RESUMEN
Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.
Asunto(s)
Conducta Alimentaria , Hipotálamo , Neuronas , Neuropéptido Y , Ratas Sprague-Dawley , Animales , Femenino , Masculino , Ratas , Desoxiglucosa/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta Alimentaria/efectos de los fármacos , Glucosa/metabolismo , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/efectos de los fármacos , Hormonas Hipotalámicas/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Melaninas/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Neuropéptidos/metabolismo , Orexinas/metabolismo , Hormonas Hipofisarias/metabolismo , Receptores de Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/genética , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Saporinas/farmacologíaRESUMEN
Organotins such as tributyltin chloride (TBT), are highly diffused environmental pollutants, which act as metabolism disrupting chemicals, i.e. may interfere with fat tissue differentiation, as well as with neuroendocrine circuits, thus impairing the control of energetic balance. We have previously demonstrated that adult exposure to TBT altered the expression of neuropeptides in the hypothalamus. In this study, we orally administered daily a solution containing oil, or TBT (0.25, 2.5, or 25 µg/kg body weight/day) to pregnant females from gestational day 8 until birth, and to their pups from day 0 until post-natal day 21. Our results showed that TBT exposure of female mice during gestation and of pups during lactation permanently altered the feeding efficiency of pups of both sexes and subcutaneous fat distribution in adult males. In addition, the neuropeptide Y system was affected at the level of the paraventricular nucleus, with a decrease in immunoreactivity in both sexes (significant in females for all TBT doses and in males only for intermediate TBT doses), while no effect was observed in other hypothalamic areas (arcuate, ventromedial and dorsomedial nuclei). Metabolic syndrome, as well as obesity and diabetes, which are significant health issues, are considered multifactorial diseases and may be caused by exposure to metabolic disruptors, both in adults and during perinatal life. In addition, our work indicates that TBT doses defined as the tolerably daily intake had a profound and sex-specific long-term effect.
Asunto(s)
Neuropéptido Y , Núcleo Hipotalámico Paraventricular , Embarazo , Masculino , Ratones , Animales , Femenino , Núcleo Hipotalámico Paraventricular/metabolismo , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Hipotálamo/metabolismo , Conducta AlimentariaRESUMEN
Fibroblast growth factor 11 (FGF11) is a member of the intracellular fibroblast growth factor family. Here, we report the central role of FGF11 in the regulation of metabolism. Lentiviral injection of Fgf11 shRNA into the arcuate nucleus of the mouse hypothalamus decreased weight gain and fat mass, increased brown adipose tissue thermogenesis, and improved glucose and insulin intolerances under high-fat diet conditions. Fgf11 was expressed in the NPY-expressing neurons, and Fgf11 knockdown considerably decreased Npy expression and projection, leading to increased expression of tyrosine hydroxylase in the paraventricular nucleus. Mechanistically, FGF11 regulated Npy gene expression through the glycogen synthase kinase 3-cAMP response element-binding protein pathway. Our study defines the physiological significance of hypothalamic FGF11 in the regulation of metabolism in response to overnutrition such as high-fat diet.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Hipotálamo , Neuropéptido Y , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Dieta Alta en Grasa , Factores de Crecimiento de Fibroblastos/genética , Hipotálamo/metabolismo , Ratones , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Obesidad/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismoRESUMEN
DNA methylation is an epigenetic modification that influences gene transcription; however, the effects of methylation-influencing chemicals on appetite are unknown. We evaluated the effects of single administration of a methyl donor, S-Adenosylmethionine (SAM), or methylation inhibitor, 5-Azacytidine (AZA), on immediate and later-age food intake in an anorexic chick model. The doses of intracerebroventricularly-injected SAM were 0 (vehicle), 0.1, 1, and 10⯵g, and of AZA were 0 (vehicle), 1, 5, and 25⯵g. When injected on day 5 posthatch, there was no effect of SAM on food intake in either fed or fasted chicks, whereas AZA increased food consumption in the fasted state but decreased it in fed chicks. We then performed a single injection (same doses) at hatch and measured food intake on day 5 in response to neuropeptide Y (NPY; 0.2⯵g) injection. Irrespective of NPY, chicks injected with 1⯵g of SAM ate more than others on day 5. In contrast, chicks injected with AZA (5 and 25⯵g doses) consumed less on day 5. In conclusion, we identified DNA methylation-regulating chemicals as regulators of food intake. AZA but not SAM affected food intake in the short-term, feeding state dependently. Later, both chemicals injected on the day of hatch were associated with food intake changes at a later age, suggesting that feeding pathways might be altered through changes in methylation.
Asunto(s)
Pollos , Hipotálamo , Animales , Pollos/genética , Pollos/metabolismo , Ingestión de Alimentos , Epigénesis Genética , Hipotálamo/metabolismo , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacologíaRESUMEN
Appetite loss or anorexia substantially decreases the quality of life in patients with cancer, depression and gastrointestinal disorders, and can lead to sarcopenia and frailty. Foods that restore appetite have been sought-for but are not currently available. Historically, onion intake was adopted to treat a variety of diseases with reduced appetite including cancer and gastrointestinal disturbances. While isoalliin is a core component of onion, the effects of isoalliin on feeding behavior and feeding centers remain unknown. Neuropeptide Y (NPY) and ghrelin are the most potent central and peripheral inducers of appetite. A Japanese kampo medicine Ninjin'yoeito activates ghrelin-responsive NPY neurons in the hypothalamic arcuate nucleus (ARC) and counteracts anorexia induced by an anti-cancer drug cisplatin. This study explored the effects of isoalliin on feeding behavior and activities of ARC neurons in mice. Isoalliin, injected intraperitoneally, dose-dependently increased food intake during dark phase (DP) and daily without altering light phase (LP) food intake. We measured cytosolic Ca2+ concentration ([Ca2+]i) in single ARC neurons including NPY neurons identified by GFP fluorescence. Isoalliin increased [Ca2+]i in 10 of 18 (55.6%) NPY neurons, a majority of which also responded to ghrelin with [Ca2+]i increases, indicating that the ARC ghrelin-responsive NPY neuron is the major target of isoalliin. Isoalliin also increased [Ca2+]i in the ARC neurons that responded to Ninjin'yoeito. These results indicate that isoalliin enhances feeding at the active period and activates ARC ghrelin-responsive NPY neurons and Ninjin'yoeito-responsive neurons. These abilities of isoalliin to stimulate DP feeding and activate ARC orexigenic neurons provide scientific evidence for the health beneficial effects of onion experienced historically and globally.
Asunto(s)
Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Cisteína/análogos & derivados , Medicamentos Herbarios Chinos/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/farmacología , Neuronas/efectos de los fármacos , Neuropéptido Y/farmacología , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Calcio/metabolismo , Cisteína/farmacología , Relación Dosis-Respuesta a Droga , RatonesRESUMEN
This study aimed to determine whether glycyl-l-glutamine (Gly-Gln; ß-endorphin (30-31)), a non-opioid peptide derived from ß-endorphin processing, modulates neuropeptide Y (NPY)-induced feeding and hypothalamic mRNA expression of peptide hormones in male broiler chicks. Intracerebroventricular injection of NPY (235 pmol) generated a hyperphagic response in ad libitum chicks within 30 min. Co-administration of Gly-Gln (100 nmol) attenuated this response, inducing a 30 % decrease. This was not attributable to Gly-Gln hydrolysis because co-administration of glycine (Gly) and glutamine (Gln) had no effect on NPY-induced hyperphagia. Gly-Gln injected alone also showed no effect. The hypothalamic pro-opiomelanocortin mRNA expression in the co-injection group was significantly higher than that in the NPY alone group. These data indicate that endogenous Gly-Gln may contribute to regulate feeding behavior via the central melanocortin system in chicks and acts as a counter regulator of the neural activity in energy metabolism.
Asunto(s)
Dipéptidos/farmacología , Ingestión de Alimentos/efectos de los fármacos , Hiperfagia/metabolismo , Hipotálamo/efectos de los fármacos , Neuropéptido Y/farmacología , Proopiomelanocortina/metabolismo , Animales , Pollos , Hipotálamo/metabolismo , MasculinoRESUMEN
Seasonal rhythms in energy balance are well documented across temperate and equatorial zones animals. The long-term regulated changes in seasonal physiology consists of a rheostatic system that is essential to successful time annual cycles in reproduction, hibernation, torpor, and migration. Most animals use the annual change in photoperiod as a reliable and robust environmental cue to entrain endogenous (i.e. circannual) rhythms. Research over the past few decades has predominantly examined the role of first order neuroendocrine peptides for the rheostatic changes in energy balance. These anorexigenic and orexigenic neuropeptides in the arcuate nucleus include neuropeptide y (Npy), agouti-related peptide (Agrp), cocaine and amphetamine related transcript (Cart) and pro-opiomelanocortin (Pomc). Recent studies also indicate that VGF nerve growth factor inducible (Vgf) in the arcuate nucleus is involved in the seasonal regulation of energy balance. In situ hybridization, qPCR and RNA-sequencing studies have identified that Pomc expression across fish, avian and mammalian species, is a neuroendocrine marker that reflects seasonal energetic states. Here we highlight that long-term changes in arcuate Pomc and Vgf expression is conserved across species and may provide rheostatic regulation of seasonal energy balance.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Factores de Crecimiento Nervioso/farmacología , Neuropéptidos/metabolismo , Proopiomelanocortina/farmacología , Proteína Relacionada con Agouti/farmacología , Proteína Relacionada con Agouti/fisiología , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Metabolismo Energético/fisiología , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Proteínas del Tejido Nervioso/farmacología , Proteínas del Tejido Nervioso/fisiología , Neuropéptido Y/farmacología , Neuropéptido Y/fisiología , Neuropéptidos/efectos de los fármacos , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/metabolismoRESUMEN
PTSD is heterogeneous disorder that can be long lasting and often has delayed onset following exposure to a traumatic event. Therefore, it is important to take a staging approach to evaluate progression of biological mechanisms of the disease. Here, we begin to evaluate the temporal trajectory of changes following exposure to traumatic stressors in the SPS rat PTSD model. The percent of animals displaying severe anxiety on EPM increased from 17.5% at one week to 57.1% two weeks after SPS stressors, indicating delayed onset or progressive worsening of the symptoms. The LC displayed prolonged activation, and dysbalance of the CRH/NPY systems, with enhanced CRHR1 gene expression, coupled with reduced mRNAs for NPY and Y2R. In the mediobasal hypothalamus, increased CRH mRNA levels were sustained, but there was a flip in alterations of HPA regulatory molecules, GR and FKBP5 and Y5 receptor at two weeks compared to one week. Two weeks after SPS, intranasal NPY at 300 µg/rat, but not 150 µg which was effective after one week, reversed SPS triggered elevated anxiety. It also reversed SPS elicited depressive/despair symptoms and hyperarousal. Overall, the results reveal time-dependent progression in development of anxiety symptoms and molecular impairments in gene expression for CRH and NPY systems in LC and mediobasal hypothalamus by SPS. With longer time afterwards only a higher dose of NPY was effective in reversing behavioral impairments triggered by SPS, indicating that therapeutic approaches should be adjusted according to the degree of biological progression of the disorder.
Asunto(s)
Expresión Génica , Hipotálamo/metabolismo , Locus Coeruleus/metabolismo , Neuropéptido Y/farmacología , Trastornos por Estrés Postraumático/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Hormona Liberadora de Corticotropina/biosíntesis , Masculino , Neuropéptido Y/biosíntesis , Ratas , Receptores de Hormona Liberadora de Corticotropina/biosíntesis , Receptores de Neuropéptido Y/biosíntesis , Proteínas de Unión a Tacrolimus/biosíntesis , Factores de TiempoRESUMEN
BACKGROUND: Dipeptidyl peptidase 4 (DPP4, CD26) is a moonlighting enzyme responsible for the proteolytic inactivation of neuropeptide Y (NPY), a peptide known for its anxiolytic effect in the central nervous system. Our previous work revealed a stress-resilient phenotype and a potentiation of short-term fear extinction in a congenic rat model deficient for DPP4 activity (DPP4mut). Here, we investigated neuroendocrine mechanisms underlying the phenotype of the DPP4mut animals. We studied the function of the hypothalamus-pituitary-adrenal (HPA) axis including the expression levels of its key genes and explored the possibility of structural NPY system changes. METHODS AND RESULTS: We find decreased expression of Nr3c1 (glucocorticoid receptor - GR) and Fkbp5 (FK506 binding protein 5) in the amygdala and the hypothalamus of the DPP4mut rats, as well as the lower stress-induced peripheral corticosterone (CORT) levels. We detect no significant alterations in basal and DEX-induced CORT levels in the DPP4mut animals. The abundance of NPY-ergic neurons in the basolateral amygdala, dentate gyrus and hippocampus did not differ between the DPP4mut and their wild type littermates. CONCLUSION: DPP4mut rats show blunted CORT response in line with their lower behavioral stress-response profile. These results are consistent with the hypothesis that increased central NPY levels elevate the threshold of stress response. We suggest that changes in the expression levels of key HPA axis genes (Nr3c1 and Fkbp5) are a consequence of the altered stress-perception of DPP4mut animals, thus further contributing to the stress-resilient phenotype.
Asunto(s)
Dipeptidil Peptidasa 4/deficiencia , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Estrés Fisiológico/fisiología , Amígdala del Cerebelo/metabolismo , Animales , Corticosterona/metabolismo , Hipotálamo/metabolismo , Neuropéptido Y/farmacología , Fenotipo , Ratas Transgénicas , Receptores de Glucocorticoides/metabolismoRESUMEN
Neuropeptide Y (NPY) expression is tightly linked with the development of stress resilience in rodents and humans. Local NPY injections targeting the basolateral amygdala (BLA) produce long-term behavioral stress resilience in male rats via an unknown mechanism. Previously, we showed that activation of NPY Y1 receptors hyperpolarizes BLA principal neurons (PNs) through inhibition of the hyperpolarization-activated, depolarizing H-current, Ih The present studies tested whether NPY treatment induces stress resilience by modulating Ih NPY (10 pmol) was delivered daily for 5 d bilaterally into the BLA to induce resilience; thereafter, the electrophysiological properties of PNs and the expression of Ih in the BLA were characterized. As reported previously, increases in social interaction (SI) times persisted weeks after completion of NPY administration. In vitro intracellular recordings showed that repeated intra-BLA NPY injections resulted in hyperpolarization of BLA PNs at 2 weeks (2W) and 4 weeks (4W) after NPY treatment. At 2W, spontaneous IPSC frequencies were increased, whereas at 4W, resting Ih was markedly reduced and accompanied by decreased levels of HCN1 mRNA and protein expression in BLA. Knock-down of HCN1 channels in the BLA with targeted delivery of lentivirus containing HCN1-shRNA increased SI beginning 2W after injection and induced stress resilience. NPY treatment induced sequential, complementary changes in the inputs to BLA PNs and their postsynaptic properties that reduce excitability, a mechanism that contributes to less anxious behavior. Furthermore, HCN1 knock-down mimicked the increases in SI and stress resilience observed with NPY, indicating the importance of Ih in stress-related behavior.SIGNIFICANCE STATEMENT Resilience improves mental health outcomes in response to adverse situations. Neuropeptide Y (NPY) is associated with decreased stress responses and the expression of resilience in rodents and humans. Single or repeated injections of NPY into the basolateral amygdala (BLA) buffer negative behavioral effects of stress and induce resilience in rats, respectively. Here, we demonstrate that repeated administration of NPY into the BLA unfolds several cellular mechanisms that decrease the activity of pyramidal output neurons. One key mechanism is a reduction in levels of the excitatory ion channel HCN1. Moreover, shRNA knock-down of HCN1 expression in BLA recapitulates some of the actions of NPY and causes potent resilience to stress, indicating that this channel may be a possible target for therapy.