UMLS:C0028754 - FACTA Search

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrolysis of triglycerides to fatty acids and glycerol in fat cells (lipolysis) is of importance for the control of lipid and carbohydrate metabolism. This process is regulated by several hormones and parahormones acting on cyclic AMP formation or breakdown, which in turn influences the activity of hormone sensitive lipase. The latter enzyme stimulates hydrolysis of triglycerides in fat cells. It is well established through in vivo and in vitro investigations that there are regional variations in the lipolytic activity of human adipose tissue. The rate of lipolysis is low in the subcutaneous femoral/gluteal region, intermediate in the subcutaneous abdominal region and high in the visceral (i.e. omental) region. In non-obese subjects the differences between the subcutaneous and visceral fat depots may be explained by site variations in the function of receptors for insulin, catecholamines and adenosine. The lipolytic beta 1 and beta 2 adrenoceptors, as well as the newly discovered beta 3, are most active in the visceral fat cells. The antilipolytic insulin receptors, alpha 2 adrenoceptors and adenosine receptors are most active in the subcutaneous fat cells. In subjects with upper-body obesity the regional variations in the action of catecholamines on lipolysis are further enhanced. Decreased action of beta 2-adrenergic receptors and increased activity of alpha 2-adrenergic adrenoceptors in combination with defects in hormone sensitive lipase function inhibits the lipolytic effect of catecholamines in subcutaneous fat cells whereas increased activity of beta 3-adrenergic receptors and decreased activity of alpha 2 adrenoceptors augment the lipolytic response in visceral fat cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differences in lipolysis between human subcutaneous and omental adipose tissues. 851 4

This study was undertaken to determine whether receptor and non-receptor components of the adenylate cyclase (AC) cascade were altered in brown adipose tissue (BAT) of 14-day-old pre-obese (fa/fa) rats, before endocrine status is strongly modified by fa gene expression. Activity of the AC catalytic subunit did not differ between the two genotypes. In fa/fa rats compared with control Fa/fa rats, there was a 50% decrease in the activity of alpha Gs (stimulated by NaF or guanosine 5'-[gamma-thio]triphosphate) but no change in protein content (Western blotting). alpha Gi function, assessed by the inhibitory action of low concentrations of guanosine 5'-[beta gamma-imido]triphosphate upon 10(-4) M forskolin-stimulated AC activity, was equally low in both genotypes. Analysis of dose-response curves for different beta-agonists revealed that (i) both the basal and the maximally stimulated activity of AC were 2-fold lower in fa/fa rats than in Fa/fa rats; (ii) BRL37344 and CGP12177 (beta 3 agonists) were less potent in fa/fa than in Fa/fa rats (Kact. multiplied by 2); (iii) noradrenaline and isoprenaline (Iso), at the low-affinity site (beta 3-AR), were less potent in fa/fa than in Fa/fa pups (Kact. increased by 30 and 20% respectively). At the high-affinity site (mainly beta 1) these two agonists were more potent in fa/fa than in Fa/fa rats (Kact. decreased by 40 and 80% respectively). In good agreement with the latter result, the beta 1-adrenergic receptor (beta 1-AR)-selective antagonist CGP20712A had more effect on the Iso-stimulated AC activity in pre-obese than in lean pups (2-fold decreased in IC50). Binding experiments with [3H]CGP12177 show that in BAT of suckling rats, beta 3-ARs represent 80% of the total beta-ARs. Bmax values for the two sites were not affected by the genotype, although the beta 3-AR mRNA concentration in BAT (quantitative reverse-transcriptase PCR) was 3-fold lower in fa/fa rats than in Fa/fa pups. In conclusion, these results provide evidence for alterations in beta 1- and beta 3-AR signalling in BAT of 14-day-old suckling pre-obese Zucker rats with a decreased activity of alpha Gs. The impaired AC responsiveness to catecholamines might be a primary contributor to the development of this genetic obesity.
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PMID:Early alterations in the brown adipose tissue adenylate cyclase system of pre-obese Zucker rat fa/fa pups: decreased G-proteins and beta 3-adrenoceptor activities. 855 20

