bibp-3226 and Body-Weight

Neuropeptide Y is a widely distributed neuropeptide that elicits a plethora of physiological effects via interaction with six different receptors (Y(1)-y(6)). Recent attention has focused on the role of neuropeptide Y in the regulation of energy homeostasis. Neuropeptide Y stimulates food intake, inhibits energy expenditure, increases body weight and increases anabolic hormone levels by activating the neuropeptide Y Y(1) and Y(5) receptors in the hypothalamus. Based on these findings, several neuropeptide Y Y(1) and Y(5) receptor antagonists have been developed recently as potential anti-obesity agents. In addition, mice lacking neuropeptide Y, the neuropeptide Y Y(1) receptor or the neuropeptide Y Y(5) receptor have been generated. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide Y Y(1) receptor antagonists, may be useful anti-obesity agents. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. In addition, patients in whom the starvation response is activated, such as formerly obese patients who have lost weight or patients with complete or partial leptin deficiency, may be the best candidates for treatment with a neuropeptide Y receptor antagonist.

Topics: Animals; Anti-Obesity Agents; Arginine; Body Weight; Energy Metabolism; Humans; Neuropeptide Y; Obesity; Pharmaceutical Preparations; Receptors, Neuropeptide Y; Structure-Activity Relationship

Administration of dextran sodium sulfate (DSS) to rodents at varying concentrations and exposure times is commonly used to model human inflammatory bowel disease (IBD). Currently, the criteria used to assess IBD-like pathology seldom include surrogate measures of visceral pain. Thus, we sought to standardize the model and then identify surrogate measures to assess effects on visceral pain. We used various 4% DSS protocols and evaluated effects on weight loss, colon pathology, biochemistry, RNA signature, and open field behavior. We then tested the therapeutic potential of NPY Y1 and/or Y2 receptor inhibition for the treatment of IBD pathology using this expanded panel of outcome measures. DSS caused weight loss and colon shrinkage, increased colon NPY and inflammatory cytokine expression, altered behaviors in the open field and induced a distinct gene metasignature that significantly overlapped with that of human IBD patients. Inhibition of Y1 and/or Y2 receptors failed to improve gross colon pathology. Y1 antagonism significantly attenuated colon inflammatory cytokine expression without altering pain-associated behaviors while Y2 antagonism significantly inhibited pain-associated behaviors in spite of a limited effect on inflammatory markers. A protocol using 7 days of 4% DSS most closely modeled human IBD pathology. In this model, rearing behavior potentially represents a tool for evaluating visceral pain/discomfort that may be pharmacologically dissociable from other features of pathology. The finding that two different NPY receptor antagonists exhibited different efficacy profiles highlights the benefit of including a variety of outcome measures in IBD efficacy studies to most fully evaluate the therapeutic potential of experimental treatments.

Topics: Animals; Arginine; Benzazepines; Body Weight; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Humans; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Receptors, Neuropeptide Y

Tail pinch stimulates food intake in rats. We investigated brain mechanisms of this response and the influence of repeated exposure. Sprague-Dawley rats received acute (5 min) or repeated (5 min/day for 14 days) tail pinch using a padded clip. Acute tail pinch increased 5-min food intake compared with control (0.92 ± 0.2 vs. 0.03 ± 0.01 g, P < 0.01). This response was inhibited by 76% by intracerebroventricular injection of BIBP-3226, a neuropeptide Y1 (NPY1) receptor antagonist, increased by 48% by astressin-B, a corticotropin-releasing factor (CRF) receptor antagonist, and not modified by S-406-028, a somatostatin subtype 2 antagonist. After the 5-min tail pinch without food, blood glucose rose by 21% (P < 0.01) while changes in plasma acyl ghrelin (+41%) and adrenocorticotropic hormone (+37%) were not significant. Two tail pinches (45 min apart) activate pontine and hindbrain catecholaminergic and hypothalamic paraventricular CRF neurons. After 14 days of repeated tail pinch, the 5-min orexigenic response was not significantly different from days 2 to 11 but reduced by 50% thereafter (P < 0.001). Simultaneously, the 5-min fecal pellet output increased during the last 5 days compared with the first 5 days (+58%, P < 0.05). At day 14, the body weight gain was reduced by 22%, with a 99% inhibition of fat gain and a 25% reduction in lean mass (P < 0.05). The orexigenic response to acute 5-min tail pinch is likely to involve the activation of brain NPY1 signaling, whereas that of CRF tends to dampen the acute response and may contribute to increased defecation and decreased body weight gain induced by repeated tail pinch.

