exenatide and Anorexia

Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT

Topics: Aminopyridines; Animals; Anorexia; Appetite; Body Weight; Dorsal Raphe Nucleus; Exenatide; Feeding Behavior; Fenclonine; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Indoles; Liraglutide; Male; Peptides; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin Antagonists; Venoms; Weight Loss

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms including hyperphagia and hyperghrelinemia. In this study, male Snord116del mice were characterized and tested for their acute and chronic responses to anorexic substances related to the ghrelin pathway. In comparison with their wild-type littermates, the food intake rate of Snord116del mice was 14% higher when fed ad libitum, and 32% to 49% higher within 12 hours after fasting. Fasted Snord116del mice were less sensitive to the acute anorexic effect of competitive antagonist [d-Lys(3)]-GHRP6, YIL-781, and reverse agonist [d-Arg(1),d-Phe(5),d-Trp(7,9),Leu(11)]-substance P (SPA) of ghrelin receptor GHS-R. All 3 GHS-R inhibitors failed to inhibit chronic food intake of either Snord116del or wild-type mice due to rapid adaptation. Although fasted Snord116del mice had normal sensitivity to the acute anorexic effect of glucagon-like peptide 1 receptor agonist exenatide, those fed ad libitum required a higher dose and more frequent delivery to achieve ∼15% suppression of long-term food intake in comparison with wild-type mice. Ghrelin, however, is unlikely to be essential for the anorexic effect of exenatide in fed mice, as shown by the fact that exenatide did not reduce ghrelin levels in fed mice and food intake of ghrelin(-/-) mice fed ad libitum could be suppressed by exenatide. In conclusion, this study suggests that GHS-R may not be an effective therapeutic target, and in contrast, exenatide may produce anorexic effect in PWS individuals.

Topics: Analysis of Variance; Animals; Anorexia; Disease Models, Animal; Eating; Exenatide; Fasting; Ghrelin; Humans; Hyperphagia; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligopeptides; Peptides; Piperidines; Prader-Willi Syndrome; Quinazolinones; Receptors, Ghrelin; RNA, Small Nucleolar; Substance P; Venoms

Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of exendin-4 in the brain, little data exists on the central effects of liraglutide, a long-acting GLP-1R agonist with much closer structural homology to native GLP-1. In lean, Long-Evans rats, we found that direct intra-third cerebroventricular (i3vt) administration of 0.26 nmol liraglutide caused a 50% reduction in food intake. However, exendin-4 produced the same reduction in food intake with 10-fold greater potency (0.02 nmol). These data are supported by similar c-Fos immunoreactivity in the hypothalamic paraventricular nuclei by exendin-4 as compared to liraglutide despite differing doses. The anorectic effects of both drugs were blocked with i3vt pre-treatment of a GLP-1R competitive antagonist, exendin(9-39), indicating that both drugs required the GLP-1R for their effects. Exendin-4, and not liraglutide, caused hyperglycemia when given i3vt prior to an oral glucose tolerance test, although liraglutide did not lower glucose. Thus, these data show that GLP-1R agonists have differing anorectic potencies in the CNS, which may account for some of their clinical differences. Additionally, we show here that the glucose lowering properties of acute administration of GLP-1R agonists are not accounted for by their central effects.

Topics: Animals; Anorexia; Eating; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperglycemia; Hypoglycemic Agents; Hypothalamus; Liraglutide; Male; Peptides; Rats; Rats, Long-Evans; Receptors, Glucagon; Venoms

Exendin-4 (Ex4), a peptide initially found in the saliva of the Gila monster, can activate the signaling pathway of the incretin hormone glucagon-like peptide-1 (GLP-1) through the GLP-1 receptor (GLP-1R). We previously reported that a chimera protein consisting of Ex4 and mouse IgG heavy chain constant regions (Ex4/Fc) can exert biological effects of GLP-1, such as improving glycemic control and ameliorating manifestations in diabetic mice. The aim of this study was to determine whether Ex4/Fc is effective in modulating energy homeostasis in mice. Our results showed that in vivo expression of Ex4/Fc by intramuscular injection of the plasmid encoding Ex4/Fc followed by local electroporation effectively decreased food intake in the mice on high-fat diet (HFD) feeding. In addition, the reduced energy intake was associated with the decreased excrements from the Ex4/Fc-treated HFD mice but not the Fc control mice. Remarkably, the Ex4/Fctreated HFD mice displayed significantly lower triglyceride (TG) levels when compared with the control mice. Interestingly, while the leptin levels were not changed, the circulating ghrelin levels were higher in Ex4/Fc mice than those in the Fc control mice. These results suggested that Ex4/Fc can improve energy metabolism and lipid metabolism through GLP-1R in mice under excessive nutrition conditions.

