Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Weight loss in obese subjects on a restricted diet given BRL 26830A, a new atypical beta adrenoceptor agonist. 289 68

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 Two subjects were withdrawn because they developed an unpleasant sensation of tremor and in all, 17 of the 20 who received BRL 26830A mentioned this side effect.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.
 ...
PMID:The effects of a new beta-adrenoceptor agonist BRL 26830A in refractory obesity. 289 57

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.
 ...
PMID:Effect of a novel thermogenic beta-adrenoceptor agonist (BRL 26830) on insulin resistance in soleus muscle from obese Zucker rats. 298 30

A cloned cDNA sequence for the unique mitochondrial uncoupling protein of rat brown adipose tissue has been used to assay the corresponding mRNA in several situations. When thermogenesis in brown adipose tissue is stimulated (exposure of adult rats to the cold, birth) a rapid and prolonged increase in the level of uncoupling protein mRNA is observed. Such an increase can be mimicked by injection of animals with a new beta-adrenoreceptor agonist BRL 26830A. Conversely it is known that mice and rats with genetic or surgical obesity have a weakly thermogenic brown adipose tissue with a reduced norepinephrine turnover. A reduced level of uncoupling protein mRNA was measured in obese fa/fa rats 10 days or 10 weeks old and in obese rats with a lesion of the ventromedial hypothalamic area but not in obese ob/ob mice. Moreover, exposure of obese animals to cold or dosing with BRL 26830A strikingly increased the level of uncoupling protein mRNA. Measurement of the relative concentration of nascent Ucp transcripts in nuclei isolated from brown adipose tissue indicates that Ucp gene is acutely (within 15 min) regulated at the level of transcription and is controlled via activation of beta-adrenoreceptors of plasma membrane. Ucp gene transcription is decreased in obese fa/fa rats but can be fully and rapidly turned on after injection of BRL 26830A.
 ...
PMID:Expression of uncoupling protein mRNA in thermogenic or weakly thermogenic brown adipose tissue. Evidence for a rapid beta-adrenoreceptor-mediated and transcriptionally regulated step during activation of thermogenesis. 302 20

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.
 ...
PMID:Pharmacological approaches to the regulation of fat metabolism. 354 89

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.
 ...
PMID:Treatment of obesity with thermogenic beta-adrenoceptor agonists: studies on BRL 26830A in rodents. 615 55

Recent studies suggest that thermogenesis in brown adipose tissue has an important role in the regulation of energy balance. Thermogenesis is effected by noradrenaline released from sympathetic nerve endings; the noradrenaline stimulates beta-adrenoceptors, causing lipolysis, and the released fatty acids then promote the uncoupling of oxidative phosphorylation from electron transport. It has been widely accepted that mammalian beta-adrenoceptors exist as two subtypes, beta 1 and beta 2, and rat brown adipocyte beta-adrenoceptors have been classed as beta 1 or as a mixed beta 1/beta 2 population. The beta 1 subtype predominates in atria, whereas the beta 2 subtype predominates in trachea. However, we have now found a novel group of beta-adrenoceptor agonists that selectively stimulate lipolysis in brown adipocytes. In contrast, isoprenaline, fenoterol and salbutamol are less potent as stimulants of lipolysis than as stimulants of atrial rate or tracheal relaxation. Therefore, beta-adrenoceptors in rat brown adipocytes are of neither the beta 1 nor beta 2 subtypes. Compounds that selectively stimulate brown adipocyte beta-adrenoceptors should have potential as thermogenic anti-obesity agents and this has been demonstrated with BRL 26830A , BRL 33725A and BRL 35135A .
 ...
PMID:Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs. 632 35