Topics: Animals; Arginine; Body Weight; Brain; Corticotropin-Releasing Hormone; Eating; Ghrelin; Male; Neurons; Neuropeptide Y; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Somatostatin

We investigated the role of neuropeptide Y Y(1) receptors in acute, chronic and withdrawal effects of nicotine with reference to feeding behavior. Rats were administered with nicotine, neuropeptide Y, neuropeptide Y Y(1) receptor agonist [Leu(31),Pro(34)]neuropeptide Y or antagonist BIBP3226 (N(2)-diphenylacetyl)-N-[(4-hydroxy-phenyl)-methyl]-D-arginine amide) via i.c.v. route, and food intake was measured at 2 and 6 h post-injection time-points. While acute nicotine or BIBP3226 reduced food intake, increase was observed following neuropeptide Y or [Leu(31),Pro(34)]neuropeptide Y. Nicotine-induced anorexia was antagonized by pre-treatment with neuropeptide Y or [Leu(31),Pro(34)]neuropeptide Y, and potentiated by BIBP3226. Furthermore, effects of chronic nicotine (i.p.) and its withdrawal, alone and in combination with BIBP3226 were evaluated with reference to feeding and body weight. Concurrent administration of BIBP3226 with nicotine prevented the development of tolerance to nicotine-induced anorexia, and withdrawal hyperphagia and weight gain. Moreover, acute BIBP3226 attenuated the hyperphagia following nicotine termination. Additionally, immunocytochemical profile of neuropeptide Y in the hypothalamus was studied following differential nicotine treatments. Acute nicotine treatment dramatically reduced neuropeptide Y immunoreactivity in the arcuate and paraventricular nuclei. Chronic nicotine administration decreased neuropeptide Y immunoreactivity in arcuate, but not in paraventricular nucleus. Nicotine withdrawal resulted in significant increase in the neuropeptide Y immunoreactivity in both the nuclei. Neuropeptide Y immunoreactivity in the lateral hypothalamus did not change following any of the treatments. The results suggest that neuropeptide Y in the arcuate and paraventricular nuclei of hypothalamus may be involved in acute, chronic and withdrawal effects of nicotine on the feeding behavior, possibly via neuropeptide Y Y(1) receptors.

Topics: Animals; Arginine; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Eating; Fluorescent Antibody Technique, Indirect; Immunohistochemistry; Injections, Intraventricular; Male; Microinjections; Neuropeptide Y; Nicotine; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Substance Withdrawal Syndrome; Time Factors

This study evaluated the role of alpha-adrenergic receptor- and neuropeptide Y (NPY) Y1 receptor-mediated vasoconstriction in the collateral circuit of the hind limb. Animals were evaluated either the same day (Acute) or 3 weeks following occlusion of the femoral artery; the 3-week animals were in turn limited to cage activity (Sed) or given daily exercise (Trained). Collateral-dependent blood flows (BFs) were measured during exercise with microspheres before and after alpha-receptor inhibition (phentolamine) and then NPY Y1 receptor inhibition (BIBP 3226) at the same running speed. Blood pressures (BPs) were measured above (caudal artery) and below (distal femoral artery) the collateral circuit. Arterial BPs were reduced by alpha-inhibition (50-60 mmHg) to approximately 75 mmHg, but not further by NPY Y1 receptor inhibition. Effective experimental sympatholysis was verified by 50-100% increases (P < 0.001) in conductance of active muscles not affected by femoral occlusion with receptor inhibition. In the absence of receptor inhibition, vascular conductance of the collateral circuit was minimal in the Acute group (0.13 +/- 0.02), increased over time in the Sed group (0.41 +/- 0.03; P < 0.001), and increased further in the Trained group (0.53 +/- 0.03; P < 0.02). Combined receptor inhibition increased collateral circuit conductances (P < 0.005), most in the Acute group (116 +/- 37%; P < 0.02), as compared to the Sed (41 +/- 6.6%; P < 0.001) and Trained (31 +/- 5.6%; P < 0.001) groups. Thus, while the sympathetic influence of the collateral circuit remained in the Sed and Trained animals, it became less influential with time post-occlusion. Collateral conductances were collectively greater (P < 0.01) in the Trained as compared to Sed group, irrespective of the presence or absence of receptor inhibition. Conductances of the active ischaemic calf muscle, with combined receptor inhibition, were suboptimal in the Acute group, but increased in Sed and Trained animals to exceptionally high values (e.g. red fibre section of the gastrocnemius: approximately 7 ml min(-1) (100 g)(-1) mmHg(-1)). Thus, occlusion of the femoral artery promulgated vascular adaptations, even in vessels that are not part of the collateral circuit. The presence of active sympathetic control of the collateral circuit, even with exercise training, raises the potential for reductions in collateral BF below that possible by the structure of the collateral circuit. However, even with release of

