RESUMEN
Epigenetics may have an important role in mood stabilizer action. Valproic acid (VPA) is a histone deacetylase inhibitor, and lithium (Li) may have downstream epigenetic actions. To identify genes commonly affected by both mood stabilizers and to assess potential epigenetic mechanisms that may be involved in their mechanism of action, we administered Li (N = 12), VPA (N = 12), and normal chow (N = 12) to Brown Norway rats for 30 days. Genomic DNA and mRNA were extracted from the hippocampus. We used the mRNA to perform gene expression analysis on Affymetrix microarray chips, and for genes commonly regulated by both Li and VPA, we validated expression levels using quantitative real-time PCR. To identify potential mechanisms underlying expression changes, genomic DNA was bisulfite treated for pyrosequencing of key CpG island 'shores' and promoter regions, and chromatin was prepared from both hippocampal tissue and a hippocampal-derived cell line to assess modifications of histones. For most genes, we found little evidence of DNA methylation changes in response to the medications. However, we detected histone H3 methylation and acetylation in the leptin receptor gene, Lepr, following treatment with both drugs. VPA-mediated effects on histones are well established, whereas the Li effects constitute a novel mechanism of transcriptional derepression for this drug. These data support several shared transcriptional targets of Li and VPA, and provide evidence suggesting leptin signaling as an epigenetic target of two mood stabilizers. Additional work could help clarify whether leptin signaling in the brain has a role in the therapeutic action of Li and VPA in bipolar disorder.
Asunto(s)
Epigénesis Genética/efectos de los fármacos , Compuestos de Litio/farmacología , Receptores de Leptina/efectos de los fármacos , Ácido Valproico/farmacología , Animales , Metilación de ADN/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Genes/efectos de los fármacos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Endogámicas BN , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Leptina/genética , TranscriptomaRESUMEN
BACKGROUND: Meal tolerance tests are frequently used to study dynamic incretin and insulin responses in the postprandial state; however, the optimal meal that is best tolerated and suited for hormonal response following surgical and medical weight loss has yet to be determined. OBJECTIVE: To evaluate the tolerability and effectiveness of different test meals in inducing detectable changes in markers of glucose metabolism in individuals who have undergone a weight loss intervention. METHODS: Six individuals who underwent surgical or medical weight loss (two Roux-en-Y gastric bypass, two sleeve gastrectomy and two medical weight loss) each completed three meal tolerance tests using liquid-mixed, solid-mixed and high-fat test meals. The tolerability of each test meal, as determined by the total amount consumed and palatability, as well as fasting and meal-stimulated glucagon-like peptide, glucose-dependent insulinotropic polypeptide, insulin and glucose were measured. RESULTS: Among the six individuals, the liquid-mixed meal was better and more uniformly tolerated with a median meal completion rate of 99%. Among the four bariatric surgical patients, liquid-mixed meal stimulated on average a higher glucagon-like peptide (percent difference: 83.7, 89), insulin secretion (percent difference: 155.1, 158.7) and glucose-dependent insulinotropic polypeptide (percent difference: 113.5, 34.3) compared with solid-mixed and high-fat meals. CONCLUSIONS: The liquid-mixed meal was better tolerated with higher incretin and insulin response compared with the high-fat and solid-mixed meals and is best suited for the evaluation of stimulated glucose homeostasis.
RESUMEN
Stress activates the hypothalamus-pituitary-adrenal (HPA) axis leading to the release of glucocorticoids (GC). Increased activity of the HPA axis and GC exposure has been suggested to facilitate the development of obesity and metabolic syndrome. Nonetheless, different stressors can produce distinct effects on food intake and may support different directions of food learning e.g. avoidance or acceptance. This study examined whether interoceptive (LiCl and exendin-4) and restraint stress (RS) support similar or distinct food learning. Female rats were exposed to different stressors after their consumption of a palatable food (butter icing). After four palatable food-stress pairings, distinct intakes of the butter icing were observed in rats treated with different stressors. Rats that received butter icing followed by intraperitoneal injections of LiCl (42.3mg/kg) and exendin-4 (10µg/kg) completely avoided the palatable food with subsequent presentations. In contrast, rats experiencing RS paired with the palatable food increased their consumption of butter icing across trials and did so to a greater degree than rats receiving saline injections. These data indicate that interoceptive and psychosocial stressors support conditioned food avoidance and acceptance, respectively. Examination of c-Fos immunoreactivity revealed distinct neural activation by interoceptive and psychosocial stressors that could provide the neural basis underlying opposite direction of food acceptance learning.
Asunto(s)
Reacción de Prevención/fisiología , Ingestión de Alimentos/fisiología , Ingestión de Alimentos/psicología , Preferencias Alimentarias/fisiología , Preferencias Alimentarias/psicología , Estrés Psicológico/psicología , Animales , Antimaníacos/farmacología , Trastorno por Atracón/psicología , Peso Corporal/fisiología , Condicionamiento Operante/fisiología , Interpretación Estadística de Datos , Exenatida , Femenino , Inmunohistoquímica , Cloruro de Litio/farmacología , Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Restricción Física , Ponzoñas/farmacologíaRESUMEN
OBJECTIVE: One developing strategy for obesity treatment has been to use combinations of differently acting pharmacotherapies to improve weight loss with fewer adverse effects. The purpose of this study was to determine whether the combination of naltrexone (Nal), an opioid antagonist acting on the reward system, and exendin-4 (Ex-4), a glucagon-like peptide 1 agonist acting on satiety signaling, would produce larger reductions in food intake than either alone in rats. Because the anorectic potencies of both compounds have been associated with nausea and malaise, the influence of these drug combinations on the acquisition of a conditioned taste aversion (CTA) was also determined. METHODS: In Experiment 1, the acute anorectic effects of Nal (0.32-3.2 mg kg(-1); intraperitoneally (i.p.)) and Ex-4 (1-10 µg kg(-1); i.p.) were assessed alone or in combination. Combinational doses were further investigated by the repeated daily administration of 1 mg kg(-1) Nal+3.2 µg kg(-1) Ex-4 for 4 days. In Experiment 2, both compounds alone or in combination were used as unconditioned stimuli in a series of CTA tests. RESULTS: Nal and Ex-4, alone or in combination, suppressed food intake in a dose-dependent manner, and the interaction on food intake between Nal and Ex-4 was additive. In the CTA paradigm, Nal (1 mg kg(-1)) alone did not support acquisition, whereas a CTA was evident with doses of Ex-4 (1 or 3.2 µg kg(-1)). Combinations of Nal and Ex-4 also resulted in a more rapid and robust acquisition of a CTA. CONCLUSION: Given that the Nal and Ex-4 combination produces additive effects on not only food intake reduction but also food aversion learning, this specific drug combination does not have the benefit of minimizing the adverse effects associated with each individual drug. These data suggest that it is necessary to evaluate both the positive and adverse effects at early stages of combinational drug development.
Asunto(s)
Depresores del Apetito/farmacología , Ingestión de Alimentos/efectos de los fármacos , Hipoglucemiantes/farmacología , Naltrexona/farmacología , Obesidad/tratamiento farmacológico , Péptidos/farmacología , Ponzoñas/farmacología , Animales , Peso Corporal/efectos de los fármacos , Interacciones Farmacológicas , Quimioterapia Combinada , Exenatida , Masculino , Obesidad/prevención & control , Ratas , Ratas Sprague-Dawley , Gusto/efectos de los fármacos , Pérdida de Peso/efectos de los fármacosRESUMEN
AIMS: The pathogenesis of obesity remains incompletely understood. Drosophila have conserved neuroendocrine and digestion systems with human and become an excellent system for studying energy homeostasis. Here, we reported a novel obesity Drosophila model, in which expression of human protein, synphilin-1 (SP1), in neurons fosters positive energy balance. SUBJECTS AND METHODS: To further understand the actions of SP1 in energy balance control, the upstream activation sequence UAS/GAL4 system was used to generate human SP1 transgenic Drosophila. We characterized a human SP1 transgenic Drosophila by assessing SP1 expression, fat lipid deposition, food intake and fly locomotor activity to determine the major behavioral changes and their consequences in the development of the obesity-like phenotype. RESULTS: Overexpression of SP1 in neurons, but not peripheral cells, increased the body weight of flies compared with that of non-transgenic controls. SP1 increased food intake but did not affect locomotor activity. SP1 increased the levels of triacylglycerol, and the size of fat body cells and lipid droplets, indicating that SP1 increased lipid-fat disposition. Survival studies showed that SP1 transgenic flies were more resistant to food deprivation. SP1 regulated lipin gene expression that may participate in SP1-induced fat deposition and starvation resistance. CONCLUSION: These studies demonstrate that SP1 expression affects energy homeostasis in ways that enhance positive energy balance and provide a useful obesity model for future pathogenesis and therapeutic studies.
