neuropeptide-y and sibutramine

Some neuropeptides and monoaminergic neurotransmitters may affect hypothalamic feeding centres, sympathetic activity and thermogenesis. Sibutramine (BTS54524; N-[1-[1(4-chloro phenyl) cyclobutyl]-3methyl N,N-dimethylamine hydrochloride monohydrate) is a new 5-HT serotonin and noradrenaline reuptake inhibitor (SNRI), antiobesity drug. The aim of this study was to evaluate the effects of the sibutramine therapy on plasma neuropeptide Y (NPY), insulin, leptin and beta-endorphin concentrations in obese patients.. Sibutramine, serotonin and noradrenaline reuptake antiobesity drug was administered for 6 months in a dose of 10 mg daily in 60 obese women (BMI 30-40 kg/m2) (mean 34 kg/m2). Plasma NPY, leptin, beta-endorphin and insulin concentrations were measured with RIA methods using commercial kits (Peninsula Lab, Linco, Peninsula Lab, Swierk respectively). The above neuropeptides levels were evaluated before and after the 6 month sibutramine therapy in 60 obese women as well as in 30 obese women on low caloric diet and in 30 of the control group.. In 85% obese patients a decrease of body weight was found after 6 month therapy with sibutramine. A decrease in total cholesterol, LDL and triglycerides and an increase in HDL were observed after the sibutramine treatment. We have demonstrated that the sibutramine therapy leads to the decrease of plasma NPY, beta-endorphin, insulin and leptin concentrations in obese patients. After low diet therapy we have observed a decrease in plasma leptin levels, however we did not find significant changes in plasma leptin, NPY, beta-endorphin and insulin concentrations.. We suggest that the effects on the disturbed activity of NPY, beta-endorphin, insulin and leptin may be involved in the mechanism of sibutramine action.

Topics: Adolescent; Adrenergic Uptake Inhibitors; Adult; Analysis of Variance; Appetite Depressants; Appetite Regulation; beta-Endorphin; Cyclobutanes; Female; Humans; Insulin; Leptin; Neuropeptide Y; Obesity; Reference Values; Selective Serotonin Reuptake Inhibitors; Statistics, Nonparametric

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anti-Obesity Agents; Appetite; Arcuate Nucleus of Hypothalamus; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Energy Intake; Ghrelin; Humans; Hunger; Intercellular Signaling Peptides and Proteins; Lactones; Leptin; Mice; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Orlistat; Peptide Fragments; Peptide Hormones; Peptide YY; Phentermine; Proteins; Receptors, Corticotropin; Receptors, Melanocortin; Weight Loss

The aim of the present work was to describe the effects of sibutramine on body weight and adiposity and to establish the potential involvement of neuropeptide Y (NPY) and orexins in the anorectic action of this drug. Male obese Zucker rats were daily administered with sibutramine (10 mg/kg, intraperitoneal) for two weeks. Carcass composition was assessed using the official methods of the Association of Official Analytical Chemists. Total body oxygen consumption was measured daily for 60 min before sibutramine or saline injection and for 30 min (from 60 to 90 min) after drug or saline injection. Hypothalamic arcuate and paraventricular nuclei, and the lateral hypothalamic area were immunostained for NPY, orexin A and orexin B. Commercial kits were used for serum determinations. Reductions in body weight and adipose tissue weights were observed after sibutramine treatment in obese Zucker rats. No changes in NPY immunostaining in the arcuate and paraventricular nuclei were found. Orexin A and orexin B immunostaining was not modified in the lateral hypothalamic area in treated rats. The reduction in body weight and adiposity induced by sibutramine was achieved by both a reduction in food intake and an increase in energy expenditure. NPY and orexins do not seem to be involved in the anorectic effect of sibutramine.

Topics: Adipose Tissue; Animals; Appetite Depressants; Body Composition; Carrier Proteins; Cyclobutanes; Drinking; Eating; Energy Metabolism; Hypothalamus; Intracellular Signaling Peptides and Proteins; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Organ Size; Oxygen Consumption; Rats; Rats, Zucker; Weight Gain

Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC(50) (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat.