Topics: Acetylcholine; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Arginine; Blood Pressure; Blood Vessels; Body Weight; Collateral Circulation; Heart Rate; Hindlimb; Ischemia; Male; Muscle, Skeletal; Phentolamine; Phenylephrine; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Regional Blood Flow; Vasoconstriction; Vasodilator Agents

Monosodium-glutamate (MSG) is neurotoxic for brain regions devoid of blood-brain barrier when it is injected at high doses during the neonatal period. Neuropeptide Y (NPY) neurons in the arcuate nucleus are particularly sensitive to MSG treatment. But, despite of the large decrease of this potent orexigenic peptide, feeding behavior is only slightly affected. We hypothesized that the hypothalamic NPY receptor system might be modified in these rats. The present study characterizes hypothalamic NPY and NPY receptors in normal and MSG-treated rats. MSG-treated rats were lighter (p < 0.01) and ate 17% less than the control rats (p < 0.01). NPY levels in the mediobasal and mediodorsal hypothalamus were reduced in MSG-treated rats compared to normal rats (-26% and -43%, p < 0.05 and p < 0.01, respectively). Combined hypothalamic Y1 and Y5 NPY receptor density was increased in MSG-treated rats compared to normal rats (+25%, p < 0.04), but affinity remained unaltered. Blockade with a selective Y1 antagonist showed that the Y1 receptor subtype represented more than 90% of the combined Y1 and Y5 receptor populations. The up-regulation of the NPY receptors is an element necessary to maintain food intake at a sufficient level to allow survival and growth of the lesioned rats.

Topics: Animals; Arginine; Body Weight; Eating; Hypothalamus; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Sodium Glutamate

The paraventricular nucleus (PVN) of the hypothalamus is known to modulate feeding, obesity, and ethanol intake. Neuropeptide-Y (NPY), which is released endogenously by neurons projecting from the arcuate nucleus to the PVN, is one of the most potent stimulants of feeding behavior known. The role of NPY in the PVN on ethanol self-administration is unknown. To address this issue, rats were trained to self-administer ethanol via a sucrose fading procedure and injector guide cannulae aimed at the PVN were surgically implanted. Microinjections of NPY and NPY antagonists in the PVN were conducted prior to ethanol self-administration sessions. All doses of NPY significantly increased ethanol self-administration and preference, and decreased water intake. The NPY antagonist D-NPY partially reduced ethanol self-administration and completely blocked the effects of an intermediate dose of NPY (10 fmol) on ethanol intake, preference, and water intake. The competitive non-peptide Y1 receptor antagonist BIBP 3226 did not significantly alter ethanol self-administration or water intake when administered alone in the PVN but it completely blocked the effect of NPY (10 fmol) on ethanol intake. NPY infused in the PVN had no effect on ethanol self-administration when tested in rats that did not have a long history of ethanol self-administration. The doses of NPY tested produced no effect on food intake or body weight measured during the 24-h period after infusion in either ethanol-experienced or ethanol-inexperienced rats. These results indicate that elevation of NPY levels in the PVN potently increases ethanol self-administration and that this effect is mediated through NPY Y1 receptors.