beta 3-Adrenoceptor (beta 3-AR) agonists were first identified more than twelve years ago and were found to be remarkably effective in animal models of obesity and Type II (non-insulin dependent) diabetes. Those that have been taken forward to clinical studies have not, however, proved so effective in humans: they have either been of limited efficacy, or their activities have been accompanied by significant side-effects. Reasons for the failure of some beta 3-AR agonists in humans have included a poor pharmacokinetic profile and, possibly, a failure of prodrugs to be metabolised to selective beta 3-AR agonists. A more fundamental problem, however, is that the human and rat beta 3-AR differ pharmacologically, and those compounds that have been evaluated in humans have much lower efficacy at the human than the rat receptor. This problem may be compounded by there being a low number of beta 3-AR relative to beta 1-AR and beta 2-AR in those tissues that mediated thermogenesis in humans, so that low efficacy compounds tend to exhibit mainly beta 1-AR or beta 2-AR-, rather than beta 3-AR-mediated effects, despite their having selective affinity for human beta 3-AR. Nevertheless, studies using CGP 12177, which is an agonist at beta 3-AR but an antagonist at beta 1-AR and beta 2-AR, demonstrate that functional beta 3-AR are present in human adipose tissue. Moreover, the association of a polymorphism in the human beta 3-AR with obesity and diabetes demonstrates that this receptor is relevant to these diseases in humans. Thus the true potential of beta 3-AR agonists in humans can only be evaluated when a compound with good selectivity and efficacy at the human beta 3-AR, coupled with a long duration of action in vivo, has been identified.
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PMID:Prospects for beta 3-adrenoceptor agonists in the treatment of obesity and diabetes. 865 38

The control of fat cell lipolysis by the catecholamines involves at least four different adrenoceptor subtypes; three beta (beta 1-, beta 2-, and beta 3-ARs) and one alpha 2-adrenoceptor (alpha 2-AR). The physiological importance of the beta- and alpha 2A-ARs varies according to the species, the sex, the age, the anatomical location of fat deposits and the degree of obesity in humans and animals. The physiological amines operate through differential recruitment of these sites on the basis of their relative affinities. This point has been assessed by in vitro studies and has partly been confirmed in in vivo experiments using selected alpha/beta-AR antagonists and in situ microdialysis. The affinity of the beta 3-AR for catecholamines is less than that of the classical beta 1- and beta 2-ARs in the various species investigated. Conversely, it is the alpha 2-AR which exhibit the highest affinity for the physiological amines in all fat cells. The relative order of affinity of the various fat cell ARs for the physiological amines defined in binding studies and in vitro assays is alpha 2 > beta 1 > or = beta 2 > beta 3 for norepinephrine and alpha 2 > beta 2 > beta 1 > beta 3 for epinephrine. When considering differential beta-AR recruitment by catecholamines, it is the beta 1-AR which is always activated at the lowest norepinephrine levels, whatever the species, while the activation of the beta 3-AR requires higher norepinephrine levels. In addition to the differential recruitment, differential regulation by hormones could also occur for each fat cell AR subtype. The alpha 2-and beta 3-ARs are less prone to desensitization and down-regulation by comparison with the beta 1- and beta 2-AR.
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PMID:Adrenergic receptors and fat cells: differential recruitment by physiological amines and homologous regulation. 869 51

We have attempted to provide a progress report on current research on the role of catecholamines and serotonin receptor subtypes in feeding control. Recent evidence suggests that only some of the several catecholamine receptor subtypes are specifically involved in feeding control. They include the beta 1/2-adrenoceptors, the alpha 1-adrenoceptors and the D1 dopamine receptors: stimulation of these receptors reduces feeding in rats. Stimulation of serotonergic 5-HT1B and 5-HT2C receptors reduces feeding and perhaps enhances the satiating effect of food. Recently, an interesting reciprocal relation between serotonin and cholecystokinin has been discovered in relation to feeding control. The serotonergic 5-HT2A receptors are involved in stress-induced anorexia and regulate the hyperphagia induced by neuropeptide Y in the nucleus paraventricularis of the hypothalamus. Both effects may involve changes in the secretion of corticotropin-releasing factor. These findings may help elaborate neuronal models of feeding control and perhaps facilitate progress in the pharmacotherapy of human obesity and eating disorders.
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PMID:Pharmacology of ingestive behaviour. 876 44