Topics: Animals; Appetite Depressants; Cerebral Ventricles; Cyclobutanes; Energy Intake; Feeding Behavior; Injections, Intraventricular; Kinetics; Neuropeptide Y; Peptide Fragments; Rats; Rats, Wistar; Rats, Zucker; Receptors, Neuropeptide Y

We studied the effects of the novel noradrenaline and serotonin (5-HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones. Chow-fed and dietary-obese (DIO) male Wistar rats were given sibutramine (3 mg kg(-1) day(-1) p.o.) or deionized water for 21 days. Sibutramine decreased food intake throughout the treatment period in both dietary-obese rats (P<0.0001) and lean rats (P<0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary-obese (P<0.005) and 8% lower in lean (P<0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine-treated dietary-obese rats (P<0.05), and in treated lean rats (P<0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P<0.005), and this was corrected by sibutramine treatment (P<0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls. The hypophagic and anti-obesity effects of sibutramine in dietary-obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones.

Topics: Adipose Tissue; Animals; Appetite Depressants; Body Weight; Cyclobutanes; Diet; Feeding Behavior; Hypothalamus; Insulin Resistance; Leptin; Male; Neurons; Neuropeptide Y; Obesity; Rats; Rats, Wistar; RNA, Messenger

Chronic administration of sibutramine lowers body weight, presumably by altering brain monoamine metabolism. Here the effect of sibutramine on sympathoadrenal function (24-h urine norepinephrine and epinephrine levels) and arcuate nucleus (ARC) neuropeptide Y (NPY) and proopiomelanocortin (POMC) expression was assessed in diet-induced obese rats fed a low-fat diet. Chronic (10 wk) sibutramine [5 mg. kg(-1). day(-1) ip; rats fed ad libitum and injected with sibutramine (AS)] lowered body weight by 15% but only transiently (3-4 wk) reduced intake compared with vehicle-treated controls [rats fed chow ad libitum and injected with vehicle daily (AV)]. Other rats food restricted (RS) to 90% of the weight of AS rats and then given sibutramine restored their body weights to the level of AS rats when allowed libitum food intake. After reequilibration, RS rats were again energy restricted to reduce their weight to 90% of AS rats, and additional vehicle-treated rats (RV) were restricted to keep their body weights at the level of AS rats for 3 wk more. Terminally, total adipose depot weights and leptin levels paralleled body weights (AV > AS = RV > RS), although AS rats had heavier abdominal and lighter peripheral depots than RV rats of comparable body weights. Sibutramine treatment increased sympathetic activity, attenuated the increased ARC NPY, and decreased POMC mRNA levels induced by energy restriction in RV rats. Thus sibutramine lowered the defended body weight in association with compensatory changes in those central pathways involved in energy homeostasis.

Topics: Adipose Tissue; Animals; Appetite Depressants; Arcuate Nucleus of Hypothalamus; Body Weight; Cyclobutanes; Energy Intake; Epinephrine; Feeding Behavior; Gene Expression Regulation; Homeostasis; Leptin; Neuropeptide Y; Norepinephrine; Obesity; Organ Size; Pro-Opiomelanocortin; Rats; RNA, Messenger

The effect of the 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake inhibitor sibutramine was studied in food deprived, neuropeptide Y (NPY)- or muscimol-injected rats. Sibutramine dose-dependently reduced feeding caused by food-deprivation (ED50 = 5.1+/-0.8 mg kg(-1)) or by NPY injection into the paraventricular nucleus of the hypothalamus (ED50 = 6.0+/-0.5 mg kg(-1)). The increase in food intake caused by muscimol injected into the dorsal raphe was not modified by sibutramine (1-10 mg kg(-1)). The hypophagic effect of 5.1 mg kg(-1) sibutramine in food-deprived rats was studied in rats pretreated with different serotonin receptor antagonists. Metergoline (non-selective, 0.3 and 1.0 mg kg(-1)), ritanserin (5-HT2A/2C, 0.5 and 1.0 mg kg(-1)) and GR127935 (5-HT1B/1D), 0.5 and 1.0 mg kg(-1)) did not modify the hypophagic effect of sibutramine, while SB206553 (5-HT2B/2C, 5 and 10 mg kg(-1)) slightly but significantly reduced it (Fint(2.53) = 3.4; P<0.05). The reduction in food intake caused by 6.0 mg kg(-1) sibutramine in NPY-injected rats was not modified by GR127935 (1.0 mg kg(-1)). The results suggest that, with the possible exception of a partial involvement of 5-HT2B/2C receptors in sibutramine's hypophagia in food-deprived rats, 5-HT1 and 5-HT2 receptor subtypes do not play an important role in the hypophagic effect of sibutramine, at least in the first 2 h after injection.

Topics: Animals; Appetite Depressants; Cyclobutanes; Dose-Response Relationship, Drug; Eating; Male; Neuropeptide Y; Oxadiazoles; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin