RESUMEN
As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Envejecimiento/metabolismo , Vivienda para Animales , Microglía/efectos de los fármacos , Compuestos Orgánicos/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Medio Social , Tejido Adiposo/metabolismo , Animales , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hormona Liberadora de Corticotropina/efectos de los fármacos , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Prueba de Tolerancia a la Glucosa , Hormona Liberadora de Gonadotropina/efectos de los fármacos , Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inflamación/genética , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/genética , Proopiomelanocortina/efectos de los fármacos , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transcriptoma/efectos de los fármacos , Pérdida de PesoRESUMEN
Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.
Asunto(s)
Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Antipsicóticos/farmacología , Hipotálamo/efectos de los fármacos , Neuropéptido Y/efectos de los fármacos , Olanzapina/farmacología , Receptores de Ghrelina/efectos de los fármacos , Receptores Histamínicos H1/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores Histamínicos H1/farmacología , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
INTRODUCTION: Ginseng polysaccharide (GPS, same as Panax polysaccharide) is a kind of polysaccharide extracted from ginseng. It has been reported that GPS has the ability to activate innate immunity, regulates blood sugar balance, and improves antioxidant capacity, but the effect on feeding behavior and its mechanism remains unclear. METHOD: To investigate the possible effect of GPS on feeding behavior of animals, mice were supplied with GPS in water, and food intake, hedonic feeding behavior, anxiety-like behavior, expression of appetite-regulation peptides in the central nervous system and glucose-related hormone levels in the serum of mice were measured. RESULTS: Ginseng polysaccharide significantly increased the average daily food intake in mice and promoted hedonic eating behavior. Meanwhile, the levels of serum glucose and glucagon were significantly reduced by GPS, and GPS promoted hypothalamic neuropeptide Y expression, inhibited proopiomelanocortin (POMC) expression, and reduced dopamine D1 receptor (DRD1) levels in the midbrain. We also found that the anxiety level of mice was significantly lower after GPS intake. In conclusion, oral supplementation with GPS promoted food intake in mice, most likely through the regulation of circulating glucose levels.
Asunto(s)
Conducta Alimentaria/efectos de los fármacos , Panax , Polisacáridos/farmacología , Animales , Ansiedad , Conducta Animal/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Suplementos Dietéticos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Ingestión de Alimentos/efectos de los fármacos , Glucagón/efectos de los fármacos , Glucagón/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Insulina/metabolismo , Masculino , Mesencéfalo/efectos de los fármacos , Mesencéfalo/metabolismo , Ratones , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/metabolismo , Proopiomelanocortina/efectos de los fármacos , Proopiomelanocortina/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/genéticaRESUMEN
Metabolic feedback from the periphery to the brain results from a dynamic physiologic fluctuation of nutrients and hormones, including glucose and fatty acids, ghrelin, leptin, and insulin. The specific interactions between humoral factors and how they influence feeding is largely unknown. We hypothesized that acute glucose availability may alter how the brain responds to ghrelin, a hormonal signal of energy availability. Acute glucose administration suppressed a range of ghrelin-induced behaviors as well as gene expression changes in hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons after ghrelin administration. Knockdown of the energy-sensing molecule AMP-activated protein kinase (AMPK) in AgRP neurons resulted in loss of the glucose effect, and mice responded as though pretreated with saline. Conversely, 2-deoxyglucose (2-DG), which decreases glucose availability, potentiated ghrelin-induced feeding and increased hypothalamic NPY mRNA levels. AMPK knockdown did not alter the additive effect of 2-DG and ghrelin on feeding. Our findings support the idea that computation of energy status is dynamic, is informed by multiple signals, and responds to acute fluctuations in metabolic state. These observations are broadly relevant to the investigation of neuroendocrine control of feeding and highlight the underappreciated complexity of control within these systems.
