Inverse Agonism at α2A Adrenoceptors Augments the Hypophagic Effect of Sibutramine in Rats

Janhunen, Sanna; Zwaal, Esther M. van der; Fleur, Susanne E. la; Adan, Roger A.H.

doi:10.1038/oby.2011.51

Cited by 16 publications

(24 citation statements)

References 42 publications

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“…The adrenergic system of zebrafish has been well characterized by many researchers, and α2a-adrenoceptors have been shown to be expressed in the hypothalamus [64]. These findings suggest the involvement of adrenergic signaling in the satiety center of the zebrafish brain, similar to that seen in mammals [65]. Mazindol, a reuptake inhibitor of norepinephrine and phentermine (a releaser of norepinephrine), acts on the hypothalamus to stimulate the adrenal glands to increase norepinephrine, subsequently reducing hunger in zebrafish (Fig.…”

Section: Discussionmentioning

confidence: 70%

A High-Throughput Fluorescence-Based Assay System for Appetite-Regulating Gene and Drug Screening

et al. 2012

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The increasing number of people suffering from metabolic syndrome and obesity is becoming a serious problem not only in developed countries, but also in developing countries. However, there are few agents currently approved for the treatment of obesity. Those that are available are mainly appetite suppressants and gastrointestinal fat blockers. We have developed a simple and rapid method for the measurement of the feeding volume of Danio rerio (zebrafish). This assay can be used to screen appetite suppressants and enhancers. In this study, zebrafish were fed viable paramecia that were fluorescently-labeled, and feeding volume was measured using a 96-well microplate reader. Gene expression analysis of brain-derived neurotrophic factor (bdnf), knockdown of appetite-regulating genes (neuropeptide Y, preproinsulin, melanocortin 4 receptor, agouti related protein, and cannabinoid receptor 1), and the administration of clinical appetite suppressants (fluoxetine, sibutramine, mazindol, phentermine, and rimonabant) revealed the similarity among mechanisms regulating appetite in zebrafish and mammals. In combination with behavioral analysis, we were able to evaluate adverse effects on locomotor activities from gene knockdown and chemical treatments. In conclusion, we have developed an assay that uses zebrafish, which can be applied to high-throughput screening and target gene discovery for appetite suppressants and enhancers.

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Section: Discussionmentioning

confidence: 70%

A High-Throughput Fluorescence-Based Assay System for Appetite-Regulating Gene and Drug Screening

et al. 2012

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“…However, increased Npy and Agrp expression was not associated with hyperphagia or decreased energy expenditure in our setting. Previous studies have shown that NPY's hyperphagic response could be prevented, and sibutramine's and bupropion's hypophagic effects potentiated by blocking pre-junctional α 2 -ARs, pointing to an important role of these receptors in regulation of caloric intake [58][59][60]. Also, earlier studies have demonstrated that the activation of central α 2 -ARs increases food intake [61].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, ablation of central α 2A -ARs can directly induce satiety, but the effect may be counterbalanced by enhanced expression of Npy and Agrp in the hypothalamus to compensate the hypophagia. The net effect is thus no significant effect on food intake, which may be the underlying cause why α 2 -AR antagonists alone are ineffective in appetite control, but show additive effects when combined with, for example, sibutramine or bupropion [58,60].…”

Section: Discussionmentioning

confidence: 99%

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

et al. 2018

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The alpha2A-adrenoceptors (α_2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α_2A^–/– mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α_2A^–/– mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α_2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α_2A^–/– mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α_2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α_2A^–/– mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α_2A^–/– mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α_2A-AR signalling promoted weight loss more efficiently than exercise with normal α_2A-AR function. These results suggest that blockade of α_2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.

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“…In rats, prazosin does not alter operant responding for food (Le et al, 2011) and has no effect on total caloric intake, meal size or number of meals eaten (Janhunen et al, 2011). In humans, there do not appear to be any reports of prazosin altering appetite, caloric intake or body weight in individuals undergoing prolonged prazosin treatment for post traumatic stress disorder (PTSD) or hypertension.…”

Section: Discussionmentioning

confidence: 99%

Prazosin Reduces Alcohol Drinking Throughout Prolonged Treatment and Blocks the Initiation of Drinking in Rats Selectively Bred for High Alcohol Intake

Froehlich

Hausauer

Federoff

et al. 2013

Alcohol Clin Exp Res

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BACKGROUND This study examined whether prazosin reduces alcohol drinking over the course of prolonged treatment and whether it blocks initiation of alcohol drinking in rats with a genetic predisposition toward high alcohol drinking, i.e, alcohol-preferring (P) rats. METHODS In study one, alcohol-experienced P rats that had been drinking alcohol 2 hrs/day for several months were treated daily with prazosin (0, 0.5, 1.0 or 2.0 mg/kg BW) for 7 weeks. In study two, alcohol-naïve P rats were treated daily with prazosin (0, 1.0 or 2.0 mg/kg BW) for two weeks prior to, or concomitantly with, initiation of alcohol access and throughout 3 weeks of alcohol availability. Prazosin treatment and alcohol access were then discontinued for 2 weeks followed by reinstatement of alcohol access without prazosin treatment for 4 weeks, followed by resumption of daily prazosin treatment (2.0 mg/kg BW) for 3 weeks. RESULTS Prazosin reduced alcohol drinking throughout 7 weeks of treatment in P rats accustomed to drinking alcohol. Following termination of prazosin treatment, alcohol drinking slowly returned to pretreatment baseline. Reduced alcohol intake was accompanied by increased water intake. In alcohol-naïve P rats, prazosin administration prior to the first opportunity to drink alcohol and throughout 3 weeks of alcohol access retarded acquisition of alcohol drinking and reduced the amount of alcohol consumed. When prazosin was administered concomitantly with the first opportunity to drink alcohol, it abolished acquisition of alcohol drinking. Discontinuation of prazosin treatment allowed expression of a genetic predisposition toward high alcohol drinking to gradually emerge. Prazosin retained the ability to reduce alcohol intake with repeated treatments. CONCLUSIONS Prazosin decreased alcohol drinking during prolonged treatment and may be useful for treating alcoholism and alcohol use disorders. Prazosin may also be useful for deterring initiation of drinking in individuals with a family history of alcoholism.

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Inverse Agonism at α2A Adrenoceptors Augments the Hypophagic Effect of Sibutramine in Rats

Cited by 16 publications

References 42 publications

A High-Throughput Fluorescence-Based Assay System for Appetite-Regulating Gene and Drug Screening

A High-Throughput Fluorescence-Based Assay System for Appetite-Regulating Gene and Drug Screening

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

Prazosin Reduces Alcohol Drinking Throughout Prolonged Treatment and Blocks the Initiation of Drinking in Rats Selectively Bred for High Alcohol Intake

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