Asunto(s)
Proteínas Portadoras/metabolismo , Ingestión de Alimentos , Metabolismo Energético , Metabolismo de los Lípidos , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Obesidad/metabolismo , Animales , Animales Modificados Genéticamente , Western Blotting , Modelos Animales de Enfermedad , Drosophila/metabolismo , Femenino , Homeostasis , Humanos , Masculino , Actividad Motora , Regulación hacia Arriba , Aumento de PesoAsunto(s)
Regulación del Apetito , Índice de Masa Corporal , Mapeo Encefálico , Encéfalo/patología , Ingestión de Alimentos/fisiología , Neuroimagen Funcional/métodos , Hambre/fisiología , Imagen por Resonancia Magnética/métodos , Obesidad/patología , Obesidad/fisiopatología , Síndrome de Prader-Willi/fisiopatología , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatología , Saciedad/fisiología , Volición , Femenino , Humanos , MasculinoRESUMEN
AIMS: The pathogenesis of obesity remains incompletely understood and the exploration of the role of novel proteins in obesity may provide important insights into its causes and treatments. Here, we report a previously unidentified role for synphilin-1 in the control of food intake and body weight. Synphilin-1, a cytoplasmic protein, was initially identified as an interaction partner of alpha-synuclein, and has implications in Parkinson's disease pathogenesis related to protein aggregation. SUBJECTS AND METHODS: To study the in vivo role of synphilin-1, we characterized a human synphilin-1 transgenic mouse (SP1) by assessing synphilin-1 expression, plasma parameters, food intake and spontaneous activity to determine the major behavioral changes and their consequences in the development of the obesity phenotype. RESULTS: Expression of human synphilin-1 in brain neurons in SP1 mice resulted in increased food intake, body weight and body fat. SP1 mice also displayed hyperinsulinemia, hyperleptinemia and impaired glucose tolerance. Pair-feeding SP1 mice to amounts consumed by non-transgenic mice prevented the increased body weight, adiposity, hyperinsulinemia and hyperleptinemia demonstrating that these were all the consequences of increased food intake. Transgenic expression of synphilin-1 was enriched in hypothalamic nuclei involved in feeding control, and fasting-induced elevated endogenous synphilin-1 levels at these sites, suggesting that synphilin-1 is an important player in the hypothalamic energy balance regulatory system. CONCLUSION: These studies identify a novel function of synphilin-1 in controlling food intake and body weight, and may provide a unique obesity model for future studies of obesity pathogenesis and therapeutics.
Asunto(s)
Proteínas Portadoras/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Hiperfagia/metabolismo , Hipotálamo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Obesidad/metabolismo , Animales , Western Blotting , Peso Corporal , Proteínas Portadoras/genética , Proteínas Portadoras/farmacología , Modelos Animales de Enfermedad , Hipotálamo/efectos de los fármacos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/farmacologíaRESUMEN
Synphilin-1 is a cytoplasmic protein with unclear function. Synphilin-1 has been identified as an interaction partner of alpha-synuclein. The interaction between synphilin-1 and alpha-synuclein has implications in Parkinson's disease. In this study, we stably overexpressed human synphilin-1 in mouse N1E-115 neuroblastoma cells. We found that overexpression of synphilin-1 shortened cell growth doubling time and increased neurite outgrowth. Knockdown of endogenous synphilin-1 caused neuronal toxicity and shortened neurite outgrowth. We further found that synphilin-1 increased activation of the extracellular signal-regulated kinases (ERK1/2) and mediated neurite outgrowth. Rotenone, mitochondrial complex I inhibitor, has been shown previously to induce dopaminergic neurodegeneration and Parkinsonism in rats and Drosophila. We found that Rotenone induced apoptotic cell death in N1E-115 cells via caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. Overexpression of synphilin-1 significantly reduced Rotenone-induced cell death, caspase-3 activation and PARP cleavage. The results indicate that synphilin-1 displays trophic and protective effects in vitro, suggesting that synphilin-1 may play a protective role in Parkinson's disease (PD) pathogenesis and may lead to a potential therapeutic target for PD intervention.
Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Rotenona/farmacología , Animales , Apoptosis/fisiología , Proteínas Portadoras/genética , Caspasa 3/metabolismo , Aumento de la Célula , Línea Celular Tumoral , Proliferación Celular , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/genética , Neuritas/fisiología , Neuronas/fisiología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Factores de Tiempo , TransfecciónRESUMEN
Multiple gut peptides are involved in the overall control of food intake. Plasma levels of gut peptides are differentially affected by food intake, and the different patterns of release around meals provides an indication of a peptide's specific role in feeding control. Ghrelin is a gastric peptide whose plasma levels are high before meals and are suppressed in response to food intake. Consistent with this pattern, ghrelin has been shown to stimulate food intake by hastening meal initiations. Cholecystokinin (CCK) is released from upper intestinal sites in response to food intake. CCK inhibits eating in a manner consistent with a role in satiety. Pancreatic glucagon and amylin play similar roles in meal termination. In contrast, the lower gut peptides, peptide YY (3-36) and glucagon-like peptide 1, are released more slowly in response to food intake and levels remain elevated for hours after a meal. This pattern of release suggests effects across multiple meals, and these peptides have been shown to inhibit food intake by both decreasing meal size and increasing the satiating potency of consumed nutrients. Together, these actions indicate multiple roles for gut peptides in feeding control.
Asunto(s)
Regulación del Apetito/fisiología , Fenómenos Fisiológicos del Sistema Digestivo , Hormonas Gastrointestinales/fisiología , Tracto Gastrointestinal/metabolismo , Hormonas Peptídicas/fisiología , Amiloide/metabolismo , Amiloide/fisiología , Animales , Depresores del Apetito/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Colecistoquinina/metabolismo , Colecistoquinina/fisiología , Ingestión de Energía/fisiología , Conducta Alimentaria/fisiología , Hormonas Gastrointestinales/metabolismo , Ghrelina/metabolismo , Ghrelina/fisiología , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos , Ratones , Neuropéptido Y , Hormonas Peptídicas/metabolismo , Respuesta de Saciedad/fisiologíaRESUMEN
OBJECTIVE: To understand the adaptation to lactation of obese rats, by studying the interplay among the gut hormone cholecystokinin (CCK), the adiposity hormone leptin and the affiliation hormone oxytocin in modulating body mass and fat storage. DESIGN: Strain differences were examined between Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking expression of functional CCK-1 receptors and Long Evans Tokushima Otsuka (LETO) controls, tested as nulliparous dams, at the 7 and 15th lactation day, at weaning (lactation day 22) or 8 weeks postweaning. MEASUREMENTS: We measured body mass, fat pads (brown, retroperitoneal and inguinal) and inguinal adipocytes. Plasma levels of leptin and oxytocin were determined. RESULTS: Fat depots of LETO female rats were larger during lactation compared to the levels found in postweaning and nulliparous female rats. LETO female rats gained weight and accumulated fat during pregnancy and lactation, returning to their normal fat levels postweaning. In contrast, OLETF female rats presented lower body weight and fat depots during the lactation period than nulliparous dams, and regained the weight and fat postweaning. Plasma leptin and oxytocin were highly correlated and followed the same pattern. OLETF leptin levels were highly correlated with fat depot and inguinal cell surface. No significant correlation was found for LETO parameters. CONCLUSIONS: Pregnancy and lactation are energy-consuming events, which naturally induce female rats to increase food intake and accumulate fat. When challenged by the demands of rapidly growing preobese OLETF pups, OLETF dams' fat stores are reduced to lean, LETO levels. During lactation, sensitivity of the oxytocinergic neurons descending from the paraventricular nuclei to the nucleus of the solitary tract to CCK is reduced. We theorized that this pathway is not available to OLETF female rats that lack functional CCK-1 receptors to mediate the signal. The current study contributes to the understanding of the female body's adaptation to lactation.