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Proteína Relacionada con Agouti/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Ghrelina/farmacología , Glucosa/farmacología , Neuronas/efectos de los fármacos , Neuropéptido Y/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Proteína Relacionada con Agouti/genética , Animales , Antimetabolitos/farmacología , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/metabolismo , Desoxiglucosa/farmacología , Técnicas de Silenciamiento del Gen , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Neuronas/metabolismo , Neuropéptido Y/genética , ARN Mensajero/metabolismoRESUMEN
Some odorants have physiological and psychological effects on organisms. However, little is known about the effects of inhaling them, particularly on the central nervous system. Using DNA microarray analysis, we obtained gene expression profiles of the hypothalamus from restraint stressed rats exposed to racemic (R,S)-linalool. Hierarchical clustering across all probe sets showed that this inhalation of (R,S)-linalool influenced the expression levels of a wide range of genes in the hypothalamus. A comparison of transcription levels revealed that the inhalation of (R,S)-linalool restored the expression of 560 stress-induced probe sets to a normal status. Gene Ontology (GO) analysis showed that these genes were associated with synaptic transmission via neurotransmitters including anxiolytic neuropeptides such as oxytocin and neuropeptide Y. These genes also included several major histocompatibility complex (MHC) class I molecules necessary for neural development and plasticity. Moreover, Upstream Regulator Analysis predicted that the hormone prolactin would be activated by the inhalation of (R,S)-linalool under stress. Our results reveal some of the molecular mechanisms associated with odor inhalation in the hypothalamus in organisms under stress.
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Expresión Génica/efectos de los fármacos , Genes MHC Clase I/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Monoterpenos/farmacología , Neuropéptido Y/efectos de los fármacos , Oxitocina/efectos de los fármacos , Estrés Psicológico/metabolismo , Monoterpenos Acíclicos , Administración por Inhalación , Animales , Masculino , Monoterpenos/administración & dosificación , Ratas , Ratas Wistar , Restricción Física , Regulación hacia ArribaRESUMEN
The hypothalamus is an important component of the nervous system, and neuropeptide Y (NPY), proopiomelanocortin (POMC), and neuromedin U (NMU) are key players in physiological regulation. Puerarin is important for nerve regulation. We investigated the effect of puerarin on the expression of NMU, NPY, and POMC genes in the hypothalamus. The results showed that the puerarin low-dose group and the other groups were significantly different (P < 0.05). However, there was no significant difference in NMU, POMC, and NPY among the groups.
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Hipotálamo/metabolismo , Isoflavonas/farmacología , Neuropéptido Y/genética , Neuropéptidos/genética , Proopiomelanocortina/genética , Animales , Regulación de la Expresión Génica , Hipotálamo/efectos de los fármacos , Neuropéptido Y/efectos de los fármacos , Neuropéptidos/efectos de los fármacos , Proopiomelanocortina/efectos de los fármacos , RatasRESUMEN
BACKGROUND: To examine whether electro-acupuncture (EA) could decrease 5-hydroxytryptamine (5-HT) and calcitonin gene-related peptide (CGRP), and increase neuro-peptide Y (NPY) in the brain-gut axis (BGA) in D-IBS using rat models. METHODS: Rats were randomly exposed to unpredictable chronic stress for 3 weeks followed by 1-hour acute restraint stress (CAS) after 7 days of rest, or daily gavage of Senna decoction (6 g/kg) plus chronic restraint stress (for a duration of 2 h, starting from 1 h prior to the gavage) for 2 weeks (ISC). The content of 5-HT, CGRP and NPY in the distal colon, spinal cord, hypothalamus was examined at the end of the treatment. RESULTS: 1. The two rat models exhibited similar characteristics, e.g., increased number of fecal pellets expelled in 1 h, decreased sacchar-intake, decreased CRD, elevated 5-HT, CGRP content and decreased NPY in the distal colon, spinal cord, hypothalamus (P < 0.05 vs. that in healthy control rats). 2. A series of equations was developed based on correlation regression analysis. The analysis results demonstrated that 5-HT mediates the changes in hypothalamus, spinal cord and colon. 5-HT and CGRP in spinal cord was closely correlated with general behavior evaluation and other transmitters in BGA. CONCLUSION: 1. In comparison to 5-HT, CGRP and NPY (particularly in the spinal cord) had closer relationship with the D-IBS symptoms induced by either stress factors or Senna decotion. 2. EA treatment could restore the brain-gut axis to balanced levels.