The metabolic syndrome is a well-known risk for the development of cardiovascular disease. In the present study the possible importance of an altered visceral adipocyte beta-adrenoceptor function in this syndrome was investigated. In 65 subjects of both sexes undergoing elective surgery for non-malignant disorders, the metabolic syndrome phenotype and the lipolytic sensitivity for various beta-adrenoceptor subtype agonists in omental adipocytes were determined. The study group represented a wide range of abdominal adipose tissue distribution (waist-to-hip ratios 0.76-1.13), but was otherwise apparently healthy. The subjects were divided into three subgroups according to their waist-to-hip (WHR) ratios: 1) WHR < 0.92; 2) WHR 0.92-1.04; 3) WHR > 1.04. The subgroups demonstrated significant differences regarding body mass index, sagittal diameter, systolic and diastolic blood pressures, plasma concentrations of glucose, insulin, triglycerides and HDL-cholesterol (p = 0.005-0.0001). Furthermore, in omental adipocytes beta 3-adrenoceptor sensitivity, but not beta 1-and beta 2-adrenoceptor sensitivities, differed significantly between the WHR subgroups (p = 0.0001). beta 3-adrenoceptor sensitivity was also related to the other components of the metabolic syndrome, although a strong covariation between WHR and beta 3-adrenoceptor sensitivity vs blood pressure and the metabolic parameters was found. The present data provide evidence of a relationship between upperbody obesity and its associated metabolic complications and also, an increased visceral fat beta 3-adrenoceptor sensitivity. We suggest that the latter finding results in an augmented release of non-esterified fatty acids from the visceral fat depot to the portal venous system. This may in turn contribute to the development of the metabolic syndrome.
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PMID:The metabolic syndrome is related to beta 3-adrenoceptor sensitivity in visceral adipose tissue. 881 9

In this study we investigated whether fat cell lipolysis could be involved in the aetiology of obesity by comparing non-obese subjects with (Hob) or without (Hnorm) a family trait for overweight. A family history of obesity was present when at least one of the first-degree relatives had body mass index of 27 kg/m2 or more. Twenty-seven healthy, drug-free non-obese adult subjects were investigated; 13 were Hob and the remaining 14 were Hnorm. Eleven Hob had at least one obese parent. Isolated fat cells from abdominal subcutaneous adipose tissue were incubated in vitro. Glycerol release (lipolysis index), mRNA levels and enzymatic activity of hormone-sensitive lipase and radioligand binding to beta 1- and beta 2-adrenoceptors were determined. The lipolytic effects of noradrenaline (major endogenous lipolytic agent), isoprenaline (a non-selective beta-adrenoceptor agonist), forskolin (a direct activator of adenylyl cyclase) and dibutyryl cyclic AMP (activating protein kinase and thereby hormone-sensitive lipase) were reduced by about 50% (p from 0.001 to 0.01). The maximum activity of hormone-sensitive lipase was reduced 50% in Hob (p < 0.05) and correlated with the lipolytic responsiveness of fat cells in the whole population (r = 0.71). However, there was no difference between the groups in steady-state mRNA levels for the enzyme. Beta 1-->, beta 2- and alpha 2-adrenoceptor sensitivity as well as beta 1- and beta 2-adrenoceptor numbers were normal in Hob. Fasting plasma insulin was 49.1 and 32.6 pmol/l, respectively in Hob and Hnorm (p = 0.01). There was, however, no significant correlation between lipolysis in vitro and plasma insulin. Thus, lipolytic catecholamine resistance in fat cells, at least partly due to impaired function of hormone-sensitive lipase, is an adipocyte abnormality associated with a family tendency to obesity.
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PMID:Adipocyte lipolysis in normal weight subjects with obesity among first-degree relatives. 885 14

