brl-26830a and Obesity

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

Several brain receptor systems can modulate food intake. Thus, in a new strategy against obesity, the patient takes submaximal doses of two drugs that act by differing mechanisms.

Topics: Adrenergic beta-Agonists; Appetite Depressants; Attitude to Health; Ethanolamines; Growth Hormone; Humans; Lactones; Lipase; Obesity; Orlistat; Recurrence; Testosterone; Treatment Failure

BRL 26830A is a beta-adrenoceptor agonist drug that shows a high degree of selectivity for thermogenesis and has potential as an antiobesity agent. We undertook a double-blind trial in 40 obese subjects who received either BRL 26830A or placebo for 18 wk. All were prescribed a 3.35 MJ (800 kcal) diet. Weight loss was 15.4 +/- 6.6 (SD) kg on BRL 26830A compared with 10.0 +/- 5.9 kg on placebo (P less than 0.02). The relative weight losses were 0.93% and 0.61%/wk, respectively. Urinary nitrogen excretion was similar in both groups and skinfold measurements indicated a 4-kg difference in fat lost, suggesting that weight loss was mainly from adipose tissue. Psychological assessments showed that BRL 26830A had no adverse effect on mood and no effect on hunger or satiety. Tremor was experienced by 12 of 16 treated subjects who completed the study. It was generally rated as mild, occurred 1 h after dosing, and tended to diminish with time on treatment. Subsequent analysis of the tremor suggested that it is an exaggeration of physiological tremor mediated through skeletal muscle beta 2 adrenoceptors.

Topics: Adrenergic beta-Agonists; Body Temperature Regulation; Double-Blind Method; Ethanolamines; Humans; Obesity; Weight Loss

BRL 26830A is a beta-adrenoceptor agonist drug that shows a high degree of selectivity for thermogenesis and has potential as an antiobesity agent. We undertook a double-blind trial in 40 obese subjects who received either BRL 26830A or placebo for 18 wk. All were prescribed a 3.35 MJ (800 kcal) diet. Weight loss was 15.4 +/- 6.6 (SD) kg on BRL 26830A compared with 10.0 +/- 5.9 kg on placebo (P less than 0.02). The relative weight losses were 0.93% and 0.61%/wk, respectively. Urinary nitrogen excretion was similar in both groups and skinfold measurements indicated a 4-kg difference in fat lost, suggesting that weight loss was mainly from adipose tissue. Psychological assessments showed that BRL 26830A had no adverse effect on mood and no effect on hunger or satiety. Tremor was experienced by 12 of 16 treated subjects who completed the study. It was generally rated as mild, occurred 1 h after dosing, and tended to diminish with time on treatment. Subsequent analysis of the tremor suggested that it is an exaggeration of physiological tremor mediated through skeletal muscle beta 2 adrenoceptors.

Topics: Adrenergic beta-Agonists; Body Temperature Regulation; Double-Blind Method; Ethanolamines; Humans; Obesity; Weight Loss

Psychological aspects of dieting, including hunger and satiety sensations were explored in obese subjects during a placebo-controlled trial of the weight reducing potential of BRL 26830A, a thermogenic beta-3-agonist drug. Successful weight loss was associated with a reduction in the severity of reported depression. The initial degree of emotional disturbance and level of learned resourcefulness appeared to influence the subsequent weight lost. Subjects described few specific hunger and satiety sensations and these sensations did not generally alter during the trial. BRL 26830A, which promoted weight loss, did not significantly influence hunger and satiety sensations and was not associated with emotional disturbances during dieting. With BRL 26830A there was a reduction in the reported somatic symptoms of anxiety which was not apparent on placebo. These results suggest that the subjects' initial psychological state influences outcome when dieting and also that dynamic changes in psychological parameters occur with successful weight loss. Further, BRL 26830A had no effect on appetite and no adverse influence on the psychological functions tested during this study.

