glucagon-like-peptide-1 and Anorexia

 Various neuropeptides play an essential role in the nutrient sensing mechanism and related homeostasis. Nesfatin-1 is a newly identified neuropeptide having anorectic activity, and nesfatin-1-containing neurons are widely distributed in the brain, including the hypothalamus and brain stem. Our previous study showed that dehydration-induced anorectic effects are mediated via the central nesfatin-1 pathway in rats. Our recent studies have also shown that peripheral anorectic peptides (cholecystokinin-8, glucagon-like peptide-1, and leptin) and an antineoplastic agent (cisplatin) caused inhibition of feeding via the central nesfatin-1 pathway in rats. Nesfatin-1-containing neurons in the central nervous system, in particular the hypothalamus and the brain stem, may mediate peripheral nutrient signals and regulate feeding behavior.

Topics: Animals; Anorexia; Antineoplastic Agents; Brain Stem; Calcium-Binding Proteins; Cholecystokinin; Cisplatin; DNA-Binding Proteins; Eating; Food; Glucagon-Like Peptide 1; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Nucleobindins; Nutritional Physiological Phenomena; Rats, Wistar; Signal Transduction

We have previously reported severe anorexia abruptly induced in rats 2-3 weeks after they have been transplanted subcutaneously with the glucagonoma MSL-G-AN. Vagotomy did not affect the time of onset and severity of anorexia, and the anorectic state resembles hunger with strongly elevated neuropeptide Y (NPY) mRNA levels in the nucleus arcuatus. We now show that circulating levels of bioactive glucagon-like peptide-1 (GLP-1) (7-36amide) start to increase above control levels exactly at the time of onset of anorexia. At this time-point, bioactive glucagon as well as total glucagon precursors and GLP-1 metabolites are already vastly elevated compared to controls. We further show that intravenous administration of very high concentrations of GLP-1 to hungry schedule-fed rats causes anorexia in a dose-dependent manner, which is blocked by the GLP-1 receptor antagonist exendin (9-39). GLP-1 (7-36amide) has a well-characterized anorectic effect but also causes taste aversion when administered centrally. The anorectic effect is blocked in rats treated neonatally by monosodium glutamate (MSG). We show that MSG treatment does not prevent the MSL-G-AN-induced anorexia, thereby suggesting a different type of anorectic function. We show a very strong component of taste aversion as anorectic rats, when presented to novel or known alternative food items, will resume normal feeding for 1 day, and then redevelop anorexia. We hypothetize that the anorexia in MSL-G-AN tumour-bearing rats correlates with a foetal processing pattern of proglucagon to both glucagon and GLP-1 (7-36amide), and is due to taste aversion. The sudden onset is characterized by a dramatic increase in circulating levels of biologically active GLP-1 (7-36amide), suggesting eventual saturation of proteolytic inactivation of its N-terminus.

Topics: Animals; Anorexia; Appetite Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagonoma; Male; Neoplasm Transplantation; Pancreatic Neoplasms; Peptide Fragments; Proglucagon; Rats; Receptors, Glucagon; Taste

Topics: Animals; Anorexia; Appetite; Cholecystokinin; Digestion; Glucagon-Like Peptide 1; Humans; Hypothalamus; Insulin; Norepinephrine

This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE-hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake (V˙O2max) and during HIIE performed 6 × 3 min running at 90% V˙O2max interspersed with 6 × 3 min active recovery at 50% V˙O2max with a 7 min warm-up and cool-down at 70% V˙O2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p <0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p <0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality.

Topics: Acylation; Adult; Altitude; Anorexia; Appetite; Appetite Regulation; Eating; Energy Intake; Energy Metabolism; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Meals; Oxygen; Oxygen Consumption; Peptide YY; Physical Exertion; Rest; Running

Type B trichothecenes commonly contaminate cereal grains and include five structurally related congeners: deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX), and nivalenol (NIV). These toxins are known to have negative effects on human and animal health, particularly affecting food intake. However, the pathophysiological basis for anorexic effect is not fully clarified. The purpose of this study is to explore the potential roles of the brain-gut peptides substance P (SP) and glucagon-like peptide-1

Topics: Amides; Animals; Anorexia; Appetite Depressants; Glucagon-Like Peptide 1; Humans; Substance P; Trichothecenes; Trichothecenes, Type B

Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a "corrinated" Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.