1. An atypical non beta 1/beta 2-adrenoceptor (AR) subtype (beta 3-AR) has been identified which is selectively stimulated by a group of ligands which mediate lipolytic and thermic responses in brown and white adipose tissue. 2. Molecular studies have shown that beta 3-AR in man are mainly expressed in visceral adipocytes, and to a lesser extent in gall-bladder and colon. In vitro studies with beta 3-AR agonists have shown activity at other sites including skeletal muscle and myocardium. 3. Regulation of beta 3-AR may differ from beta 1/beta 2-AR subtypes in that continuous agonist exposure does not result in receptor down-regulation. 4. A polymorphism of the human beta 3-AR gene (Trp64Arg) has been identified which is associated with obesity, insulin resistance and an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM). Studies are required to establish whether expression of the mutant gene results in altered metabolic responses to beta 3-AR stimulation in man. 5. There is accumulating evidence to support a therapeutic role of beta 3-AR agonists in NIDDM because of anti-obesity and anti-diabetic activity, as a consequence of thermogenic effects as well as increased insulin sensitivity and glucose tolerance. 6. Selectivity studies with BRL35135 and isoprenaline in humans have demonstrated a beta 3-AR mediated component to thermogenesis which is dissociated from beta 1/beta 2-mediated effects on carbohydrate and fat metabolism. Similar studies have suggested a functional beta 3-AR mediating cardiac but not airway responses in humans. An evaluation of beta 3-AR agonists in irritable bowel syndrome may be warranted in view of colonic antimotility properties in vitro.
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PMID:Clinical pharmacology of beta 3-adrenoceptors. 887 18

The sympathoadrenal system plays an important role in the regulation of both energy intake and energy expenditure (EE), and the sympathetic nervous system (SNS) offers a dual target for pharmacological intervention directed at weight loss in obese patients. The sizes of the fat-free mass and fat mass are the major determinants of resting EE, but studies using different techniques have shown that differences in sympathetic activity can account for an additional proportion of the variation between individuals. Differences in thermogenic responses to food can also be explained by different abilities to activate the sympathoadrenal system. A low resting EE for a given body composition is one manifestation of the genetically determined predisposition to obesity. A low sympathetic activity may be one factor responsible but, as yet, no conclusive evidence has been found. In dietary treatment programmes of obesity, patients with high levels of EE and greater SNS activity achieve greater long-term weight loss than those with lower levels. Pharmacological stimulation with sympathomimetic compounds suppresses appetite and increases energy expenditure through stimulation of beta 1, beta 2, and beta 3-receptor subtypes. During chronic treatment, the beta 3-mediation may predominate due to down-regulation of beta 1- and beta 2-receptors. An improved understanding of the aetiological role of the SNS in the development of obesity in genetically susceptible individuals may permit tailoring of pharmacological intervention.
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PMID:The sympathetic nervous system as a target for intervention in obesity. 896 68

The cloning, sequencing and expression in model systems of the previously unidentified beta 3-adrenoceptor recently led to an extensive functional characterization. Ligand binding and adenylate cyclase activation studies helped define a specific profile that is quite distinct from that of the beta 1- and beta 2-adrenoceptors, but strongly reminiscent of most of the 'atypical' beta-adrenoceptor-mediated responses reported in earlier pharmacological studies. More recently, a naturally occurring variation in the human beta 3-adrenoceptor has been correlated with hereditary obesity and with increased dynamic capacity to add on weight and develop non-insulin dependent diabetes in Western obese patients. Donny Strosberg and France Pietri-Rouxel describe how results now provide a consistent picture of an important role for the human beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity and diabetes.
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PMID:Function and regulation of the beta 3-adrenoceptor. 965 87

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