Topics: Animals; Anorexia; Appetite Depressants; Cell Line; Cell Proliferation; Culture Media, Conditioned; Diet, High-Fat; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Islets of Langerhans; Mice; Peptides; Receptors, Glucagon; Recombinant Fusion Proteins; Venoms

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Anorexia; Antimetabolites; Appetite Regulation; Cell Line; Deoxyglucose; Drinking; Eating; Energy Metabolism; Exenatide; Fructose; Glucagon-Like Peptide-1 Receptor; Glucose; Hypoglycemic Agents; Hypothalamus; Male; Mice; Mice, Knockout; Motor Activity; Neurons; Peptides; Receptors, Glucagon; Ribonucleotides; Signal Transduction; Venoms

A physiological role in satiety is proposed for glucagon-like peptide-1 (GLP-1), secreted by the distal intestine in response to ingested nutrients. Here we report that in rats, ip injection of the GLP-1 receptor (GLP-1-R) antagonist exendin 9-39 (Ex9) elicited hyperphagia, but only at times of day when intake is otherwise low. Furthermore, ip administration of Ex9 attenuated satiety induced by either a voluntarily consumed sucrose meal (by 100%) or an intragastric glucose load (by 40%). To determine whether these effects involve blockade of GLP-1-R in brain or at a peripheral site, we injected Ex9 either centrally (into the third ventricle) or peripherally (ip) prior to GLP-1 injected either centrally or peripherally. Anorexia induced by peripheral GLP-1 was fully blocked by peripheral, but not central, pretreatment with Ex9, whereas the opposite was true for anorexic effect of central GLP-1. Thus, ip Ex9 appears to attenuate satiety via peripheral GLP-1-R blockade. Finally, anorexia induced by ip injection of exendin-4 (a GLP-1-R agonist) was due to both reduced meal size and increased duration between meals. We conclude that GLP-1 released from the intestine in response to ingested nutrients is a physiologically active satiety signal.

Topics: Animals; Anorexia; Eating; Exenatide; Glucagon-Like Peptide-1 Receptor; Injections; Male; Peptides; Rats; Receptors, Glucagon; Satiety Response; Venoms

Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting GLP-1 receptor (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of GLP-1 and Ex4, but it is possible that the two peptides control feeding via distinct mechanisms.. In this study, the anorectic effects of intracerebroventricular GLP-1 and Ex4, and the sensitivity of these effects to GLP-1r antagonism, were compared in rats. In addition, the GLP-1r dependence of the anorectic effect of intracerebroventricular Ex4 was assessed in GLP-1r(-/-) mice.. Intracerebroventricular Ex4 was 100-fold more potent than GLP-1 at reducing food intake, and this effect was insensitive to GLP-1r antagonism. However, GLP-1r antagonists completely blocked the anorectic effect of intraperitoneal Ex4. Despite the insensitivity of intracerebroventricular Ex4 to GLP-1r antagonism, intracerebroventricular Ex4 failed to reduce food intake in GLP-1r(-/-) mice.. These data suggest that although GLP-1rs are required for the actions of Ex4, there appear to be key differences in how GLP-1 and Ex4 interact with central nervous system GLP-1r and in how Ex4 interacts with GLP-1r in the brain versus the periphery. A better understanding of these unique differences may lead to expansion and/or improvement of GLP-1-based therapies for type 2 diabetes and obesity.

Topics: Animals; Anorexia; Body Weight; Dose-Response Relationship, Drug; Exenatide; Feeding Behavior; Glucagon-Like Peptide 1; Hypoglycemic Agents; Immunohistochemistry; Injections, Intraperitoneal; Injections, Intraventricular; Mice; Mice, Inbred C57BL; Peptides; Proto-Oncogene Proteins c-fos; Rats; Rats, Long-Evans; Venoms

Leptin reduces food intake in part by enhancing satiety responses to gastrointestinal signals produced in response to food consumption. Glucagon-like peptide 1 (GLP-1), secreted by the intestine when nutrients enter the gut, is one such putative satiety signal. To investigate whether leptin enhances the anorexic effects of GLP-1, rats received either saline or a subthreshold dose of leptin before intraperitoneal injection of either GLP-1 or Exendin-4 (Ex4; a GLP-1 receptor agonist). Leptin pretreatment strongly enhanced anorexia and weight loss induced by GLP-1 or Ex4 over 24 h. Conversely, fasting attenuated the anorexic response to GLP-1 or Ex4 treatment via a leptin-dependent mechanism, as demonstrated by our finding that the effect of fasting was reversed by physiological leptin replacement. As expected, Ex4 induced expression of c-Fos protein, a marker of neuronal activation, in hindbrain areas that process afferent input from satiety signals, including the nucleus of the solitary tract and area postrema. Unexpectedly, leptin pretreatment blocked this response. These findings identify physiological variation of plasma leptin levels as a potent regulator of GLP-1 receptor-mediated food intake suppression and suggest that the underlying mechanism is distinct from that which mediates interactions between leptin and other satiety signals.

Topics: Animals; Anorexia; Exenatide; Fasting; Glucagon-Like Peptide-1 Receptor; Injections, Intraventricular; Leptin; Obesity; Peptides; Rabbits; Rats; Rats, Mutant Strains; Receptors, Cell Surface; Receptors, Glucagon; Receptors, Leptin; Thinness; Venoms