Topics: Adrenergic beta-Agonists; Adult; Affect; Analysis of Variance; Diet, Reducing; Double-Blind Method; Ethanolamines; Female; Humans; Hunger; Male; Middle Aged; Obesity; Psychological Tests; Satiation; Weight Loss

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

Beta-adrenoceptor agonists have recently been shown to promote substantial loss of adipose tissue in laboratory animals. One of these BRL, 26830A, increases thermogenesis in human volunteers and has been shown to enhance the rate of weight reduction in patients adhering to a strict reducing regimen. Forty-three post-menopausal or sterilized female subjects suffering from refractory obesity participated in a double-blind placebo-controlled study, the treatment group receiving BRL 26830A 50 mg qid. Two subjects were withdrawn because they developed an unpleasant sensation of tremor and in all, 17 of the 20 who received BRL 26830A mentioned this side effect. There was no change in erect or supine blood pressure or in resting heart rate. There was no significant difference in weight change during the 6-week study. It is concluded that BRL 26830A does not appear to promote weight reduction in subjects unable to adhere strictly to their dietary regime.

Topics: Adrenergic beta-Agonists; Adult; Aged; Blood Pressure; Body Temperature Regulation; Double-Blind Method; Ethanolamines; Female; Humans; Middle Aged; Obesity; Random Allocation; Tremor

There are a variety of methods whereby pharmacotherapy can induce weight loss. These include reducing food intake, impairing absorption of nutrients, inhibiting lipid biosynthesis and increasing energy expenditure. Various drugs are currently being evaluated which exert these modes of action. There are a large number of existing thermogenic drugs, though for one reason or another, they do not appear to be of practical value in the management of obesity. Three novel agents are BRL 26830A, LY 104 119 and RO 16-8714. These agents are chemically similar and all have lipolytic effects particularly in brown adipose tissue. BRL 26830A has been evaluated in man with conflicting results. The possible advantages and limitations of thermogenic agents in human obesity are discussed. Although the animal results are encouraging, it is advisable to take a cautious view regarding their therapeutic potential.

Topics: 2-Hydroxyphenethylamine; Animals; Appetite Depressants; Clinical Trials as Topic; Ethanolamines; Humans; Hypolipidemic Agents; Lipids; Obesity; Rats; Thiophenes; Thyroid Hormones

We compared the effects of hypothalamic obesity induced by neonatal monosodium glutamate (MSG) treatment between spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Newborn WKY and SHR were injected intraperitoneally with 4 mg/kg body weight of MSG daily for 5 days. At 6 months of age, the obesity of SHR was more advanced than that of WKY, but at 14 months of age the severity of obesity was similar between the two strains. Hypertriglyceridemia was enhanced in MSG-treated SHR as compared with MSG-treated WKY. Systolic blood pressure measured by the tail-cuff method was consistently lower in MSG-treated SHR than in control SHR, whereas blood pressure was not affected by neonatal MSG treatment in WKY. Food restriction reduced body weight more in control SHR than in control WKY, with the former also showing enhanced ketogenesis. Neonatal MSG treatment abolished the accelerated reduction of body weight in SHR. Serum leptin concentration was markedly increased in MSG-treated obese rats, though no differences were seen between WKY and SHR in the control or MSG-treated groups. Serum leptin was closely correlated with both Lee obese index and mesenteric fat weight over the strain. Blood flow in interscapular brown adipose tissue (BAT) measured by Laser Doppler flowmetry was significantly increased in response to beta3-adrenoceptor agonist BRL26830A in both the control and MSG-treated rats. However, the response of blood flow was not affected by MSG treatment or strain difference. The present study demonstrated some strain differences in response to neonatal MSG treatment between WKY and SHR. These differences could not be explained by the difference in serum leptin level or beta3-adrenergic reactivity in BAT.

Topics: Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blood Pressure; Disease Models, Animal; Energy Intake; Ethanolamines; Female; Food Additives; Hypertension; Leptin; Male; Obesity; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Sodium Glutamate; Weight Loss

BRL 26830A, a beta adrenoceptor agonist, has been shown to have antiobesity and antidiabetic properties in rodents. The aim of this study was to study the effects of chronic BRL 26830A treatment (20 mg/kg/day for 9 weeks) on weight gain and the development of insulin resistance in gold-thioglucose-injected mice (GTG). BRL 26830A slowed the rate of weight gain in GTG such that mice weighed significantly less between 2 w and 7 w of treatment. However, at the time of sacrifice (9 w), there was no difference in body weight between treated and untreated GTG. The obesity-induced reduction in lipogenesis in brown adipose tissue (BAT) was increased 9 fold to greater than CON levels. However, weight and fatty acid (FA) content of BAT were reduced, suggesting increased lipid turnover and thermogenesis. Lipogenesis, FA content and fat pad weight were unchanged in white adipose tissue (WAT) and decreased in liver of GTG. Glucose tolerance was improved in both CON and GTG. Hyperglycemia, hyperinsulinemia and changes in cardiac and hepatic glucose oxidation as indicated by PDHC activity were normalized. Serum triglycerides and non-esterified fatty acids were reduced. Thus, chronic BRL 26830A treatment prevented the development of insulin resistance and attenuated weight gain, but did not prevent the development of obesity in this model.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Aurothioglucose; Blood Glucose; Body Composition; Ethanolamines; Fatty Acids; Glycogen; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred CBA; Obesity; Pyruvate Dehydrogenase Complex; Weight Gain