Topics: Animals; Anorexia; Blood Glucose; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycemic Control; Humans; Hypoglycemic Agents; Peptides; Receptors, Glucagon

The overlap in neurobiological circuitry mediating the physiological and behavioral response to satiation and noxious/stressful stimuli are not well understood. The interaction between serotonin (5-HT) and glucagon-like peptide-1 (GLP-1) could play a role as upstream effectors involved in mediating associations between anorectic and noxious/stressful stimuli. We hypothesize that 5-HT acts as an endogenous modulator of the central GLP-1 system to mediate satiation and malaise in rats. Here, we investigate whether interactions between central 5-HT and GLP-1 signaling are behaviorally and physiologically relevant for the control of food intake and pica (i.e., behavioral measure of malaise). Results show that the anorexia and body weight changes induced by administration of exogenous hindbrain 5-HT are dependent on central GLP-1 receptor signaling. Furthermore, anatomical evidence shows mRNA expression of 5-HT2C and 5-HT3 receptors on GLP-1-producing preproglucagon (PPG) neurons in the medial nucleus tractus solitarius by fluorescent in situ hybridization, suggesting that PPG neurons are likely to express both of these receptors. Behaviorally, the hypophagia induced by the pharmacological activation of both of these receptors is also dependent on GLP-1 signaling. Finally, 5-HT3, but not 5-HT2C receptors, are required for the anorectic effects of the interoceptive stressor LiCl, suggesting the hypophagia induced by these 5-HT receptors may be driven by different mechanisms. Our findings highlight 5-HT as a novel endogenous modulator of the central GLP-1 system and suggest that the central interaction between 5-HT and GLP-1 is involved in the control of food intake in rats.

Topics: Animals; Anorexia; Feeding Behavior; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Lithium Chloride; Male; Neurons; Ondansetron; Peptide Fragments; Pica; Proglucagon; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin, 5-HT3; Rhombencephalon; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Signal Transduction; Solitary Nucleus; Stress, Psychological; Weight Loss

The cancer anorexia-cachexia syndrome (CACS) is a frequent and severe condition in cancer patients. Currently, no pharmacological treatment is approved for the therapy of CACS. Centrally, glucagon-like peptide-1 (GLP-1) is expressed in the nucleus tractus solitarii (NTS) and is implicated in malaise, nausea and food aversion. The NTS is reciprocally connected to brain sites implicated in the control of energy balance including the area postrema (AP), which mediates CACS in certain tumour models. Given the role of GLP-1 as a mediator of anorexia under acute sickness conditions, we hypothesized that brainstem GLP-1 signalling might play a role in the mediation of CACS. Using hepatoma tumour-bearing (TB) rats, we first tested whether the chronic delivery of the GLP-1R antagonist exendin-9 (Ex-9) into the fourth ventricle attenuates CACS. Second, we investigated whether a genetic knockdown of GLP-1 expression in the NTS ameliorates CACS. Ex-9 attenuated anorexia, body weight loss, muscle and fat depletion compared to TB controls. Similarly, TB animals with a knockdown of GLP-1 expression in the NTS had higher food intake, reduced body weight loss, and higher lean and fat mass compared to TB controls. Our study identifies brainstem GLP-1 as crucial mediator of CACS in hepatoma TB rats. The GLP-1R represents a promising target against CACS and possibly other forms of disease-related anorexia/cachexia.

Topics: Animals; Anorexia; Brain Stem; Cachexia; Carcinoma, Hepatocellular; Cell Line, Tumor; Central Nervous System Agents; Eating; Gene Knockdown Techniques; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Male; Neoplasm Transplantation; Neurons; Rats, Inbred BUF; Syndrome; Weight Loss

Anorexia is a hallmark of animal and human exposed to T-2 toxin, a most poisonous trichothecene mycotoxins contaminating various cereal grains including wheat, corn and barley. Although this adverse effect has been well characterized in several animal species, the underlying mechanisms are unclear. The goal for this study was to elucidate the roles of two gut satiety hormones, glucagon-like peptide-1

Topics: Animals; Anorexia; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Female; Glucagon-Like Peptide 1; Mice; Mice, Inbred Strains; Peptide Fragments; T-2 Toxin