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuropéptido Y/farmacología , Canales de Potasio/efectos de los fármacos , Resiliencia Psicológica/efectos de los fármacos , Amígdala del Cerebelo/citología , Animales , Ansiedad/genética , Ansiedad/psicología , Fenómenos Electrofisiológicos/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Relaciones Interpersonales , Masculino , Microinyecciones , Neuropéptido Y/administración & dosificación , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: The objective of this study was to determine the influence of dietary macronutrient composition on central NPY's orexigenic effect in chicks. METHODS: Day-of-hatch chicks were fed one of three diets (3000 kcal ME/kg) ad libitum from hatch: high carbohydrate (HC), high fat (HF; 30% ME derived from soybean oil), and high protein (HP; 25 vs. 22% CP). In Experiment 1, chicks received intracerebroventricular injections of 0 (vehicle), 0.2, or 2.0â nmol NPY on day 4 and food intake was recorded for 6 hours. In Experiment 2, chicks were given all three diets before and after injection. In Experiment 3, hypothalamus was collected at 1-hour post-injection for gene expression analysis. RESULTS: The HC diet-fed chicks responded with a greater increase, while the chicks fed the HF diet had a lower threshold response in food intake to NPY. Neuropeptide Y dose-dependently increased food intake in chicks fed the HC and HP diets. Chicks administered 0.2â nmol NPY preferred the HC and HP diets over the HF diet. Relative quantities of hypothalamic NPYR1 and MC4R mRNA were reduced by NPY in chicks that consumed the HP and HC diets, respectively. DISCUSSION: Consumption of the HC diet was associated with the most robust NPY-induced increase in food intake. Injection of NPY accentuated differences among dietary groups in hypothalamic gene expression of several appetite-associated factors, results suggesting that the NPY/agouti-related peptide and melanocortin pathways are associated with some of the diet- and NPY-induced differences observed in this study.
Asunto(s)
Dieta , Expresión Génica , Hipotálamo/efectos de los fármacos , Neuropéptido Y/farmacología , Animales , Apetito/efectos de los fármacos , Pollos , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Hipotálamo/metabolismo , Infusiones Intraventriculares , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Receptores de Neuropéptido Y/genética , Receptores de Neuropéptido Y/metabolismoRESUMEN
Early-life stress (ES) is a risk factor for metabolic disorders (e.g. obesity) with a notoriously higher prevalence in women compared to men. However, mechanisms underlying these effects remain elusive. The development of the hypothalamic feeding and metabolic regulatory circuits occurs mostly in the early sensitive postnatal phase in rodents and is tightly regulated by the metabolic hormones leptin and ghrelin. We have previously demonstrated that chronic ES reduces circulating leptin and alters adipose tissue metabolism early and later in life similarly in both sexes. However, it is unknown whether chronic ES might also affect developmental ghrelin and insulin levels, and if it induces changes in hypothalamic feeding circuits, possibly in a sex-dependent manner. We here show that chronic ES, in the form of exposure to limited nesting and bedding material from postnatal day (P)2 to P9 in mice, affects ghrelin levels differently, depending on the form of ghrelin (acylated vs desacylated), on age (P9 vs P14) and on sex, while insulin levels were similarly increased in both sexes after ES at P9. Even though ghrelin levels were more strongly affected in ES-exposed females, hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) fiber density at P14 were similarly altered in both sexes by ES. In the paraventricular nucleus of the hypothalamus, both NPY and AgRP fiber density were increased, while in the arcuate nucleus of the hypothalamus, NPY was increased and AgRP unaltered. Additionally, the hypothalamic mRNA expression of ghrelin's receptor (i.e. growth hormone secretagogue receptor) was not affected by ES. Taken together, the specific alterations found in these important regulatory circuits after ES might contribute to an altered energy balance and feeding behavior in adulthood and thereby to an increased vulnerability to develop metabolic disorders.
Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Ghrelina/metabolismo , Neuropéptido Y/metabolismo , Tejido Adiposo/metabolismo , Proteína Relacionada con Agouti/farmacología , Animales , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/metabolismo , Conducta Alimentaria/efectos de los fármacos , Femenino , Ghrelina/genética , Ghrelina/farmacología , Hipotálamo/metabolismo , Insulina/genética , Insulina/metabolismo , Insulina/farmacología , Leptina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptido Y/farmacología , Obesidad/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Factores Sexuales , Estrés Psicológico/fisiopatologíaRESUMEN
Spontaneously hypertensive rats (SHR) have high sympathetic tone and progressive hypertension. Chronic calorie-restriction prevents hypertension. Their food intake (FI) and body weight are lower than in normotensive (NT) controls, even on a high-fat diet, suggesting a dysregulation of energy homeostasis. We assumed enhanced activity of hypothalamic anorexigenic melanocortins and diminished tone of orexigenic neuropeptide Y (NPY) in the background. FI of male SHR and NT Wistar rats was recorded in a FeedScale system upon intracerebroventricular injection of NPY, melanocortin ligands alpha-melanocyte-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP) or during a 7-day intracerebroventricular infusion of melanocortin antagonist HS024. Alpha-MSH, NPY, and AgRP immunoreactivities were semi-quantified in the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus in NT vs. SHR. Proopiomelanocortin gene expression was also assessed by quantitative RT-PCR in the ARC. Melanocortin-induced anorexia was stronger, FI induced by NPY or HS024 was smaller and delayed in SHR. Cellular alpha-MSH-specific signal density was higher in the ARC of SHR as evaluated by immunofluerescence, which was supported by PCR data. In the PVN, no differences in alpha-MSH-, NPY-, or AgRP-immunosignal were observed. Our results suggest that a higher melanocortin production/responsiveness and lower NPY responsiveness may contribute to the body weight dysregulation of SHR.
Asunto(s)
Metabolismo Energético , Homeostasis , Hipertensión/metabolismo , Proteína Relacionada con Agouti/farmacología , Animales , Peso Corporal , Hormonas/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Neuropéptido Y/farmacología , Fragmentos de Péptidos/farmacología , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Wistar , alfa-MSH/farmacologíaRESUMEN
Neuropeptide Y (NPY) is an important neurotransmitter in the control of energy metabolism. Several studies have shown that obesity is associated with increased levels of NPY in the hypothalamus. We hypothesized that the central release of NPY has coordinated and integrated effects on energy metabolism in different tissues, resulting in increased energy storage and decreased energy expenditure (EE). We first investigated the acute effects of an intracerebroventricular (ICV) infusion of NPY on gene expression in liver, brown adipose tissue, soleus muscle, and sc and epididymal white adipose tissue (WAT). We found increased expression of genes involved in gluconeogenesis and triglyceride secretion in the liver already 2-hour after the start of the NPY administration. In brown adipose tissue, the expression of thermogenic genes was decreased. In sc WAT, the expression of genes involved in lipogenesis was increased, whereas in soleus muscle, the expression of lipolytic genes was decreased after ICV NPY. These findings indicate that the ICV infusion of NPY acutely and simultaneously increases lipogenesis and decreases lipolysis in different tissues. Subsequently, we investigated the acute effects of ICV NPY on locomotor activity, respiratory exchange ratio, EE, and body temperature. The ICV infusion of NPY increased locomotor activity, body temperature, and EE as well as respiratory exchange ratio. Together, these results show that an acutely increased central availability of NPY results in a shift of metabolism towards lipid storage and an increased use of carbohydrates, while at the same time increasing activity, EE, and body temperature.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Expresión Génica/efectos de los fármacos , Neuropéptido Y/administración & dosificación , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Corticosterona/sangre , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Neuropéptido Y/farmacología , Ratas , Ratas WistarRESUMEN
The potent orexigenic peptide neuropeptide Y (NPY) has been considered as a possible endogenous ligand for a subpopulation of sigma receptors (SigR). However, their mutual interaction with reference to feeding behavior remains poorly understood. In the present study, we explored the possible interaction between sigma1 receptors (Sig1R) agonist, pentazocine, and NPY on food intake in satiated rats. While pentazocine dose-dependently reduced the food intake, NPY significantly increased it at 2, 4 and 6h post injection time points. In combination studies, pretreatment with NPY (0.1 nmol/rat, intra-PVN) normalized the inhibitory effect of pentazocine (60 µg/rat, intra-PVN) on food intake. Similarly, pre-treatment with pentazocine (30 µg/rat, intra-PVN) significantly antagonized the orexigenic effect of NPY (0.5 and 1.0 nmol/rat, intra-PVN). Moreover, pentazocine treatment decreased NPY immunoreactivity in arcuate (ARC), paraventricular (PVN), dorsomedial (DMH) and ventromedial (VMH) nuclei of hypothalamus. However, no change was observed in lateral hypothalamus (LH). Study implicates the reduced NPY immunoreactivity for the anorectic effect observed following pentazocine injections. Therefore, the concomitant activation of the NPYergic system along with the Sig1R agonist treatment may serve a useful purpose in the management of the unwanted side effects related to energy homeostasis.