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Terapia por Acupuntura , Síndrome del Colon Irritable/enzimología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Péptido Relacionado con Gen de Calcitonina/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Colon/metabolismo , Diarrea , Modelos Animales de Enfermedad , Hipotálamo , Masculino , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Médula Espinal/metabolismoRESUMEN
UNLABELLED: Chronic stress may produce a decrease in central NPY expression and subjects exposed to it may prove hypersensitivity to a novel stressor with dysfunctions in the NPY system and cardiovascular maladaptation to stress, even hypertension. Upregulation of NPY expression may contribute to successful behavioral adaptation to stress by reducing cardiovascular tone and suppressing anxious behaviors. Adaptogens, a new class of metabolic regulators stimulate NPY expression and release. The aim of this study is to increase tolerance and adaptation to stress of hypersensitive to novel stressor, occupational chronic stress exposed subjects with cardiovascular maladaptation to mild new stressor using adaptogens as part of prevention protocol. MATERIAL AND METHODS: 40 military personnel with known cardiostressor reactional mode and occupational chronic stress exposure were exposed to mild novel stressor: occupational medicine routine evaluation and clinically assessed for maladaptative cardiovascular response prior and before application of 30 day prevention protocol. Employees were randomly split in two groups, one receiving standard prevention protocol (lifestyle counseling) plus adaptogens in multiple dose administration, twice daily and the other receiving only standard prevention protocol. RESULTS: We found significant statistic differences in all cardiovascular parameters in adaptogen group and only in diastolic blood pressure in control group. CONCLUSIONS: Adaptogens could be an important factor in successful prevention protocols of chronic occupational stress dysfunctions involving NPY systems.
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Adaptación Fisiológica/efectos de los fármacos , Adaptación Psicológica/efectos de los fármacos , Sistema Cardiovascular/efectos de los fármacos , Eleutherococcus , Neuropéptido Y/efectos de los fármacos , Exposición Profesional/efectos adversos , Extractos Vegetales/uso terapéutico , Rhodiola , Schisandra , Trastornos por Estrés Postraumático/tratamiento farmacológico , Adulto , Biomarcadores/sangre , Sistema Cardiovascular/fisiopatología , Estudios de Casos y Controles , Enfermedad Crónica , Consejo/métodos , Frutas , Humanos , Hipertensión/fisiopatología , Hipertensión/prevención & control , Masculino , Persona de Mediana Edad , Personal Militar , Neuropéptido Y/sangre , Fitoterapia/métodos , Extractos Vegetales/administración & dosificación , Raíces de Plantas , Medición de Riesgo , Trastornos por Estrés Postraumático/sangre , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/fisiopatología , Resultado del TratamientoRESUMEN
The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid beta oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid beta oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent manner.
Asunto(s)
Ácidos Grasos/metabolismo , Ghrelina/farmacología , Proteínas de Homeodominio/genética , Hipotálamo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuropéptidos/efectos de los fármacos , Factores de Transcripción/metabolismo , Proteína Relacionada con Agouti/efectos de los fármacos , Proteína Relacionada con Agouti/genética , Animales , Ingestión de Alimentos , Femenino , Regulación de la Expresión Génica , Masculino , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/genética , Neuropéptidos/genética , Ratas , Factores Sexuales , Factores de Transcripción/genéticaRESUMEN
It is well documented that neonatal neurosteroid administration influences brain development. In our previous studies, administration of pregnenolone, the precursor of neurosteroids, during the neonatal period altered the activity of dopamine (DA) in the striatum. Furthermore, neonatal treatment with pregnenolone or dehydroepiandrosterone (DHEA) increased synapse-related protein synapsin I as well as neuropeptide Y (NPY) in the hippocampus. The present study examined the effects of neonatal treatment with pregnenolone or DHEA on synapsin I, DA transporter (DAT), dynorphin A, and NPY in the striatum and the core and shell of the nucleus accumbens at post-puberty. Administration of pregnenolone or DHEA during the neonatal period increased immunodensity of synapsin I in the dorsomedial or ventrolateral striatum. DAT immunodensity in the striatum and the nucleus accumbens core as well as dynorphin A immunodensity in the nucleus accumbens core were increased in DHEA-treated but not in pregnenolone-treated rats. In addition, the size, but not numbers, of NPY-positive cells in the nucleus accumbens core was increased in pregnenolone- and DHEA-treated rats. The results suggest that neurosteroid levels during the neonatal period have larger impact on synaptic formation, development of DA and NPY systems in the nigrostriatal rather than the mesolimbic pathway.
