RESUMEN
BACKGROUND & AIM: The association between habitual coffee or caffeine consumption and age at onset (AAO) of Huntington's disease (HD) is unclear. We employed Mendelian randomization to investigate the causal relationship between coffee consumption and AAO of HD. METHODS: The instrumental variable including 14 independent genetic variants associated with coffee consumption was selected from a genome-wide association study (GWAS) meta-analysis of 375,833 individuals of European ancestry. Genetic association estimates for AAO of HD were obtained from the Genetic Modifiers of Huntington's Disease Consortium GWAS meta-analysis including 9064 HD patients of European ancestry. The inverse variance weighted method was used to evaluate the causal estimate and a comprehensive set of analyses tested the robustness of our results. RESULTS: Genetically predicted higher coffee consumption was associated with an earlier AAO of HD (ß = -1.84 years, 95% confidence interval = -3.47 to -0.22, P = 0.026). Results were robust to potential pleiotropy and weak instrument bias. CONCLUSIONS: This genetic study suggests high coffee consumption is associated with an earlier AAO of HD. Coffee is widely consumed and thus our findings, if confirmed, offers a potential way to delay the onset of this debilitating autosomal dominant disease.
Asunto(s)
Café , Ingestión de Líquidos/genética , Enfermedad de Huntington/genética , Adulto , Edad de Inicio , Causalidad , Encuestas sobre Dietas , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Estimated heritability of coffee intake ranges from 0.36 to 0.58, however, these point estimates assume that inherited effects are the same throughout the distribution of coffee intake, i.e., whether consumption is high or low relative to intake in the population. Quantile regression of 4788 child-parent pairs and 2380 siblings showed that offspring-parent and sibling concordance became progressively greater with increasing quantiles of coffee intake. Each cup/day increase in the parents' coffee intake was associated with an offspring increase of 0.020 ± 0.013 cup/day at the 10th percentile of the offsprings' coffee intake (slope ± SE, NS), 0.137 ± 0.034 cup/day at their 25th percentile (P = 5.2 × 10-5), 0.159 ± 0.029 cup/day at the 50th percentile (P = 5.8 × 10-8), 0.233 ± 0.049 cup/day at the 75th percentile (P = 1.8 × 10-6), and 0.284 ± 0.054 cup/day at the 90th percentile (P = 1.2 × 10-7). This quantile-specific heritability suggests that factors that distinguish heavier vs. lighter drinkers (smoking, male sex) will likely manifest differences in estimated heritability, as reported.
Asunto(s)
Café/metabolismo , Ingestión de Líquidos/genética , Familia , Femenino , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Modelos Estadísticos , Carácter Cuantitativo Heredable , Factores de Riesgo , FumadoresRESUMEN
Nesfatin/nucleobindin-2 (nesf/NUCB2), a precursor of the anorexigenic protein nesfatin-1, is selectively expressed in the hypothalamic nuclei, which are central to the regulation of the autonomic nervous system. The present study sought to investigate the involvement of nesf/NUCB2 in the regulation of blood pressure and ingestive behavior, by using nesf/NUCB2-transgenic (Tg) mice. Blood pressure and heart rates were measured under conscious and unconscious conditions. Twenty-four-hour water intake and urine volume of male nesf/NUCB2-Tg mice and their littermates in metabolic cages were measured. After killing, kidney weight was measured and the mRNA expression of epithelial sodium channel (ENaC)-α and ENaC-γ was measured in the hypothalamus and kidney with real-time PCR. Systolic, diastolic and mean blood pressure were significantly higher in nesf/NUCB2-Tg mice, but pulse rate was not affected in conscious mice. In contrast, isoflurane anesthesia prevented an increase in blood pressure in the nesf/NUCB2-Tg mice. Twenty-four-hour water intake and urine volume were significantly higher in the nesf/NUCB2-Tg mice than in their non-Tg littermates. Urine sodium concentration was significantly lower in the nesf/NUCB2-Tg mice, although the serum sodium concentration and urine sodium excretion were not different between the genotypes. Kidney weight was significantly higher in the nesf/NUCB2-Tg mice than their non-Tg littermates, although there were no clear differences in the kidney histological findings between genotypes. The mRNA expression of ENaC-γ, but not ENaC-α, was decreased in the hypothalami of nesf/NUCB2-Tg mice. Our data suggested that Nesf/NUCB2 is involved in the regulation of blood pressure in the brain.