Glucagon-like peptide 1 (GLP-1) neurons of the caudal brainstem project to many brain areas, including the lateral septum (LS), which has a known role in stress responses. Previously, we showed that endogenous GLP-1 in the LS plays a physiologic role in the control of feeding under non-stressed conditions, however, central GLP-1 is also involved in behavioral and endocrine responses to stress. Here, we asked whether LS GLP-1 receptors (GLP-1R) contribute to stress-induced hypophagia. Male rats were implanted with bilateral cannulas targeting the dorsal subregion of the LS (dLS). In a within-subjects design, shortly before the onset of the dark phase, rats received dLS injections of saline or the GLP-1R antagonist Exendin (9-39) (Ex9) prior to 30 min restraint stress. Food intake was measured continuously for the next 20 h. The stress-induced hypophagia observed within the first 30 min of dark was not influenced by Ex9 pretreatment, but Ex9 tended to blunt the effect of stress as early as 1 and 2 h into the dark phase. By 4-6 h, there were significant stress X drug interactions, and Ex9 pretreatment blocked the stress-induced suppression of feeding. These effects were mediated entirely through changes in average meal size; stress suppressed meal size while dLS Ex9 attenuated this effect. Using a similar design, we examined the role of dLS GLP-1R in the neuroendocrine response to acute restraint stress. As expected, stress potently increased serum corticosterone, but blockade of dLS GLP-1Rs did not affect this response. Together, these data show that endogenous GLP-1 action in the dLS plays a role in some but not all of the physiologic responses to acute stress.

Topics: Animals; Anorexia; Central Nervous System Agents; Corticosterone; Cross-Over Studies; Disease Models, Animal; Eating; Feeding Behavior; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Male; Peptide Fragments; Rats, Wistar; Restraint, Physical; Septum of Brain; Stress, Psychological

Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish.

Topics: Animals; Anorexia; Appetite; Appetite Depressants; Cholecystokinin; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Goldfish; Intestinal Mucosa; Intestines; Male; Oligopeptides; Peptide YY; Protein Precursors; Receptors, Ghrelin

Estrogens suppress feeding in part by enhancing the response to satiation signals. Glucagon-like peptide 1 (GLP-1) acts on receptor populations both peripherally and centrally to affect food intake. We hypothesized that modulation of the central GLP-1 system is one of the mechanisms underlying the effects of estrogens on feeding. We assessed the anorexic effect of 0, 1, and 10μg doses of GLP-1 administered into the lateral ventricle of bilaterally ovariectomized (OVX) female rats on a cyclic regimen of either 2μg β-estradiol-3-benzoate (EB) or oil vehicle 30min prior to dark onset on the day following hormone treatment. Central GLP-1 treatment significantly suppressed food intake in EB-treated rats at both doses compared to vehicle, whereas only the 10μg GLP-1 dose was effective in oil-treated rats. To follow up, we examined whether physiologic-dose cyclic estradiol treatment influences GLP-1-induced c-Fos in feeding-relevant brain areas of OVX females. GLP-1 significantly increased c-Fos expression in the area postrema (AP) and nucleus of the solitary tract (NTS), and the presence of estrogens may be required for this effect in the paraventricular nucleus of the hypothalamus (PVN). Together, these data suggest that modulation of the central GLP-1 system may be one of the mechanisms by which estrogens suppress food intake, and highlight the PVN as a region of interest for future investigation.

Topics: Animals; Anorexia; Appetite Regulation; Eating; Estradiol; Female; Glucagon-Like Peptide 1; Hypothalamus; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Solitary Nucleus

Deoxynivalenol (DON), which is a Type B trichothecene mycotoxin produced by Fusarium, frequently contaminates cereal staples, such as wheat, barley and corn. DON threatens animal and human health by suppressing food intake and impairing growth. While anorexia induction in mice exposed to DON has been linked to the elevation of the satiety hormones cholecystokinin and peptide YY3-36 in plasma, the effects of DON on the release of other satiety hormones, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), have not been established. The purpose of this study was to determine the roles of GLP-1 and GIP in DON-induced anorexia. In a nocturnal mouse food consumption model, the elevation of plasma GLP-1 and GIP concentrations markedly corresponded to anorexia induction by DON. Pretreatment with the GLP-1 receptor antagonist Exendin9-39 induced a dose-dependent attenuation of both GLP-1- and DON-induced anorexia. In contrast, the GIP receptor antagonist Pro3GIP induced a dose-dependent attenuation of both GIP- and DON-induced anorexia. Taken together, these results suggest that GLP-1 and GIP play instrumental roles in anorexia induction following oral exposure to DON, and the effect of GLP-1 is more potent and long-acting than that of GIP.