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Cuerpo Estriado/efectos de los fármacos , Deshidroepiandrosterona/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Pregnenolona/farmacología , Adyuvantes Inmunológicos/farmacología , Animales , Animales Recién Nacidos , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dinorfinas/efectos de los fármacos , Dinorfinas/metabolismo , Inmunohistoquímica , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/metabolismo , Núcleo Accumbens/crecimiento & desarrollo , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Sinapsinas/efectos de los fármacos , Sinapsinas/metabolismo , Tiempo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
In the study we evaluated the effects of infusion of exogenous leptin to the third ventricle of the brain on the expression of immunoreactive (ir) neuropeptide Y (NPY) neurons in the hypothalamus and ir gonadotrophin releasing hormone (GnRH) nerve terminals in the median eminence of prepubertal lambs in the conditions of short fasting. Merino female sheep (n=16) were randomly divided into four groups, two fed with standard feeds and two fasted for 72 h. One standard and one fasted groups were infused with Ringer saline (controls), remaining standard and fasted groups with leptin (25 microg/120 microl/h), for 4 h during three consecutive days, and then slaughtered. Ir NPY and ir GnRH were localized by immunohistochemistry using specific polyclonal antibodies. Detection of both hormones was followed by the image analysis and expressed as the percent area stained and integral density of immunostaining. In the hypothalami from all groups the ir NPY perikarya and varicose nerve fibers were localized in three distinct sub-areas, in the arcuate (ARC), paraventricular and periventricular nuclei. In fasted sheep the percent area and integral density for immunoreactivity of NPY increased significantly (P<0.001) in three sub-areas compared to the standard-fed animals. Leptin infusion lowered the both parameters (P<0.001) but solely in the ARC NPY population of fasted sheep. The percent area and integral density of immunostaining for ir GnRH in fasted sheep revealed the augmentation (P<0.001) compared to standard-fed sheep. Leptin infusions diminished (P<0.001) both parameters in fasted, without effects in standard-fed lambs. In conclusion, the enhanced by fasting immunoreactivity of the ARC NPY perikarya and varicose nerve fibers and restrained immunoreaction of GnRH terminals in the median eminence were reversed by exogenous leptin. It is suggested that leptin can affect GnRH release via ARC NPY neurons in conditions of deficit of nutrients in prepubertal, female lambs.
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Ayuno/fisiología , Hormona Liberadora de Gonadotropina/metabolismo , Leptina/administración & dosificación , Neuronas/efectos de los fármacos , Neuropéptido Y/metabolismo , Factores de Edad , Animales , Femenino , Hormona Liberadora de Gonadotropina/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Inyecciones Intraventriculares , Neuronas/metabolismo , Neuropéptido Y/efectos de los fármacos , OvinosRESUMEN
RATIONALE: Despite irrefutable epidemiologic evidence, cigarette smoking remains the major preventable cause of lung disease morbidity worldwide. The appetite-suppressing effect of tobacco is a major behavioral determinant of smoking, but the underlying molecular and neuronal mechanisms are not understood. Neuropeptide Y (NPY) is an orexigenic neuropeptide, whose activity in the hypothalamic paraventricular nucleus governs appetite. OBJECTIVES: To compare the effects of smoke exposure and equivalent food restriction on body weight, organ mass, cytokines, and brain NPY in Balb/c mice. METHODS: A pair-feeding study design compared smoke exposure (4 wk; 1 cigarette, 3 x /d, 5 d/wk) to equivalent food restriction (pair-fed) and sham-exposed control mice. RESULTS: Smoke exposure rapidly induced mild anorexia. After 4 wk, smoke-exposed and pair-fed groups were lighter than control mice (22.0 +/- 0.2, 23.2 +/- 0.5, 24.9 +/- 0.4 g, respectively; p < 0.05). Brown and white fat masses were only reduced by smoke exposure, relative to control mice. NPY concentration in the paraventricular nucleus was significantly and paradoxically reduced by smoke exposure, despite lower plasma leptin concentrations; this was not observed in the pair-fed group experiencing 19% food restriction. Adipose mRNA expression of uncoupling proteins, inflammatory cytokines interleukin 6 and tumor necrosis factor alpha, and adipose triglyceride lipase was decreased by smoke exposure, and even lower in pair-fed mice. CONCLUSIONS: In contrast to food restriction, smoke exposure caused a reduction in hypothalamic NPY and fat mass, and regulated adipose cytokines. These findings may contribute to understanding weight loss in smoking-related lung disease and in the design of more effective smoking cessation strategies.