Asunto(s)
Adaptación Fisiológica , Lactancia , Obesidad/fisiopatología , Receptores de Colecistoquinina/fisiología , Adipocitos/patología , Tejido Adiposo/patología , Animales , Peso Corporal , Modelos Animales de Enfermedad , Femenino , Hipertrofia/patología , Hipertrofia/fisiopatología , Leptina/sangre , Mutación , Obesidad/sangre , Obesidad/patología , Oxitocina/sangre , Ratas , Ratas Endogámicas OLETF , Receptores de Colecistoquinina/deficiencia , Receptores de Colecistoquinina/genética , Destete , Aumento de PesoRESUMEN
Within the dorsomedial hypothalamus (DMH), cholecystokinin (CCK) has been proposed to modulate neuropeptide Y (NPY) signaling to affect food intake. However, the neural circuitry underlying the actions of this CCK-NPY signaling system in the controls of food intake has yet to be determined. We sought to characterize the feeding inhibition and brain neural activation produced by CCK administration into the DMH of rats. We determined the time course of feeding inhibitory effects of exogenous DMH CCK, assessed NPY gene expression in the DMH in response to DMH CCK administration, and characterized c-Fos activation in the entire brain induced by CCK injection into the DMH using c-Fos like immunohistochemistry. We found that parenchymal injection of CCK into the DMH decreased food intake during the entire 22 h observation period, with a primary effect in the first 4 h, and down-regulated NPY gene expression in the DMH. c-Fos immunohistochemistry revealed that DMH CCK increased the number of c-Fos positive cells in the paraventricular nucleus (PVN), arcuate nucleus, suprachiasmatic nucleus and retrochiasmatic area as well as in the contralateral DMH. This pattern of activity is different from that produced by peripherally administered CCK which is short acting and primarily activates neurons in the nucleus of the solitary tract and area postrema, as well as the PVN and DMH. Together, these data suggest that DMH CCK plays an important role in the control of food intake, and does so by activating different pathways from those activated by peripheral CCK.
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Colecistoquinina/metabolismo , Ingestión de Alimentos/fisiología , Hipotálamo/fisiología , Animales , Expresión Génica , Inmunohistoquímica , Hibridación in Situ , Masculino , Neuronas/metabolismo , Neuropéptido Y/biosíntesis , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Ratas , Ratas Sprague-DawleyRESUMEN
A strong candidate gene for schizophrenia and major mental disorders, disrupted-in-schizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. To evaluate the neuronal and behavioral effects of mutant DISC1, the Tet-off system under the regulation of the CAMKII promoter was used to generate transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but led to a mild enlargement of the lateral ventricles and attenuation of neurite outgrowth in primary cortical neurons. These morphological changes were associated with decreased protein levels of endogenous mouse DISC1, LIS1 and SNAP-25. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. The results show that the neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia. The present mouse model may facilitate the study of aspects of the pathogenesis of schizophrenia.
Asunto(s)
Conducta Animal/fisiología , Síntomas Conductuales/genética , Encéfalo/patología , Mutación , Proteínas del Tejido Nervioso/genética , Esquizofrenia , Animales , Animales Recién Nacidos , Síntomas Conductuales/etiología , Modelos Animales de Enfermedad , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Ventrículos Laterales/patología , Masculino , Ratones , Ratones Transgénicos , Peso Molecular , Esquizofrenia/genética , Esquizofrenia/patología , Esquizofrenia/fisiopatologíaRESUMEN
Leptin amplifies feeding inhibition and neural activation produced by either cholecystokinin or intragastric preloads, suggesting that leptin may increase the efficacy of gastrointestinal meal-related signals. To determine whether leptin would similarly potentiate the feeding inhibitory actions of another putative satiety peptide, we evaluated the effects of third ventricular leptin administration on food intake and c-Fos activation in response to systemically administered bombesin (BN). Leptin (3.5 microg) was administered 1 h before either 0.9% saline or BN (0.32 and 1.0 nmol/kg) followed by 30-min access to Ensure liquid diet. Although neither leptin nor 0.32 nmol/kg BN alone suppressed Ensure intake, the combination reduced intake by 28%. The higher BN dose (1.0 nmol/kg) produced a significant suppression by itself but was further enhanced in the presence of leptin. Consistent with the behavioral results, c-Fos activation in the nucleus of the solitary tract was increased by combined dosages of leptin and 0.32 nmol/kg BN beyond the individual response to either peptide. In the presence of leptin, BN produced a 3.4- to 5.2-fold increase in the number of c-Fos-positive cells in the nucleus of the solitary tract compared with when BN was given alone. These data provide further support for the hypothesis that the effect of leptin on food intake may be mediated, in part, by modulating meal-related satiety signals.