Topics: Administration, Oral; Animals; Anorexia; Dose-Response Relationship, Drug; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Mice; Trichothecenes

Topics: Animals; Anorexia; Appetite Regulation; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Feeding Behavior; Female; Glucagon-Like Peptide 1; Mice; Peptide Fragments; Satiety Response; Signal Transduction; T-2 Toxin; Time Factors; Trichothecenes; Up-Regulation

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

A high-altitude environment causes appetite loss in unacclimatised humans, leading to weight reduction. Ghrelin, cholecystokinin (CCK), and glucagon like peptide-1 (GLP-1), are gut hormones involved in the regulation of food intake and energy metabolism. The liver is an important site of metabolic regulation, and together with the gut it plays a role in food intake regulation. This study intends to study the time-dependent changes occurring in plasma gut hormones, PPARα, PPARδ, and PGC1α, in the stomach and liver during hypoxia.. Male Sprague Dawley rats were exposed to hypobaric hypoxia in a decompression chamber at 7620 m for different durations up to seven days.. Hypoxia increased circulating ghrelin from the third day onwards while CCK and GLP-1 decreased immediately. An increase in ghrelin, ghrelin receptor protein levels, and GOAT mRNA levels in the stomach was observed. Stomach cholecystokinin receptor (CCKAR), PPARα, and PPARδ decreased. Liver CCKAR decreased during the first day of hypoxia and returned to normal levels from the third day onwards. PPARα and PGC1α expression increased while PPARδ protein levels reduced in the liver on third day.. Hypoxia alters the expression of ghrelin and ghrelin receptor in the stomach, CCKAR in the liver, and PPAR and its cofactors, which might be possible role players in the contribution of gut and liver to anorexia at high altitude.

Topics: Animals; Anorexia; Cholecystokinin; Disease Models, Animal; Gastric Mucosa; Gene Expression Regulation; Ghrelin; Glucagon-Like Peptide 1; Hypoxia; Liver; Male; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Sprague-Dawley

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

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.

Topics: Animals; Anorexia; Body Weight; Cachexia; Cell Line, Tumor; Chemokine CCL2; Drugs, Chinese Herbal; Ghrelin; Glucagon-Like Peptide 1; Inflammation; Interleukin-6; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred BALB C; Muscles; Neoplasm Transplantation; Neoplasms; Peptide YY; Plant Preparations; Tumor Necrosis Factor-alpha

Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

Topics: Animals; Anorexia; Behavior, Animal; Capsaicin; Cholecystokinin; Disease Models, Animal; Energy Intake; Feeding Behavior; Glucagon-Like Peptide 1; Infusions, Intravenous; Injections, Intraperitoneal; Intestinal Mucosa; Intestine, Small; Male; Neuritis; Neurons, Afferent; Peptide Fragments; Peptide YY; Rats; Vagus Nerve; Vagus Nerve Diseases

GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3(rd) cerebroventricularly (i3vt)-administered GLP-1 to reduce food intake. However, fasted animals maintained the anorexic response to melanotan II, a melanocortin receptor agonist, indicating a specific effect of fasting on GLP-1 action. We also found that i3vt administration of leptin, which is also decreased with fasting, was not able to potentiate GLP-1 action in fasted animals. However, we did find that CNS glucose sensing is important in GLP-1 action. Specifically, we found that i3vt injection of 2DG, a drug that blocks cellular glucose utilization, and AICAR which activates AMPK, both blocked GLP-1-induced reductions in food intake. To examine the role of glucokinase, an important CNS glucose sensor, we studied glucokinase-heterozygous knockout mice, but found that they responded normally to peripherally administered GLP-1 and exendin-4. Interestingly, oral, but not i3vt or IP glucose potentiated GLP-1's anorectic action. Thus, CNS and peripheral fuel sensing are both important in GLP-1-induced reductions in food intake.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinase Kinases; Animals; Anorexia; Fasting; Glucagon-Like Peptide 1; Glucokinase; Glucose; Heterozygote; Incretins; Male; Mice; Mice, Knockout; Protein Kinases; Rats; Rats, Long-Evans; Ribonucleotides

Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200μg/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100μg/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100μg/kg) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways.