Topics: Alcohol Drinking; Animals; Arginine; Body Weight; Dose-Response Relationship, Drug; Ethanol; Hypothalamus; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Rats, Long-Evans; Water

In mammals, neuropeptide Y (NPY) is a potent orexigenic factor. In the present study, third brain ventricle (intracerebroventricular) injection of goldfish NPY (gNPY) caused a dose-dependent increase in food intake in goldfish, and intracerebroventricular administration of NPY Y1-receptor antagonist BIBP-3226 decreased food intake; the actions of gNPY were blocked by simultaneous injection of BIBP-3226. Goldfish maintained on a daily scheduled feeding regimen display an increase in NPY mRNA levels in the telencephalon-preoptic area and hypothalamus shortly before feeding; however, a decrease occured in optic tectum-thalamus. In both fed and unfed fish, brain NPY mRNA levels decreased after scheduled feeding. Restriction in daily food ration intake for 1 wk or food deprivation for 72 h resulted in increased brain NPY mRNA levels. Results from these studies demonstrate that NPY is a physiological brain signal involved in feeding behavior in goldfish, mediating its effects, at least in part, through Y1-like receptors in the brain.

Topics: Animals; Anti-Anxiety Agents; Arginine; Body Weight; Brain Chemistry; Diet; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Female; Food Deprivation; Gene Expression; Goldfish; Growth Hormone; Injections, Intraventricular; Male; Neuropeptide Y; Receptors, Neuropeptide Y; RNA, Messenger; Third Ventricle

Pubertal development results from the coordinate secretion of gonadotropin-releasing hormone (GnRH) by hypothalamic GnRH neurons. Central administration of neuropeptide Y (NPY) to prepubertal rats can indefinitely delay sexual maturation by inhibiting this GnRH secretion. The aim of the present study was to further investigate the physiological role of NPY in pubertal development, and to assess the potential involvement of its Y1 receptor subtype in this setting. The timing of pubertal development was determined in juvenile female rats receiving chronic i.c.v. infusion of a specific Y1 receptor antagonist (BIBP 3226), and compared with controls. Although treatment with BIBP 3226 did not affect the age at vaginal opening, animals receiving the Y1 antagonist experienced a quicker progression through puberty, corroborated by a significant increase in pituitary luteinizing hormone content. This effect of BIBP3226 on the gonadotrope axis occurred without apparent toxicity, but was accompanied by a transient decrease in body weight gain on the first day of treatment, suggesting an effect on appetite. Together, our results add to the evidence in favour of a role for NPY in the onset of puberty. They are entirely consistent with the proposed inhibition exerted by endogenous hypothalamic NPY before the onset of pubertal development. They also suggest that the Y1 subtype of NPY receptors is involved in this effect.

Topics: Aging; Animals; Arginine; Body Weight; Female; Hypothalamus; Luteinizing Hormone; Neuropeptide Y; Pituitary Gland; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Sexual Maturation; Vagina; Weight Gain

This study aimed to elucidate possible age-related changes in islet blood perfusion in lean and obese C57BL/6 mice. Obese mice aged 1 mo were hyperglycemic and hyperinsulinemic and had an increased islet blood flow compared with age-matched lean mice. This augmented blood flow could be abolished by pretreatment with leptin. The islet blood perfusion was, in contrast to this, markedly decreased in obese 6- to 7-mo-old animals compared with age-matched lean mice. Reversal of hyperglycemia, but not hyperinsulinemia, in these obese mice with phlorizin normalized the islet blood flow. Spontaneous reversal of hyperglycemia, but not hyperinsulinemia, was seen in the 12-mo-old obese mice. Islet blood perfusion in obese mice at this age did not differ compared with lean mice. It is suggested that the initial increase in islet blood flow in obese mice is due to the leptin deficiency. The subsequent decrease in islet blood perfusion is probably caused by the chronic hyperglycemia. The described islet blood flow changes may be of importance for impairment of islet function in obese-hyperglycemic mice.

Topics: Aging; Animals; Arginine; Blood Glucose; Body Weight; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Pancreas; Perfusion; Phlorhizin; Proteins; Receptors, Leptin; Receptors, Neuropeptide Y; Regional Blood Flow