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Regulación del Apetito/efectos de los fármacos , Neuropéptido Y/efectos de los fármacos , Fumar/fisiopatología , Pérdida de Peso/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Anorexia/etiología , Peso Corporal/efectos de los fármacos , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Hipotálamo/metabolismo , Interleucina-6/metabolismo , Canales Iónicos , Leptina/sangre , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Proteínas Mitocondriales , Neuropéptido Y/metabolismo , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteína Desacopladora 1 , Proteína Desacopladora 3RESUMEN
AIMS/HYPOTHESIS: Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats. METHODS: Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed. RESULTS: Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats. CONCLUSIONS/INTERPRETATION: This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.
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Intolerancia a la Glucosa/genética , Hipotálamo/efectos de los fármacos , Obesidad/terapia , Proopiomelanocortina/administración & dosificación , Proopiomelanocortina/genética , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Envejecimiento/fisiología , Proteína Relacionada con Agouti , Animales , Peso Corporal/genética , Colesterol/sangre , Dependovirus/genética , Ingestión de Alimentos , Ácidos Grasos no Esterificados/sangre , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/farmacología , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Péptidos y Proteínas de Señalización Intercelular , Leptina/sangre , Masculino , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/genética , Obesidad/genética , Obesidad/metabolismo , Hormonas Peptídicas/efectos de los fármacos , Hormonas Peptídicas/genética , Ratas , Ratas Endogámicas F344 , Receptor de Melanocortina Tipo 3/efectos de los fármacos , Receptor de Melanocortina Tipo 3/genética , Receptor de Melanocortina Tipo 4/efectos de los fármacos , Receptor de Melanocortina Tipo 4/genética , Triglicéridos/sangreRESUMEN
While there have been many studies in various species examining the mode of central leptin action on food intake, there is however a paucity of data in birds. We have, therefore, addressed this issue in broiler chickens because this strain was selected for high growth rate, hence high food intake. Continuous infusion of recombinant chicken leptin (8 microg/kg/h) during 6 h at a constant rate of 3 ml/h resulted in a significant reduction (49-57%) of food intake in 3-week-old broiler chickens (P < 0.05). The effect of leptin within the central nervous system (CNS) was mediated via selective hypothalamic neuropeptides. Leptin significantly decreased the expression of its receptor (Ob-R), neuropeptide Y (NPY), orexin (ORX), and orexin receptor (ORXR) (P < 0.05), but not that of agouti-related protein (AgRP) (anabolic/orexigenic effectors) in chicken hypothalamus. However, the catabolic/anorexigenic neuropeptides namely proopiomelanocortin (POMC) and corticotropin-releasing hormone (CRH) mRNA levels remained unchanged after leptin treatment. Despite the absence of leptin effect on AgRP (the antagonist of melanocortin receptor MCR) and POMC (the precursor of alpha-melanocyte stimulating hormone which is a potent agonist for MCR), leptin significantly decreased the expression of MCR-4/5 gene in chicken hypothalamus (P < 0.05) suggesting that leptin acts directly (as ligand) or indirectly (via other ligands) on MCRs to regulate food intake in birds. Additionally, leptin down-regulated the expression of fatty acid synthase (FAS) gene in chicken hypothalamus, indicating an additional pathway of leptin action on food intake such as described for FAS inhibitors. These findings provide new insight into the mechanism of leptin control of food intake in chickens.