Topics: Animals; Anorexia; Body Weight; Eating; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heterozygote; Liraglutide; Male; Mice; Mice, Mutant Strains; Receptor, Melanocortin, Type 4; Receptor, Serotonin, 5-HT2C; Receptors, Glucagon; Satiety Response; Signal Transduction

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

Nitric oxide (NO) is known as an orexigenic factor in the brain of mammals and mediates the feeding-stimulatory effect of other factors such as neuropeptide Y (NPY). In neonatal chicks, however, we recently reported that NO might have an anorexigenic effect and suggested that the feeding-regulatory mechanism in chicks might be different from that in mammals regarding NO. In the present study, we investigated the involvement of NO in the effect of other orexigenic and anorexigenic factors in neonatal chicks. Intracerebroventricular co-injection of N(G)-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, did not affect NPY- and prolactin-releasing peptide-induced feeding behavior. On the other hand, the co-injection of l-NAME significantly attenuated the anorexigenic effect of corticotropin-releasing hormone (CRH). The anorexigenic effects of glucagon-like peptide-1, alpha-melanocyte-stimulating hormone and ghrelin were not affected by the l-NAME treatment. These results suggest that NO might mediate the anorexigenic effect of CRH in the brain of neonatal chicks.

Topics: alpha-MSH; Animals; Animals, Newborn; Anorexia; Chickens; Corticotropin-Releasing Hormone; Drug Combinations; Ghrelin; Glucagon-Like Peptide 1; Hypothalamic Hormones; Male; Neuropeptide Y; Neuropeptides; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Prolactin-Releasing Hormone

Glucagon-like peptide-1 (GLP-1) is recognized as an anorexic peptide in the brain of chicks. However, the mechanism underlying the inhibition of feeding has not been well studied. It is reported that GLP-1 activates neurons containing corticotrophin-releasing factor (CRF) in the brain of mammals. Since CRF is also an anorexic peptide, it is possible that the anorexic effect of GLP-1 is mediated by CRF in chicks. The present study was carried out to test this. First, we determined plasma corticosterone (CORT) concentrations after intracerebroventricular (ICV) injection of GLP-1 and found that this treatment increased CORT release in layer chicks. The CORT-releasing effect was partly attenuated by co-injection of astressin, a CRF receptor antagonist, demonstrating that GLP-1 stimulated CORT secretion by activation of CRF neurons. CRF neurons also appear to be involved in mediating the inhibition of food intake by GLP-1 because this effect was also partly attenuated by astressin. Furthermore, we demonstrated that the anorexic effect of GLP-1 was weaker in broiler than layer chicks. The present results suggest that the anorexic effect of GLP-1 might be mediated by CRF neurons in the chick brain and that the sensitivity of the inhibitory response to GLP-1 differs between chick strains.

Topics: Animals; Animals, Newborn; Anorexia; Brain; Chickens; Corticosterone; Corticotropin-Releasing Hormone; Eating; Feeding Behavior; Glucagon-Like Peptide 1; Injections, Intraventricular; Male; Neurons; Neuroprotective Agents; Peptide Fragments; Species Specificity

In rats, central administration of glucagon-like peptide-1 (GLP-1) elicits symptoms of visceral illness like those caused by the toxin lithium chloride (LiCl), including anorexia, conditioned taste aversion (CTA) formation, and neural activation in the hypothalamus and hindbrain including activation of brainstem preproglucagon cells. Most compellingly, pharmacological antagonists of the GLP-1 receptor (GLP-1R) block several effects of LiCl in rat. The major goal of these experiments was to further test the hypothesis that the central nervous system GLP-1 system is critical to the visceral illness actions of LiCl by using mice with a targeted disruption of the only described GLP-1R. First, we observed that, like the rat, LiCl activates preproglucagon neurons in wild-type mice. Second, GLP-1R -/- mice demonstrated normal anorexic and CTA responses to LiCl. To test the possibility that alternate GLP-1Rs mediate aversive effects, we examined the ability of GLP-1 to produce a CTA in GLP1R -/- mice. Although lateral ventricular GLP-1 produced a CTA in wild-type mice, it did not produce a CTA in GLP-1R -/- mice. Furthermore, the same GLP-1R antagonist that can block the aversive effects of LiCl in the rat failed to do so in the mouse. These results support the conclusion that in mouse, unlike in rat, GLP-1R signaling is not required for the visceral illness response to LiCl. Such species differences are an important consideration when comparing results from rat and mouse studies.

