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

The ratio of alpha- to beta-receptors is thought to regulate the lipolytic index of adipose depots. To determine whether increasing the activity of the beta 1-adrenergic receptor (AR) in adipose tissue would affect the lipolytic rate or the development of this tissue, we used the enhancer-promoter region of the adipocyte lipid-binding protein (aP2) gene to direct expression of the human beta 1 AR cDNA to adipose tissue. Expression of the transgene was seen only in brown and white adipose tissue. Adipocytes from transgenic mice were more responsive to beta AR agonists than were adipocytes from nontransgenic mice, both in terms of cAMP production and lipolytic rates. Transgenic animals were partially resistant to diet-induced obesity. They had smaller adipose tissue depots than their nontransgenic littermates, reflecting decreased lipid accumulation in their adipocytes. In addition to increasing the lipolytic rate, overexpression of the beta 1 AR induced the abundant appearance of brown fat cells in subcutaneous white adipose tissue. These results demonstrate that the beta 1 AR is involved in both stimulation of lipolysis and the proliferation of brown fat cells in the context of the whole organism. Moreover, it appears that it is the overall beta AR activity, rather than the particular subtype, that controls these phenomena.
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PMID:Transgenic mice overexpressing the beta 1-adrenergic receptor in adipose tissue are resistant to obesity. 899 85

Human HDL are heterogeneous in their metabolism and comprise small, nascent pre-beta-HDL and more mature alpha-HDL. Evidence exists that pre-beta 1-HDL is the initial acceptor of cellular free cholesterol, which then transfers sequentially to other pre-beta species and then, after esterification, into alpha-HDL. As HDL particles are themselves transformed during this process, we postulated that in disorders in which HDL-cholesterol is low, such as obesity, the distribution of HDL particles may be disturbed. In this study, we analyzed the HDL profile in 23 obese and 18 lean subjects, and further investigated the effects of dietary change in 15 obese subjects. HDL were separated by two-dimensional nondenaturing electrophoresis and the apoA-I content in each fraction was quantified. alpha 1-HDL in obese subjects was significantly lower (P < 0.001) and alpha 2-, alpha 3-, and pre-beta 1-HDL were significantly higher (P < 0.05 for alpha 2-HDL, P < 0.001 for alpha 3- and pre-beta 1-HDL) than in lean subjects. On stepwise regression analysis, body mass index accounted for 52% (negatively) of the variance in alpha 1-HDL and for 16% and 33% (positively) for the variances in alpha 3- and pre-beta 1-HDL, respectively. alpha 1- and pre-beta 3-HDL increased significantly after low-fat, oleic acid-rich, or alpha-linolenic acid-rich diets. The profile of alpha-HDL particles and also of pre-beta-HDL particles therefore shifted to smaller species in obese subjects, and this was influenced by dietary fat. Increased pre-beta 1-HDL-apoA-I in obese subjects is likely to derive from increased HDL catabolism but may also reflect diminished transformation of pre-beta 1- to pre-beta 2-HDL which might reduce capacity for reverse cholesterol transport and partly explain lower HDL-cholesterol levels.
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PMID:Altered properties of high density lipoprotein subfractions in obese subjects. 910 41

The beta 3 subtype of adrenaline and noradrenaline receptors has now been extensively characterized at the structural and functional levels. Ligand binding and adenylyl cyclase activation studies helped define a beta-adrenergic profile that is quite distinct from that of the beta 1- and beta 2-adrenergic receptors, but strongly reminiscent of most of the "atypical" responses reported in earlier pharmacologic studies. Human, other large mammal, and rodent receptors share most of the characteristic beta 3 properties, although obvious species-specific differences have been identified. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to be correlated with hereditary obesity in Pima Indians and in Japanese individuals, and in Western obese patients with increased dynamic capacity to add on weight and develop non-insulin-dependent diabetes mellitus (NIDDM). A mild weight increase was also shown to develop in female, but not male, mice in which the beta 3 receptor gene was disrupted. Taken together, these results now provide a consistent picture of an important role of the beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity.
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PMID:Structure and function of the beta 3-adrenergic receptor. 913 Dec 60

The anti-obesity and anti-diabetic effects of a highly specific beta 3-adrenoceptor agonist, CL316,243 (CL; beta 1: beta 2: beta 3 = 0:1:100,000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and Long-Evans Tokushima Otsuka (control) rats. Daily injection of CL (0.1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27%; control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5'-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue.
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PMID:Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat. 915 Jun 93

Cardiovascular complications of obesity are more common in men than women. Sex differences in visceral fat lipolysis may be of importance in this respect, since increased release of free fatty acids (FFAs) from visceral fat to the liver by the portal venous system has been thought to cause several metabolic complications due to obesity, such as hypertension, hyperlipidemia, and glucose intolerance. The aim of this study was to investigate sex differences in clinical characteristics and visceral fat mobilization in obesity. Obese subjects (22 male and 23 female) undergoing elective surgery were matched for body mass index and age. The males had both higher waist-to-hip ratio (WHR), sagittal diameter, blood pressure, fat-cell volume, plasma insulin, glucose, and triglyceride and lower HDL cholesterol levels than the females. The rate of norepinephrine-induced FFA and glycerol release was twofold higher in men (P = .02). No significant reutilization of FFA was observed. The difference in maximum norepinephrine-induced rate of lipolysis between men and women was independent of both WHR and sagittal diameter and was an independent regressor for levels of plasma glucose and plasma HDL cholesterol. Fat-cell volume was an independent regressor for plasma triglycerides and blood pressure. No sex differences in the lipolytic sensitivity to beta 1- or beta 2-adrenoceptor-specific agonists or in the antilipolytic effect of insulin were observed. However, the lipolytic beta 3-adrenoceptor sensitivity was 12 times higher (P = .004) and the antilipolytic alpha 2-adrenoceptor sensitivity 17 times lower (P = .003) in men. Furthermore, lipolysis induced by agents acting at the adenylate cyclase and protein kinase A levels were almost twofold enhanced in men. However, no sex difference in maximum hormone-sensitive lipase activity was observed. In conclusion, in obesity, catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat-cell volume but also to a decrease in the function of alpha 2-adrenoceptors, an increase in the function of beta 3-adrenoceptors, and an increased ability of cyclic AMP to activate hormone-sensitive lipase. These factors may contribute to gender-specific differences in metabolic and cardiovascular disturbances accompanied by obesity.
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PMID:Sex differences in visceral fat lipolysis and metabolic complications of obesity. 926 Dec 82

1. Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. 2. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. 3. Sibutramine (10 mg kg-1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the alpha 1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg-1, i.p.), and partially antagonized by the beta 1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg-1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg-1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg-1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg-1, p.o.). 4. By contrast, the alpha 2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg-1, i.p.) and the beta 2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg-1, i.p.) did not reduce the decrease in food intake induced by sibutramine. 5. These results demonstrate that beta 1-adrenoceptors, 5-HT2A/2C-receptors and particularly alpha 1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.
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PMID:Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat. 928 94

The major regulator of lipolysis in white adipocytes and brown adipocytes is cAMP and the actions of cAMP are mediated by protein kinase A (PKA). Multiple subunits of PKA, including RII beta, R1 alpha, C alpha, and C beta 1, are expressed in fat cells but the major holoenzyme assembled under normal conditions contains RII beta and C alpha. Targeted disruption of the RII beta gene in mice revealed that both white and brown adipocytes are capable of compensating by increasing the level of RI alpha. Nevertheless, the mice display a lean phenotype, have an elevated metabolic rate due to activation and induction of uncoupling protein in brown fat, and are resistant to diet-induced obesity and insulin resistance. Although the metabolic disturbances in white and brown fat tissue may explain most of the phenotypic changes, the loss of neuronal expression of RII beta may also contribute to the alterations in energy balance. Specific neuronal defects have been characterized that prevent the normal changes in gene expression seen with drugs that act through the dopaminergic pathway. The RII beta mutant mouse provides an interesting model of obesity resistance and demonstrates that chronic changes in the PKA signaling system can lead to stable alterations in energy storage and utilization.
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PMID:Cyclic AMP, PKA, and the physiological regulation of adiposity. 976 7

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans.
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PMID:Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update. 1033 19

The characterization in 1989 of the gene encoding the beta 3-adrenoceptor helped to interpret the results of pharmacological experiments on atypical effects of catecholamines distinct from the classical activation of beta 1 and beta 2 adrenoceptors. In rodents, the beta 3 adrenoceptor is abundantly expressed in white adipose tissue where energy is stored in the form of triglycerides and in brown adipose tissue that is specialized for thermogenesis. Treatment of rodents with beta 3 adrenoceptor agonists induces a weight loss related to the stimulation of lipolysis in the two types of tissues. These results led to propose the use of these agonists for the treatment of human obesity and NIDDM. However, the poor lipolytic effect of these agonists in human adipose tissue and the recent discovery of functional beta 3 adrenoceptors in the human heart raise new questions on the therapeutic use of beta 3-adrenoceptor agonists in man. In the human ventricle, these agonists induce a negative inotropic effect. In vessels, stimulation of beta 3-adrenoceptors produces a vasodilation. If these effects are conserved in the failing heart, they could shed a new light on the pathogenic role of the hyperadrenergism associated with cardiac failure, as well as on its treatment with beta-adrenoceptor blockers.
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PMID:[Beta 3 adrenergic receptor: physiologic role and potential therapeutic applications]. 1138 23

Uncoupling protein (UCP) is a transporter family present in the mitochondrial inner membrane, and as its name suggests, it uncouples respiration from ATP synthesis by dissipating the transmembrane proton gradient as heat. UCP is now recognized as a key molecule in metabolic thermogenesis such as cold- and diet-induced heat production, which is a significant component of energy expenditure, and its dysfunction contributes to the development of obesity. Among the UCP family, UCP-1 is expressed exclusively in brown adipose tissue (BAT), while UCP-2 is present in many organs and UCP-3 is in skeletal muscle. BAT thermogenesis by UCP-1, which has been studied most extensively, is controlled directly by sympathetic nerves principally through the beta-adrenergic action of norepinephrine. Since the beta 3-adrenoceptor is present primarily in adipose tissues, its selective agonists stimulate BAT thermogenesis and also lipid mobilization in white adipose tissue without any noticeable effect on beta 1- and beta 2-adrenoceptos. Therefore, beta 3-adrenoceptor agonists would be promising for the pharmacotherapy of obesity. UCP gene expression is up regulated by ligands for nuclear receptors such as thyroid hormone receptor, peroxisome proliferator-activated receptors (PPAR) and retinoid-X receptor. Long chain fatty acids and some of their metabolites are known to activate PPAR and thereby lead to abundant expression of UCP, which may also contribute to increase in energy expenditure and prevention of obesity. The activity of UCP is suppressed by purine nucleotides but activated by fatty acids. Thus, fatty acids increase UCP-mediated thermogenesis by direct activation of UCP and also by increased gene expression, implying some specific fatty acids or their derivatives as an effective anti-obesity tool.
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PMID:[Mitochondrial uncoupling protein as a target of pharmacotherapy for obesity]. 1172 36


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