Asunto(s)
Presión Sanguínea/genética , Proteínas de Unión al Calcio/genética , Proteínas de Unión al ADN/genética , Canales Epiteliales de Sodio/genética , Proteínas del Tejido Nervioso/genética , Animales , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/metabolismo , Ingestión de Líquidos/genética , Ingestión de Alimentos/genética , Canales Epiteliales de Sodio/metabolismo , Hipotálamo/metabolismo , Riñón/anatomía & histología , Riñón/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Nucleobindinas , Tamaño de los Órganos/genéticaRESUMEN
The association between the single nucleotide polymorphism rs762551 in the cytochrome P450 family 1, subfamily A2 gene (CYP1A2) and caffeine consumption remains controversial. We conducted a meta-analysis to clarify this potential association. Twelve studies were selected from articles retrieved from the and Google Scholar databases, and the data were analyzed to determine the odds ratio (OR) of genotypes AA (conferring fast caffeine metabolism) vs AC + CC (conferring slow caffeine metabolism). Comparisons were made between 6161 high caffeine consumers and 3219 low caffeine consumers. The overall analysis showed a significant association between genotype AA and coffee intake [OR = 1.13, 95% confidence interval (CI) = 1.03-1.24; Q = 19.23, P = 0.06; I2 = 43%]. In subgroup analyses, the association was also found within male, younger, and Caucasian subjects (OR = 1.21, 95%CI = 1.08- 1.35; OR = 1.71, 95%CI = 1.18-2.48; OR = 1.29, 95%CI = 1.12-1.49, respectively) but not in female, older, and Asian subjects (OR = 0.98, 95%CI = 0.83-1.15; OR = 0.83, 95%CI = 0.56-1.22; OR = 0.91, 95%CI = 0.71-1.17, respectively). Therefore, the rs762551 AA genotype may lead to higher coffee intake, especially in males, younger age groups, and individuals of Caucasian ethnicity. Our data highlight the need to test other CYP1A2 polymorphisms showing significance in genome-wide association studies to clarify the association with caffeine intake in the Asian population.
Asunto(s)
Café , Citocromo P-450 CYP1A2/genética , Ingestión de Líquidos/genética , Conducta Alimentaria/etnología , Polimorfismo de Nucleótido Simple , Adulto , Factores de Edad , Anciano , Pueblo Asiatico , Estudios de Casos y Controles , Ingestión de Líquidos/etnología , Conducta de Ingestión de Líquido , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Población BlancaRESUMEN
Nesfatin-1, a post-translational product of the nucleobindin-2 (NucB2) gene, is produced in several brain areas known to be important in neuroendocrine, autonomic and metabolic function, including the hypothalamus and medulla. The hallmark action of the peptide is its ability at picomole doses to inhibit food and water intake in rodents and, indeed, the effect on water intake is more pronounced than that on food intake. In preliminary studies, we observed a decrease in hypothalamic NucB2 expression in response to overnight water deprivation even when food was present, which reversed when water was returned to the animals. We therefore hypothesised that the effect of nesfatin-1 on water drinking was independent of its anorexigenic action. Indeed, rats administered nesfatin-1 i.c.v. consumed significantly less water than controls in response to a subsequent, dipsogenic dose of angiotensin II, or upon return of water bottles after 18 h of fluid restriction (food present), or in response to a hypertonic challenge. Pretreatment with an antisense oligonucleotide against nesfatin-1 significantly reduced levels of immunoreactive nesfatin-1 in the hypothalamic paraventricular nucleus and resulted in exaggerated drinking responses to angiotensin II. The results obtained in the present study suggest that locally produced nesfatin-1 may be an important component of the hypothalamic mechanisms controlling fluid and electrolyte homeostasis.