BRL 26830A is a thermogenic beta-adrenergic agonist drug which has an anti-obesity effect in animals and diet-restricted obese man. This study was undertaken in obese subjects who were not calorie restricted to assess the effect of three weeks drug administration on energy expenditure and glucose, amino acid and fatty acid metabolism in the post-absorptive and fed states. Stable isotope tracers were employed to determine kinetic data both at baseline and during adrenaline infusion. There was no evidence of BRL 26830A causing a major shift in fuel metabolism or having an anabolic effect. Baseline plasma concentrations of glycerol (P less than 0.01) and palmitate (P less than 0.01) were reduced, glucose remained within the normal range, whereas insulin decreased after BRL 26830A. The hypoaminoacidaemic effect of adrenaline was attenuated by BRL 26830A (P less than 0.01 for branched-chain amino acids, P less than 0.05 for total amino acids). The results suggest that BRL 26830A improves insulin sensitivity and causes selective down-regulation of adrenergic receptors. The increased insulin sensitivity may be a useful therapeutic effect for this class of drug and suggests a possible role in the treatment of obese non-insulin dependent diabetic patients.

Topics: Adrenergic beta-Agonists; Adult; Amino Acids; Blood Glucose; Energy Metabolism; Epinephrine; Ethanolamines; Female; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Obesity; Palmitic Acid; Palmitic Acids; Time Factors

The anti-obesity and anti-diabetic actions of BRL 26830A, beta 3-adrenoceptor agonist, (2 mg/kg administered intramuscularly daily for 2 weeks) were evaluated in obese diabetic Yellow KK mice and C57B1 control mice. The following parameters were compared in the treated vs. control animals: brown adipose tissue (BAT) thermogenesis, resting metabolic rate (RMR), insulin receptors in adipocytes, and blood glucose and serum insulin levels during a glucose overloading test. BRL 26830A significantly increased BAT thermogenesis and RMR but it decreased the amount of white adipose tissue without affecting food intake. Those actions contributed to the mitigation of obesity in Yellow KK mice. BRL 26830A also increased the concentration of insulin receptors and decreased the levels of serum insulin and blood glucose during the glucose overloading test in Yellow KK mice. In the glucose overloading test performed one hour after BRL 26830A injection, insulin secretion was significantly increased and the blood glucose level was markedly decreased in both groups. These observations suggest that BRL 26830A possesses anti-obesity and anti-diabetic actions and consequently may be useful for treating obesity as well as non-insulin-dependent diabetes mellitus with obesity.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Ethanolamines; Guanosine Diphosphate; Insulin; Male; Mice; Mice, Inbred Strains; Mitochondria; Obesity; Organ Size; Oxygen Consumption; Proteins

Half of the mice in both the monosodium-L-glutamate (MSG)-induced obesity and saline control groups were given BRL 26830A via a gastric tube at a daily dose of 5 mg/kg for 2 weeks, and the other half given distilled water. BRL 26830A administration significantly increased guanosine-5'-diphosphate (GDP)-binding in brown adipose tissue (BAT) and the resting metabolic rate (RMR), and significantly reduced retroperitoneal white adipose tissue (WAT) pads in both groups. It also markedly reduced body weight in MSG obese mice that had reduced BAT thermogenesis and decreased RMR. However, food intake was unchanged in both groups. Neither beta 1- nor beta 2-selective antagonists affected the increase of RMR induced by BRL 26830A, but a non-selective beta-antagonist completely inhibited its increase. These results suggest that BRL 26830A, which is a new beta-adrenoceptor agonist, stimulates BAT thermogenesis, increases RMR, and reduces WAT, thus contributing to the mitigation of obesity.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Basal Metabolism; Ethanolamines; Female; Guanosine Diphosphate; Mice; Mice, Obese; Obesity; Temperature