Topics: Animals; Anorexia; Avoidance Learning; Brain Diseases; Glucagon; Glucagon-Like Peptide 1; Lithium Chloride; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Neurons; Peptide Fragments; Proglucagon; Protein Precursors; Rats; Species Specificity; Taste

The present study was carried out to investigate whether the hypothalamus is involved in the anorexic effect of glucagon-like peptide-1 (GLP-1) in chicks. To examine this, Fos expression in the chick hypothalamus were immunohistochemically detected after intracerebroventricular (ICV) injection of 30-pmol GLP-1. ICV injection of GLP-1 stimulated the expression of Fos-like immunoreactive (FLI) cells in the ventromedial hypothalamic nucleus (VMN). When 15-pmol GLP-1 was directly injected into the chick VMN, the chick's food intake was significantly decreased compared with the control treatment. Microinjection of GLP-1 into the (LHA) also inhibited feeding in chicks, although ICV injection of GLP-1 did not stimulate FLI expression in the brain area. These results suggest that VMN and some brain regions are involved in the anorexic effect of GLP-1 in chicks.

Topics: Animals; Anorexia; Chickens; Feeding Behavior; Glucagon; Glucagon-Like Peptide 1; Hypothalamus; Injections, Intraventricular; Male; Peptide Fragments; Protein Precursors; Proto-Oncogene Proteins c-fos; Ventromedial Hypothalamic Nucleus

Topics: Animals; Anorexia; Eating; Genes, fos; Glucagon; Glucagon-Like Peptide 1; Hindlimb; Injections, Intraventricular; Peptide Fragments; Protein Precursors; Rats; Signal Transduction; Vagus Nerve

Intracerebroventricular administration of glucagon-like peptide-1 (7-36) amide (GLP-1) reduces food intake and produces symptoms of visceral illness, such as a conditioned taste aversion (CTA). The central hypothesis of the present work is that separate populations of GLP-1 receptors mediate the anorexia and taste aversion associated with GLP-1 administration. To test this hypothesis, we first compared the ability of various doses of GLP-1 to induce anorexia or CTA when administered into either the lateral or fourth ventricle. Lateral and fourth ventricular GLP-1 resulted in reduction of food intake at similar doses, whereas only lateral ventricular GLP-1 resulted in a CTA. Such data indicate that both hypothalamic and caudal brainstem GLP-1 receptors are likely to participate in the ability of GLP-1 to reduce food intake. We also hypothesized that the site that must mediate the ability of GLP-1 to induce visceral illness is in the central nucleus of the amygdala (CeA). Administration of 0.2 or 1.0 microg of GLP-1 (7-36) but not the inactive GLP-1 (9-36) resulted in a strong CTA with no accompanying anorexia. In addition, bilateral CeA administration of 2.5 microg of a GLP-1 receptor antagonist before intraperitoneal administration of the toxin lithium chloride resulted in a diminished CTA. Together, these data indicate that separate GLP-1 receptor populations mediate the multiple responses to GLP-1. These results indicate that GLP-1 is a flexible system that can be activated under various circumstances to alter the ingestion of nutrients and/or produce other visceral illness responses, depending on the ascending pathways of the GLP-1 system that are recruited.