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Pollos/fisiología , Conducta Alimentaria/fisiología , Hipotálamo/efectos de los fármacos , Leptina/administración & dosificación , Proteína Relacionada con Agouti , Animales , Southern Blotting , Corticosterona/sangre , Hormona Liberadora de Corticotropina/biosíntesis , Hormona Liberadora de Corticotropina/efectos de los fármacos , Cartilla de ADN , Ácido Graso Sintasas/biosíntesis , Ácido Graso Sintasas/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Infusiones Intravenosas , Péptidos y Proteínas de Señalización Intercelular , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Leptina/sangre , Neuropéptido Y/biosíntesis , Neuropéptido Y/efectos de los fármacos , Neuropéptidos/biosíntesis , Neuropéptidos/efectos de los fármacos , Receptores de Orexina , Orexinas , Proopiomelanocortina/biosíntesis , Proopiomelanocortina/efectos de los fármacos , Proteínas/efectos de los fármacos , ARN Mensajero/análisis , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/efectos de los fármacos , Receptores Acoplados a Proteínas G , Receptores de Leptina , Receptores de Melanocortina/agonistas , Receptores de Melanocortina/antagonistas & inhibidores , Receptores de Melanocortina/efectos de los fármacos , Receptores de Neuropéptido/biosíntesis , Receptores de Neuropéptido/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Hormonas Tiroideas/sangreRESUMEN
OBJECTIVE: To study the relationship between neuropeptide Y (NPY) and diabetes by examining the content and distribution of NPY and its mRNA expression in the hypothalamus and pancreas of STZ-diabetic rats. METHODS: Thirty Wistar rats were randomly divided into 3 groups (diabetic group, diabetic insulin treatment group, and control group). After feeding for 24 weeks, the rats were sacrificed. The expression of NPY in the hypothalamus and pancreas was detected with immunohistochemistry and in situ hybridization. RESULTS: (1) The hypothalamic content of NPY and its mRNA were significantly increased in STZ-diabetic rats in comparison with normal controls. Increased expression of NPY mRNA was found only in the arcuate nucleus and not in the paraventricular nucleus in diabetic rats, suggesting that NPY was produced in the arcuate nucleus. (2) The hypothalamic content of NPY and its mRNA in STZ-diabetic rats were visibly reduced after insulin treatment compared with that in untreated diabetic rats. This supports the hypothesis that insulin deficiency in the brain may be responsible for increased hypothalamic NPY gene expression in diabetic rats. (3) The increase of hypothalamic NPY in STZ diabetic rats associated with hyperphagia and polydipsia could be reversed by insulin replacement, suggesting that increased hypothalamic NPY contributes to the pathophysiological progress of the diabetic state. (4) The present study demonstrated for the first time that the content of NPY and its mRNA in the pancreas was increased in STZ-diabetic rats, and that the distribution of NPY-positive cell in islets was changed from the periphery to the whole islet. The content and distribution of NPY and its mRNA in islets were not changed by insulin treatment. CONCLUSION: Increased NPY in the hypothalamus results in hypophagia and polydipsia, while the implication of increased NPY in the pancreas of diabetic rats is not clear.
Asunto(s)
Diabetes Mellitus Experimental/genética , Neuropéptido Y/genética , ARN Mensajero/metabolismo , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inmunohistoquímica , Hibridación in Situ , Insulina/uso terapéutico , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Ratas , Ratas WistarRESUMEN
We compared the estradiol/progesterone-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release between normally fed and leptin-supplemented starved ovariectomized female rats and studied also the effect of hyper-leptinaemia on the steroid-induced hormonal release in normally fed ovariectomized rats. Three days' starvation completely abolished steroid-induced LH and FSH release. Significant recovery of the hormonal release was shown in the leptin-supplemented starved group. The magnitudes of LH and FSH release in the normally fed animals with a higher dose of leptin were statistically the same as those in the normally fed group without leptin. These observations indicate that physiological concentrations of circulating leptin exert a stimulatory effect on steroid-induced LH and FSH release.
