthesis and, therefore, no change in blood glucose occurs. Improvements in glucose tolerance occur in 24-h fasted rats and mice. BRL 26830A has thermogenic activity and it is suggested that this might be linked to increased glucose utilization. Brown adipose tissue (BAT) of C57Bl/KSJ db/db mice has a reduced maximum glycolytic capacity relative to lean littermates. Treatment with BRL 26830A increased the glycolytic capacity 10-fold.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Temperature Regulation; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Ethanolamines; Glucose; Glucose Tolerance Test; Mice; Mice, Obese; Rats; Rats, Inbred Strains; Rats, Zucker

The effects of a novel compound, BRL 26830A, on energy balance in normal and obese mice have been investigated. BRL 26830A reduced body weight or weight gain in genetically (ob/ob), goldthioglucose, and cafeteria diet obese mice and genetically obese (fa/fa) Zucker rats. Weight reduction was due to reduced body lipid content. BRL 26830A caused little or no reduction in food intake in these animals but it increased metabolic rate and in genetically obese mice this thermic effect was increased by repeat dosing. BRL 26830A did not reduce body weight gain in the lean counterparts of the genetically obese animals. Its thermic effect was smaller in the lean than the genetically obese mice and it caused an increase in food intake in the lean mice. The thermic effect of BRL 26830A was inhibited by dl- but not d-propranolol. BRL 26830A largely overcame the depression in metabolic rate caused by fasting.

Topics: Adrenergic beta-Agonists; Animals; Body Composition; Body Temperature Regulation; Body Weight; Energy Intake; Energy Metabolism; Ethanolamines; Female; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Obesity; Phenethylamines; Propranolol; Rats; Rats, Zucker; Time Factors