The thermogenic beta 3-adrenoceptor agonist BRL 26830A has been shown to increase weight loss in dieting subjects but tremor was a frequent adverse effect. We have investigated the magnitude and nature of this tremor after a single oral dose in 18 subjects. Two complementary techniques were used to attach the recording apparatus to the subjects to give both isotonic and isometric measures of tremor. Increases of 84% and 40% respectively were found due to exaggeration of physiological tremor presumably mediated through concomitant beta 2-adrenoceptor stimulation. The use of beta 3-adrenoceptor agonist drugs in the treatment of obesity may increase but the development of an agent without tremor inducing properties would be an obvious advantage.

Topics: Adrenergic beta-Agonists; Ethanolamines; Humans; Obesity; Receptors, Adrenergic, beta; Tremor

The effect of a new type of antidiabetic agent, BRL 26830A, has been tested in obese mice. Since this drug increases thermogenesis, insulin receptor binding and kinase activity were studied in brown adipose tissue and skeletal muscle of mice made obese by gold thioglucose. At 1 mg.kg-1.day-1, a 3-wk treatment normalized the glycemia and increased the uncoupling protein content of brown adipose tissue. The insulin receptor number and its associated kinase activity increased only in brown adipose tissue. At 2 mg.kg-1.day-1, additional effects, i.e., a 20% reduction in body weight and a normalization of insulin receptor number both in brown adipose tissue and in skeletal muscle, were observed. All those results were obtained even though hyperinsulinemia was not corrected. At the higher drug dosage, insulin receptor kinase activity evolved in direct proportion to the receptor number in brown adipose tissue. By contrast, in skeletal muscle, the receptor kinase activity toward exogenous substrates increased more than the receptor number, suggesting that the alteration of insulin receptor kinase activity previously reported in skeletal muscle of obese mice was partly reversed by BRL 26830A. None of these parameters was modified by the drug in lean mice. These results show that, even without affecting obesity, BRL 26830A improves insulin resistance in obese mice, probably through its effect on insulin receptors. This action prevails in brown adipose tissue, supporting the idea that this tissue plays an important role in glucose homeostasis. Thermogenic drugs could thus be powerful agents for the treatment of noninsulin-dependent diabetics.

Topics: Adipose Tissue; Animals; Aurothioglucose; Blood Glucose; Body Temperature Regulation; Ethanolamines; Hypoglycemic Agents; Insulin; Kinetics; Male; Mice; Obesity; Phosphorylation; Protein-Tyrosine Kinases; Receptor, Insulin

The size and morphological characteristics of muscles from diabetic obese (db/db) mice and their normal lean littermates were investigated. The soleus muscles were similar in size in diabetic and normal mice but the biceps brachii and gastrocnemius were significantly lighter in the diabetic animals. In the biceps brachii the small size resulted from an overall reduction in fibre diameter, which was most acute in the fast white fibres, and an increase in the proportion of smaller fast intermediate fibres. Treatment of diabetic mice with BRL 26830 a thermogenic, beta-adrenoceptor agonist, restored the weight, fibre diameter and fibre type composition of the biceps brachii to that of lean littermates. This treatment also increased the weight of the gastrocnemius, together with its protein content. Since BRL 26830 restored normoglycaemia in the diabetic mice, without decreasing their body weight, we suppose that it improved insulin action in their muscles and this, in turn, stimulated muscle growth.

Topics: Adrenergic beta-Agonists; Animals; Body Temperature Regulation; Diabetes Mellitus; Diabetes Mellitus, Experimental; Ethanolamines; Female; Insulin Resistance; Mice; Mice, Inbred C57BL; Muscles; Obesity

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

Young lean (Fa/?) and obese (fa/fa) rats were treated with the thermogenic beta-adrenoceptor agonist, BRL 26830, for 3 weeks. In lean rats this treatment had no effect on body weight but there was a marked increase in the insulin sensitivity of soleus muscle strips with respect to glycolytic rate. Treatment of obese rats with BRL 26830 produced a small but not significant decrease in body weight but the sensitivity of both glycolysis and glycogen synthesis to insulin was increased so that muscles of treated obese rats showed similar insulin sensitivity to untreated lean rats. It is suggested that such changes are unlikely to be merely a secondary consequence of an anti-obesity action.