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Regulación del Apetito/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Neuropéptido Y/farmacología , Neurotransmisores/farmacología , Pentazocina/farmacología , Receptores sigma/agonistas , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Receptor Sigma-1RESUMEN
As in mammals, fatty acid (FA) metabolism plays diverse and vital roles in regulating food intake in fish. Multiple lines of evidence suggest that the effect of FA metabolism on food intake is linked to changes in the level of neuropeptide Y (NPY) in the hypothalamus of the rainbow trout. In mammals, the evidence suggests that FA metabolism regulates feeding via hypothalamic NPY. NPY is therefore considered an important factor that mediates the modulation of food intake by FA metabolism in vertebrates. The stimulatory effect of NPY on food intake is well known. However, to the best of our knowledge, the effect of NPY on FA metabolism in the hypothalamus has not been examined. In this study, we cloned the cDNA of four key enzymes involved in FA metabolism and assessed the effect of energy status and NPY on their mRNA expression in the hypothalamus of grouper. The full-length cDNAs of UCP2 and CPT1a and the partial coding sequence (CDS) of ACC1 and FAS were isolated from the grouper hypothalamus. These genes are expressed in the hypothalamus and during the organogenetic stage of embryogenesis. A feeding rhythm study showed that the hypothalamic expression level of NPY and CPT1a was highly correlated with feeding rhythm. Long-term fasting was found to significantly induce the hypothalamic mRNA expression of NPY, CPT1a and UCP2. An in vitro study demonstrated that NPY strongly stimulated CPT1a and UCP2 mRNA expression in a time- and dose-dependent manner. Collectively, these results suggest that these four genes related to FA metabolism may play a role in regulating food intake in grouper and, that NPY modulates FA metabolism in the grouper hypothalamus. This study showed, for the first time in vertebrates, the effect of NPY on the gene expression of FA metabolism-related enzymes.
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Lubina/genética , Ingestión de Alimentos/efectos de los fármacos , Proteínas de Peces/genética , Hipotálamo/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Neuropéptido Y/farmacología , ARN Mensajero/genética , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Secuencia de Aminoácidos , Animales , Lubina/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Clonación Molecular , Cartilla de ADN , Ingestión de Alimentos/genética , Ayuno , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Ácidos Grasos/metabolismo , Proteínas de Peces/metabolismo , Regulación de la Expresión Génica , Hipotálamo/metabolismo , Canales Iónicos/genética , Canales Iónicos/metabolismo , Metabolismo de los Lípidos/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Especificidad de Órganos , ARN Mensajero/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Proteína Desacopladora 2RESUMEN
Pancreatic ß-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through G(i) activation of Y(1) and SSTR(1&5) receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca(2+)](i)) activity upon glucose stimulation, whereas SST alters this response. G(ßγ)-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca(2+)](i). mSIRK-induced G(ßγ) activation does not modulate glucose metabolism but increases [Ca(2+)](i) activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through G(ßγ) inhibition of Ca(2+) activity, while NPY activates a Ca(2+)-independent pathway mediated by G(α). GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies.