Topics: Amygdala; Animals; Anorexia; Appetite Regulation; Behavior, Animal; Catheterization; Conditioning, Psychological; Dose-Response Relationship, Drug; Eating; Fourth Ventricle; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraperitoneal; Injections, Intraventricular; Lateral Ventricles; Lithium Chloride; Male; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Long-Evans; Receptors, Glucagon; Signal Transduction; Taste; Visceral Afferents

The present study examined possible interactions between central glucagon-like peptide-1 (GLP-1) and oxytocin (OT) neural systems by determining whether blockade of GLP-1 receptors attenuates OT-induced anorexia and vice versa. Male rats were acclimated to daily 4-h food access. In the first experiment, rats were infused centrally with GLP-1 receptor antagonist or vehicle, followed by an anorexigenic dose of synthetic OT. Access to food began 20 min later. Cumulative food intake was measured every 30 min for 4 h. In the second experiment, rats were infused with OT receptor blocker or vehicle, followed by synthetic GLP-1 [(7-36) amide]. Subsequent food intake was monitored as before. The anorexigenic effect of OT was eliminated in rats pretreated with the GLP-1 receptor antagonist. Conversely, GLP-1-induced anorexia was not affected by blockade of OT receptors. In a separate immunocytochemical study, OT-positive terminals were found closely apposed to GLP-1-positive perikarya, and central infusion of OT activated c-Fos expression in GLP-1 neurons. These findings implicate endogenous GLP-1 receptor signaling as an important downstream mediator of anorexia in rats after activation of central OT neural pathways.

Topics: Animals; Anorexia; Eating; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraventricular; Male; Neurons; Neurotransmitter Agents; Oxytocin; Peptide Fragments; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Receptors, Oxytocin; Signal Transduction

The present study sought to determine whether central glucagon-like peptide-1 (GLP-1)-receptor signalling contributes to the anorexigenic effects of systemically administered lithium chloride (LiCl). Male Sprague-Dawley rats with chronic intracerebroventricular (ICV) cannulas were acclimated to a feeding schedule that included daily 30-min access to palatable mash. In the first experiment, ICV infusion of a GLP-1-receptor antagonist [exendin-4-(3-39)] significantly attenuated (10 microgram dose) or completely blocked (20 microgram dose) the inhibition of food intake produced by subsequent ICV infusion of GLP-1-(7-36) amide (5 microgram). In the second experiment, rats were infused with 0, 10, or 20 microgram of the GLP-1-receptor antagonist ICV, followed by injection of 0.15 M LiCl (50 mg/kg ip) or the same volume of 0.15 M NaCl. The ability of LiCl treatment to suppress food intake was significantly attenuated in rats that were pretreated with the GLP-1-receptor antagonist. These results support the view that central mechanisms underlying LiCl-induced anorexia include a prominent role for endogenous GLP-1 neural pathways.

Topics: Animals; Anorexia; Brain; Dose-Response Relationship, Drug; Eating; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Injections, Intraventricular; Lithium Chloride; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Glucagon

We have isolated a stable, transplantable, and small glucagonoma (MSL-G-AN) associated with abrupt onset of severe anorexia occurring 2-3 wk after subcutaneous transplantation. Before onset of anorexia, food consumption is comparable to untreated controls. Anorexia is followed by adipsia and weight loss, and progresses rapidly in severity, eventually resulting in reduction of food and water intake of 100 and 80%, respectively. During the anorectic phase, the rats eventually become hypoglycemic and hypothermic. The tumor-associated anorexia shows no sex difference, and is not affected by bilateral abdominal vagotomy, indicating a direct central effect. The adipose satiety factor leptin, known to suppress food intake by reducing hypothalamic neuropeptide Y (NPY) levels, was not found to be expressed by the tumor, and circulating leptin levels were reduced twofold in the anorectic phase. A highly significant increase in hypothalamic (arcuate nucleus) NPY mRNA levels was found in anorectic rats compared with control animals. Since elevated hypothalamic NPY is among the most potent stimulators of feeding and a characteristic of most animal models of hyperphagia, we conclude that the MSL-G-AN glucagonoma releases circulating factor(s) that overrides the hypothalamic NPY-ergic system, thereby eliminating the orexigenic effect of NPY. We hypothesize a possible central role of proglucagon-derived peptides in the observed anorexia.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Drinking; Female; Glucagon; Glucagon-Like Peptide 1; Glucagonoma; Male; Neoplasm Transplantation; Neuropeptide Y; Pancreatic Neoplasms; Peptide Fragments; Protein Precursors; Rats; RNA, Messenger; Weight Loss