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Hormona Folículo Estimulante/metabolismo , Leptina/farmacología , Leptina/fisiología , Hormona Luteinizante/metabolismo , Ovariectomía , Análisis de Varianza , Animales , Peso Corporal , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/fisiología , Óxido Nítrico/fisiología , Ratas , Medicina Reproductiva , Inanición/tratamiento farmacológico , Inanición/metabolismo , Factores de TiempoRESUMEN
To explore the role of agouti-related protein (AGRP) in diabetic hyperphagia changes in hypothalamic AGRP mRNA levels were examined in diabetic rats. Rats rendered diabetic by streptozotocin displayed marked hyperglycemia (blood glucose 456.0+/-8.4 mg/dl versus 71.8+/-1.9 mg/dl) and hyperphagia (36.9+/-1.0 g/day versus 22.0+/-0.4 g/day), that was associated with a 286.6+/-4.4% increase in hypothalamic AGRP mRNA and a 178.9+/-13.5% increase in hypothalamic NPY mRNA. Insulin treatment of diabetic rats partially corrected blood glucose (147.4+/-13.1 mg/dl) and ameliorated hyperphagia (26.6+/-2.0 g/day). Insulin replacement was also associated with a return of hypothalamic AGRP mRNA (111.7+/-8.3% of controls) and NPY mRNA (125.0+/-8.9% of controls) from the elevated levels that were observed in untreated diabetic rats. In contrast to insulin treated rats, sodium orthovanadate treated diabetic rats remained significantly hyperglycemic (361.5+/-12.5 mg/dl). However, despite their persistent hyperglycemia, orthovanadate treated diabetic rats were still observed to have a significant reduction of hypothalamic AGRP mRNA (138.7+/-11.4%) and NPY mRNA (129.9+/-9.8%). Simultaneous measurement of serum leptin revealed suppressed levels in both untreated diabetic (0.5+/-0.1 ng/ml) and sodium orthovanadate treated rats (0.5+/-0.1 ng/ml) compared to non-diabetic controls (2.1+/-0.1 ng/ml). These data indicate that AGRP is a mediator of diabetic hyperhpagia and suggest that insulin can directly influence hypothalamic AGRP and NPY mRNA expression.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Hiperfagia/metabolismo , Proteínas/metabolismo , Proteína Relacionada con Agouti , Animales , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipotálamo/metabolismo , Insulina/sangre , Insulina/farmacología , Péptidos y Proteínas de Señalización Intercelular , Leptina/sangre , Masculino , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Vanadatos/farmacologíaRESUMEN
Orexins (orexin-A and -B) are recently identified neuropeptides, which are thought to be implicated in the regulation of feeding behavior. We used a NPY-Y1 receptor specific antagonist, BIBO3304, to examine whether NPY is involved in orexin-induced feeding behavior. Intracerebroventricular administration of orexin-A (10 nmol) induced food intake in rats (food intake for 3 h; vehicle 0.3+/-0.2 g vs. orexin-A 10 nmol, 4.0+/-0.5 g, n=4). Orexin-induced feeding behavior was partially inhibited by prior administration of BIBO3304 (3 h food intake: orexin-A 10 nmol, 4.0+/-0.5 g vs. BIBO3304 (60 microgram) + orexin-A 10 nmol, 2.2+/-0.2 g, n=4). A low dose of BIBO3304 (30 microgram) did not show a significant inhibitory effect. BIBO3457, an inactive enantiomer, used as a negative control, did not show any inhibitory effect on orexin-A-induced feeding behavior. Fos expression was observed in NPY-containing neurons in the arcuate nucleus 1 h after orexin-A (10 nmol) was administered intracerebroventricularly (control 0.3+/-0.08%, orexin-A 10.2+/-0.8%, n=5 rats/group). These observations suggest that NPY is involved in orexin-induced feeding behavior. However, BIBO3304 did not completely abolish the effect of orexin-A. These results suggest that orexin-A elicits feeding behavior partially via the NPY pathway. The NPY system could be the one of downstream pathways by which orexin-A induces feeding behavior. Another pathway may also be involved in orexin-A-induced feeding behavior, because BIBO3304 did not completely abolish orexin-A-induced feeding behavior.