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Insulina/metabolismo , Neuropéptido Y/farmacología , Somatostatina/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Glucosa/farmacología , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Vías Secretoras/efectos de los fármacos , Factores de TiempoRESUMEN
While neuropeptide Y (NPY) has been studied extensively per its pronounced role in food intake stimulation as well as its role in central pathways governing eating disorders, it has to our knowledge not been studied in polygenic models of hypo- and hyperphagia. Thus, the present study was designed to measure central NPY-associated food intake in lines of chickens that have undergone long-term genetic selection for low (LWS) or high (HWS) body weight and exhibit hypo- and hyperphagia, respectively. LWS chicks did not respond with any magnitude of altered food intake to any dose of NPY tested, while HWS chicks responded to all doses of NPY at similar magnitudes throughout the duration of observation. Both lines responded with similar increases in c-Fos immunoreactivity in the lateral hypothalamus and both divisions of the paraventricular nucleus; there were no significant line or line by treatment interactions. These data support the hypothesis that differences exist in the central NPY system of chicks from LWS and HWS lines and may provide novel insight for understanding NPY control of appetite.
Asunto(s)
Anorexia/psicología , Apetito/efectos de los fármacos , Pollos/fisiología , Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/fisiología , Neuropéptido Y/farmacología , Animales , Peso Corporal/fisiología , Ingestión de Alimentos/genética , Inmunohistoquímica , Inyecciones Intraventriculares , Neuropéptido Y/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Neuropeptide Y (NPY) is expressed in the hypothalamus where it exerts orexigenic actions within the feeding control circuit. While NPY stimulates feeding in juvenile and adult animals, it is not known whether NPY influences food intake at earlier life stages. We investigated a role for NPY in regulating feeding at two stages of the life cycle of an amphibian, the Western spadefoot toad Spea hammondii. We administered NPY by intracerebroventricular (i.c.v.) injection to juvenile toads or prometamorphic tadpoles, and monitored locomotion, feeding behavior and/or food intake. Injection of NPY (20 or 200 ng/g BW) into juvenile toads decreased the latency to, and increased the number of strikes at prey, and the number of crickets eaten compared to uninjected or vehicle-injected controls. By contrast, injection of NPY (0.02-20 ng/g BW) into prometamorphic tadpoles caused a dose-dependent decrease in time spent foraging compared to controls. Blocking NPY signaling in the prometamorphic tadpole brain by i.c.v. injection of a general NPY receptor antagonist increased foraging, and partly blocked the action of exogenous NPY on foraging. Taken together, our findings show a developmental reversal in NPY actions on feeding in an amphibian, with the peptide having a characteristic orexigenic action in the juvenile toad, but an inhibitory action on foraging in the prometamorphic tadpole. The anorexigenic action of NPY in the tadpole correlates with a decrease in feeding that occurs at metamorphic climax when the tadpole's gut and cranium remodels for the transition to a carnivorous diet.
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Anfibios/metabolismo , Neuropéptido Y/farmacología , Anfibios/crecimiento & desarrollo , Animales , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Hipotálamo/metabolismo , LarvaRESUMEN
Depression and eating disorders are frequently associated, but the molecular pathways responsible for co-occurrence of altered mood, appetite and body weight are not yet fully understood. Neuropeptide Y (NPY) has potent antidepressant and orexigenic properties and low central NPY levels have been reported in major depression. In the present study, we hypothesized that in patients with major depression alteration of mood, appetite and body weight may be related to NPY-reactive autoantibodies (autoAbs). To test this hypothesis, we compared plasma levels and affinities of NPY-reactive autoAbs between patients with major depression and healthy controls. Then, to evaluate if changes of NPY autoAb properties can be causally related to altered mood and appetite, we developed central and peripheral passive transfer models of human autoAbs in mice and studied depressive-like behavior in forced-swim test and food intake. We found that plasma levels of NPY IgG autoAbs were lower in patients with moderate but not with mild depression correlating negatively with the Montgomery-Åsberg Depression Rating Scale scores and with immobility time of the forced-swim test in mice after peripheral injection of autoAbs. No significant differences in NPY IgG autoAb affinities between patients with depression and controls were found, but higher affinity of IgG autoAbs for NPY was associated with lower body mass index and prevented NPY-induced orexigenic response in mice after their central injection. These data suggest that changes of plasma levels of anti-NPY autoAbs are relevant to altered mood, while changes of their affinity may participate in altered appetite and body weight in patients with depressive disorder.