Topics: Animals; Blood Glucose; Ethanolamines; Glycogen; Insulin Resistance; Lactates; Lactic Acid; Male; Muscles; Obesity; Rats; Rats, Zucker; Receptors, Adrenergic, beta

The maximal activities of the key glycolytic enzymes hexokinase and 6-phosphofructokinase, were reduced in brown adipose tissue in db/db mice compared to their lean littermates. Treatment of db/db mice with the thermogenic beta-adrenoceptor agonist, BRL 26830, restored normoglycaemia. The only significant increase in activity of hexokinase and 6-phosphofructokinase in the BRL 26830-treated db/db mice occurred in brown adipose tissue where the total tissue activity increased 10- and 11-fold respectively. These changes together with increased 2-deoxyglucose uptake in vivo suggest that brown adipose tissue can play a quantitatively important role in the removal of glucose from the blood.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Deoxyglucose; Diabetes Mellitus, Experimental; Ethanolamines; Female; Glycolysis; Hexokinase; Ketoglutarate Dehydrogenase Complex; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Muscles; Obesity; Phosphofructokinase-1

Studies on BRL 26830A in rodents have shown that thermogenic beta-adrenoceptor agonists have potential for the therapy of obesity. BRL 26830A reduced body weight gain in ob/ob mice and fa/fa rats by reducing lipid accumulation. It had no effect on lean body mass. BRL 26830A did not reduce food intake, its anti-obesity effect being due to stimulation of energy expenditure. This thermic effect was enhanced in the obese animals by repeat dosing. BRL 26830A did not affect body weight gain in the lean counterparts of the obese animals because its thermic effect in lean animals was reduced by repeat dosing. Brown adipose tissue is an important site of BRL 26830A-induced thermogenesis. A single dose of BRL 26830A raised brown adipose tissue temperature, depleted brown adipose tissue lipid and unmasked GDP-binding sites in brown adipose tissue mitochondria. Repeat dosing caused hypertrophy of brown adipose tissue and improved cold tolerance in mice. In-vitro studies showed that the rat brown adipocyte beta-adrenoceptor does not fall into the beta 1/beta 2 classification and BRL 28410, which mediates the biological effects of BRL 26830A in vivo, selectively stimulated the brown adipocyte receptor. It is concluded that BRL 26830A achieves its anti-obesity effect by mimicking natural mechanisms involved in thermogenesis and the control of body weight.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Body Temperature Regulation; Energy Metabolism; Ethanolamines; Mice; Mice, Obese; Obesity; Rats

The suggestion that defective thermoregulatory thermogenesis in the genetically obese (ob/ob) mouse is due to a low thermic response to noradrenaline has been investigated using both noradrenaline and the longer-acting sympathomimetic compounds, ephedrine and BRL 26830A. Below thermoneutrality (23.5 degrees C) the metabolic rate of obese mice was lower than that of their lean littermates, whereas at a thermoneutral temperature (31 degrees C) the metabolic rate of the obese mice was as high as that of lean mice. This confirms the view that the ob/ob mouse has defective thermoregulatory thermogenesis. However, in C57BL/6 mice, this defect is not due to a failure to respond to noradrenaline, because at 31 degrees C the maximum thermic effects of noradrenaline, ephedrine and BRL 26830A were as high in obese as in lean mice and at 23.5 degrees C they were higher in obese than in lean mice. Furthermore, the response of brown adipose tissue to beta-adrenoceptor stimulation appears normal since noradrenaline caused a normal rise in brown adipose tissue temperature, and treatment with noradrenaline or BRL 26830A in vivo caused a normal increase in GDP binding by brown adipose tissue mitochondria. At 31 degrees C propranolol depressed metabolic rate equally in lean and obese C57BL/6 mice, whereas at 23.5 degrees C it depressed metabolic rate more in lean than obese mice. In contrast to C57BL/6 mice, Aston ob/ob mice showed a reduced thermic response to noradrenaline. These results suggest that defective thermoregulatory thermogenesis in the ob/ob mouse is primarily due to a reduced ability to raise sympathetic tone, but in some strains an additional failure in the thermic response to noradrenaline may develop.

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Energy Metabolism; Ephedrine; Ethanolamines; Female; Guanosine Diphosphate; Kinetics; Metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Norepinephrine; Obesity; Propranolol; Sympathomimetics

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