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Proteínas Portadoras/metabolismo , Proteínas Portadoras/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Hipotálamo/citología , Masculino , Vías Nerviosas/citología , Receptores de Orexina , Orexinas , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G , Receptores de NeuropéptidoRESUMEN
1. The thiazolidinedione BRL 49653 (rosiglitazone) induces hyperphagia and weight gain in obese, insulin-resistant fatty Zucker rats but not in lean insulin-sensitive rats. We investigated whether these responses might involve neuropeptide Y (NPY), leptin and insulin. 2. BRL 49653 (1 mg kg(-1) day(-1), orally) was given for 7 or 20 days to fatty and lean Zucker and Wistar rats. 3. In lean rats of either strain, BRL 49653 had no effect on food intake, body weight, plasma insulin and corticosterone, NPY or NPY mRNA levels. 4. Fatty rats given BRL 49653 showed a 30% increase in food intake and accelerated body weight gain (both P<0.01) after 7 and 20 days, but without significant changes in regional hypothalamic NPY or NPY mRNA levels. 5. Plasma leptin levels were twice as high in untreated fatty Zucker rats as in lean rats (P<0.01), but were unaffected by BRL 49653 given for 20 days. However, BRL 49653 reduced insulin levels by 42% and increased corticosterone levels by 124% in fatty rats (both P<0.01). 6. Hyperphagia induced in fatty Zucker rats by BRL 49653 does not appear to be mediated by either a fall in circulating leptin levels or increased activity of hypothalamic NPYergic neurones. The fall in plasma insulin and/or rise in corticosterone levels during BRL 49653 treatment may be involved, consistent with the postulated role of these hormones in the control of food intake.
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Ingestión de Alimentos/efectos de los fármacos , Hipoglucemiantes/farmacología , Hipotálamo/efectos de los fármacos , Neuropéptido Y/efectos de los fármacos , Proteínas/efectos de los fármacos , Tiazoles/farmacología , Tiazolidinedionas , Animales , Estimulantes del Apetito/metabolismo , Peso Corporal/efectos de los fármacos , Hiperfagia/inducido químicamente , Hipoglucemiantes/administración & dosificación , Hipotálamo/metabolismo , Leptina , Masculino , Neuropéptido Y/metabolismo , Proteínas/metabolismo , Ratas , Ratas Wistar , Ratas Zucker , Rosiglitazona , Tiazoles/administración & dosificaciónRESUMEN
Neuropeptide Y (NPY) is a major hypothalamic peptide which is implicated in the regulation of energy balance and in the activation of the hypothalamo-pituitary adrenal axis. This study aimed primarily to determine the effects on regional hypothalamic NPY levels, of catabolism and weight loss induced in rats by the synthetic glucocorticoid, dexamethasone, injected daily at a dose of 0.4 mg/kg for 7 days. NPY concentrations were significantly raised in the paraventricular nucleus (PVN) of male Wistar rats (45%, p = 0.009; n = 10) compared with saline-injected controls (n = 10). Body weight (p less than 0.001) and food intake (p less than 0.001) were significantly reduced, plasma insulin concentrations were increased (p less than 0.001), but there was no change in glucose concentrations. Chronic dexamethasone treatment did not cause the marked NPY increases in the arcuate nucleus (ARC) and other hypothalamic regions which have been observed in other catabolic states causing weight loss. One possible explanation is the high insulin levels induced by dexamethasone, which may have prevented compensatory hyperphagia by suppressing an increase in hypothalamic NPYergic activity. We also examined the acute effects of a single dexamethasone injection on regional hypothalamic levels, to determine whether the drug had a direct action separate from that due to sustained weight loss. In the acute study, groups of rats (n = 7) were examined at 4 h after a single injection of dexamethasone or saline. NPY concentrations were significantly increased in the lateral hypothalamic area (LHA), (60%, p = 0.008) when compared with saline-injected controls, but there was no change in body weight or glucose or insulin concentrations during the 4h interval. Altered transport or release of NPY in the lateral hypothalamic area may be a result of acute feedback regulation by glucocorticoids on the hypothalamus.