Asunto(s)
Bombesina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Leptina/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Rombencéfalo/efectos de los fármacos , Rombencéfalo/metabolismo , Animales , Área Postrema/metabolismo , Sinergismo Farmacológico , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Leptina/administración & dosificación , Masculino , Ratas , Ratas Sprague-Dawley , Respuesta de Saciedad/efectos de los fármacos , Núcleo Solitario/metabolismoRESUMEN
Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.
Asunto(s)
Depresores del Apetito/farmacología , Regulación del Apetito/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Péptido YY/farmacología , Animales , Animales Endogámicos , Apetito/efectos de los fármacos , Apetito/fisiología , Depresores del Apetito/uso terapéutico , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ambiente , Humanos , Metaanálisis como Asunto , Ratones , Obesidad/tratamiento farmacológico , Fragmentos de Péptidos , Péptido YY/administración & dosificación , Péptido YY/sangre , Péptido YY/uso terapéutico , Ratas , Reproducibilidad de los Resultados , Estrés Fisiológico/complicaciones , Estrés Fisiológico/fisiopatologíaRESUMEN
BACKGROUND AND AIMS: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. METHODS: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. RESULTS: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by alpha- and beta-adrenoceptor antagonists. HSC from dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(-/-) mice, as evidenced by reduced hepatic accumulation of alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-beta1 and collagen, and increased liver fibrosis. CONCLUSIONS: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.
Asunto(s)
Cirrosis Hepática/fisiopatología , Neurotransmisores/fisiología , Sistema Nervioso Simpático/fisiopatología , Animales , Apoptosis , Comunicación Autocrina , Catecolaminas/biosíntesis , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al GTP/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Norepinefrina/metabolismo , Norepinefrina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos/metabolismoRESUMEN
Bombesin (BN) interacts with two mammalian receptor subtypes termed gastrin-releasing peptide (GRP)-preferring (GRP-R) and neuromedin B (NMB)-preferring (NMB-R) that may mediate the satiety action of BN. We examined the feeding behavior of mice that were deficient in the GRP-R (GRP-R KO) to assess the overall contribution of this receptor subtype in the feeding actions of BN-related peptides. GRP-R KO mice failed to suppress glucose intake in response to systemically administered BN and GRP(18-27), whereas both peptides elicited a potent reduction of intake in wild-type (WT) mice. Neither GRP-R KO nor WT mice suppressed glucose intake following NMB administration. Unlike the impaired responses to BN-like peptides, the feeding inhibitory action of cholecystokinin was enhanced in GRP-R KO mice. Consistent with behavioral results, GRP-R KO mice also exhibited a reduction in c-Fos immunoreactivity in the nucleus of the solitary tract (NTS) and paraventricular nucleus (PVN) following peripheral administration of BN. An evaluation of meal patterns showed that GRP-R KO mice ate significantly more at each meal than WT mice, although total 24 h food consumption was equivalent. A long-term analysis of body weight revealed a significant elevation in GRP-R KO mice compared with WT littermates beginning at 45 weeks of age. These data suggest that the GRP-R mediates the feeding effects of BN-like peptides and participates in the termination of meals in mice.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Neuroquinina B/análogos & derivados , Receptores de Bombesina/deficiencia , Respuesta de Saciedad/efectos de los fármacos , Animales , Autorradiografía , Peso Corporal/efectos de los fármacos , Bombesina/metabolismo , Bombesina/farmacología , Química Encefálica , Colecistoquinina/farmacología , Masculino , Ratones , Ratones Noqueados , Neuroquinina B/metabolismo , Neuroquinina B/farmacología , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/análisis , Receptores de Bombesina/genéticaRESUMEN