We have found previously that arotinolol, an alpha/beta-adrenergic blocker, increases blood flow in brown adipose tissue (BAT) in a similar extent as BRL 26830A, a beta 3-adrenoceptor agonist. We tested the hypothesis that arotinolol activates thermogenesis in BAT, leading to weight loss in monosodium-L-glutamate-induced (MSG-induced) obese mice and saline-treated controls. Six weeks of standard animal feed (CE-2) containing arotinolol hydrochloride (350 mg/kg CE-2), which reduced mean blood pressure in MSG-treated mice, significantly increased the mitochondrial protein content in BAT, and activated the specific and total binding of guanosine-5'-diphosphate (GDP) in BAT mitochondria, leading to a reduction of obesity in both MSG- and saline-treated mice vs. the control groups fed with CE-2 diet alone. However, six weeks of CE-2 diet containing propranolol hydrochloride (525 mg/kg CE-2) a non-selective beta-blocker, markedly reduced the specific and total binding of GDP in BAT mitochondria, leading to weight gain in both MSG- and saline-treated mice. These findings support the hypothesis, that arotinolol activates BAT thermogenesis, leading to weight loss.
 ...
PMID:The alpha/beta-adrenergic receptor blocker arotinolol activates the thermogenesis of brown adipose tissue in monosodium-L-glutamate-induced obese mice. 752 Mar 14

This study was undertaken to determine whether administration of a thermogenic beta-agonist drug to Zucker fatty rats could correct some of the earliest metabolic defects detectable in brown adipose tissue (BAT). Fa/fa and fa/fa littermates were given oral administration of BRL-35135 from 8 to 16 days of age. In fa/fa rats, the lipid content of white and brown adipose tissues was significantly reduced. In the BAT of fa/fa rats, thermogenic capacity was restored to the level observed in Fa/fa rats, whereas hyperactivity of fatty acid synthetase was abolished, and a deficit in lipoprotein lipase (activity and mRNA) was partly corrected. Hyperinsulinemia in fa/fa pups was significantly reduced. The decreased content of GLUT-4 mRNA that characterized BAT of fa/fa pups was also restored to normal. At variance with observations in preobese rats, BRL had very little or no effect on lean Fa/fa rats. The present study reveals that chronic administration of a beta-agonist drug early in life prevents emergence of most of the metabolic abnormalities that characterize fa/fa rats at the onset of obesity. This suggests that impaired sympathetic activity may play a role in the development of this genetic obesity.
 ...
PMID:Effect of the beta-adrenoceptor agonist BRL-35135 on development of obesity in suckling Zucker (fa/fa) rats. 761 76

This study was undertaken to determine whether acute injection of the beta-adrenoceptor BRL 35135, which is known to activate thermogenesis, could correct the earliest detectable metabolic abnormalities that characterize brown (BAT) and white (WAT) adipose tissues of pre-obese Zucker rats. In 14-day-old pups, a single intraperitoneal injection of BRL (10 micrograms/g, 3 h before sacrifice) had no effect on uncoupling protein mRNA content in BAT of lean pups, whereas the low level of this mRNA was restored to normal in pre-obese rats. Both lipoprotein lipase (LPL) activity and mRNA content, which were decreased in BAT of pre-obese compared to lean pups (-60%), were stimulated after BRL injection. However, this effect was more pronounced in fa/fa than in Fa/fa rats (+100% and +50%, respectively). In BAT, the increase in fatty acid synthetase (FAS) activity observed in fa/fa rats compared to their lean Fa/fa littermates was not reduced. In WAT, the stimulation of beta-adrenergic receptors had no effect on lipid storage capacity, since FAS and LPL activities remained unchanged. In conclusion, pre-obese Zucker fa/fa rats are responsive to BRL 35135 treatment: acute administration of this drug was able to improve impaired thermogenesis and to correct temporarily other abnormalities of early emergence in BAT. This treatment had no effect in WAT. Taken together, our data reinforce the hypothesis that reduced sympathetic activity in BAT is one of the primary lesions of the obese rat which may play a key role in the development of this genetic obesity.
 ...
PMID:Acute injection of beta-adrenoceptor agonist BRL 35135 corrects both impaired uncoupling protein and lipoprotein lipase gene expression but not hypercapacity of lipogenesis in brown adipose tissue of suckling fa/fa rats. 791 94


<< Previous 1 2 3 4 5 Next >>