In order to examine differential strain susceptibility to neurotoxic effects of amphetamine and to assess the potential role of superoxide radicals in amphetamine-induced dopaminergic damage, the drug was injected to mice with different levels of copper/zinc superoxide dismutase (Cu/Zn SOD) enzyme. Administration of amphetamine (10 mg/kg, i.p., given every 2 h, a total of four times) to wild-type CD-1 and C57BL/6J mice caused significant decreases in dopamine and 3,4-dihydroxyphenylacetic acid levels, in [(125)I]RTI-121-labeled dopamine transporters as well as a significant depletion in the concentration of dopamine transporter and vesicular monoamine transporter 2 proteins. The amphetamine-induced toxic effects were less prominent in CD-1 mice, which have much higher levels of Cu/Zn SOD activity (0.69 units/mg of protein) in their striata than C57BL/6J animals (0.007 units/mg of protein). Transgenic mice on CD-1 and C57BL/6J background, which had striatal levels of Cu/Zn SOD 2.57 and 1.67 units/mg of protein, respectively, showed significant protection against all the toxic effects of amphetamine. The attenuation of toxicity observed in transgenic mice was not caused by differences in amphetamine accumulation in wild-type and mutant animals. However, CD-1-SOD transgenic mice showed marked hypothermia to amphetamine whereas C57-SOD transgenic mice did not show a consistent thermic response to the drug. The data obtained demonstrate distinctions in the neurotoxic profile of amphetamine in CD-1 and C57BL/6J mice, which show some differences in Cu/Zn SOD activity and in their thermic responses to amphetamine administration. Thus, these observations provide evidence for possible complex interactions between thermoregulation and free radical load in the long-term neurotoxic effects of this illicit drug of abuse.
Asunto(s)
Anfetamina/toxicidad , Regulación de la Temperatura Corporal , Estimulantes del Sistema Nervioso Central/toxicidad , Dopamina/metabolismo , Proteínas del Tejido Nervioso , Neuropéptidos , Terminales Presinápticos/metabolismo , Superóxido Dismutasa/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Western Blotting , Encéfalo/metabolismo , Núcleo Caudado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Radicales Libres/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Masculino , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Putamen/metabolismo , Especificidad de la Especie , Proteínas de Transporte Vesicular de Aminas Biógenas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
Palatable food stimulates neural systems implicated in drug dependence; thus sugar might have effects like a drug of abuse. Rats were given 25% glucose solution with chow for 12 h followed by 12 h of food deprivation each day. They doubled their glucose intake in 10 days and developed a pattern of excessive intake in the first hour of daily access. After 30 days, receptor binding was compared to chow-fed controls. Dopamine D-1 receptor binding increased significantly in the accumbens core and shell. In contrast, D-2 binding decreased in the dorsal striatum. Binding to dopamine transporter increased in the midbrain. Opioid mu-1 receptor binding increased significantly in the cingulate cortex, hippocampus, locus coeruleus and accumbens shell. Thus, intermittent, excessive sugar intake sensitized D-1 and mu-1 receptors much like some drugs of abuse.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Sacarosa en la Dieta/administración & dosificación , Sacarosa en la Dieta/farmacología , Ingestión de Alimentos/fisiología , Receptores Dopaminérgicos/metabolismo , Receptores Opioides mu/metabolismo , Animales , Ingestión de Alimentos/efectos de los fármacos , Femenino , Glucosa/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Peptides from cocaine- and amphetamine-regulated transcript (CART) reduce food intake in rats when injected into the lateral ventricle. Hypothalamic and hindbrain sites important in the control of feeding contain CART-immunoreactive fibers. To further define the site of CART's anorectic action, we compared feeding and other behavioral responses to third or fourth ventricular (3V, 4V) CART-(55-102) in 6-h food-deprived rats, both before and after cerebral aqueduct occlusion. 3V CART reduced the volume of Ensure consumed and resulted in fewer observations of eating and grooming within the 30-min test session. These reductions were significantly attenuated by aqueduct obstruction. 4V CART suppressed Ensure intake and resulted in decreased observations of feeding both with and without aqueduct blockade. 3V CART produced flat-backed postures and movement-associated tremors that were prevented by aqueduct obstruction. 4V CART also produced these signs, both with and without aqueduct blockade. We conclude that the major hypophagic effect of intracerebroventricular CART is mediated at a hindbrain site. The association of CART-induced feeding suppression with altered motor behavior questions the specificity of intracerebroventricular CART for actions on feeding.