Asunto(s)
Proteínas de Unión al Calcio/fisiología , Proteínas de Unión al ADN/fisiología , Ingestión de Líquidos/genética , Proteínas del Tejido Nervioso/fisiología , Angiotensina II/administración & dosificación , Angiotensina II/farmacología , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/farmacología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/farmacología , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta de Ingestión de Líquido/fisiología , Evaluación Preclínica de Medicamentos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/fisiología , Inyecciones Intraventriculares , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/farmacología , Nucleobindinas , Ratas , Ratas Sprague-Dawley , Sed/efectos de los fármacos , Sed/fisiología , Distribución Tisular/efectos de los fármacos , Privación de Agua/fisiología , Equilibrio Hidroelectrolítico/efectos de los fármacos , Equilibrio Hidroelectrolítico/genéticaRESUMEN
Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).
Asunto(s)
Moléculas de Adhesión Celular/genética , Café/genética , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Ingestión de Líquidos/genética , Estudio de Asociación del Genoma Completo/métodos , Antígenos de Neoplasias/genética , Proteínas Reguladoras de la Apoptosis/genética , Cafeína/farmacología , Línea Celular , Femenino , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica/métodos , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Población Blanca/genéticaRESUMEN
Hypocretin (Hcrt) cell loss is responsible for narcolepsy, but Hcrt's role in normal behavior is unclear. We found that Hcrt knock-out mice were unable to work for food or water reward during the light phase. However, they were unimpaired relative to wild-type (WT) mice when working for reward during the dark phase or when working to avoid shock in the light or dark phase. In WT mice, expression of Fos in Hcrt neurons occurs only in the light phase when working for positive reinforcement. Expression was seen throughout the mediolateral extent of the Hcrt field. Fos was not expressed when expected or unexpected unearned rewards were presented, when working to avoid negative reinforcement, or when given or expecting shock, even though these conditions elicit maximal electroencephalogram (EEG) arousal. Fos was not expressed in the light phase when light was removed. This may explain the lack of light-induced arousal in narcoleptics and its presence in normal individuals. This is the first demonstration of such specificity of arousal system function and has implications for understanding the motivational and circadian consequences of arousal system dysfunction. The current results also indicate that comparable and complementary specificities must exist in other arousal systems.
Asunto(s)
Reacción de Prevención/fisiología , Ritmo Circadiano/fisiología , Condicionamiento Operante/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Luz/efectos adversos , Neuronas/metabolismo , Neuropéptidos/metabolismo , Refuerzo en Psicología , Análisis de Varianza , Animales , Encéfalo/citología , Ritmo Circadiano/genética , Ingestión de Líquidos/genética , Ingestión de Alimentos/genética , Electroencefalografía , Electromiografía , Electrochoque/efectos adversos , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuropéptidos/deficiencia , Orexinas , Esquema de Refuerzo , Análisis EspectralRESUMEN
Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.
Asunto(s)
Apetito/genética , Conducta Adictiva/genética , Hipotálamo/fisiología , Sodio en la Dieta/administración & dosificación , Hormona Adrenocorticotrópica/administración & dosificación , Hormona Adrenocorticotrópica/fisiología , Animales , Apetito/efectos de los fármacos , Apetito/fisiología , Conducta Adictiva/fisiopatología , Evolución Biológica , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Líquidos/genética , Ingestión de Líquidos/fisiología , Femenino , Estudio de Asociación del Genoma Completo , Hipotálamo/efectos de los fármacos , Instinto , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Psicológicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Sprague-Dawley , RecompensaRESUMEN
The effects of ghrelin and obestatin regulation of food intake are different in mammals and chickens. We investigated central effects of ghrelin and obestatin in lines of chickens selected 50 generations for high (HWS) or low (LWS) body weight. We hypothesized that the effect of ghrelin and obestatin on food intake in 5-day-old chicks is mediated by the AMP-activated protein kinase (AMPK) system and selection for body weight alters the brain's response to ghrelin and obestatin by changing the neuronal AMPK system. Although intracerebroventricular (ICV) ghrelin injection decreased food intake in both lines, the threshold for the anorexigenic effect of central ghrelin was lower in LWS than HWS chicks. Obestatin caused a linear dose-dependent increase in food intake in HWS but not LWS chicks. ICV injection of 0.4 nmol ghrelin inhibited hypothalamic AMPK related gene expression and phosphorylation of AMPK α and acetyl-CoA carboxylase (ACC) with the magnitude of inhibition different in the two lines. In contrast, ICV injection of 4 nmol obestatin did not affect mRNA expression of AMPK system or phosphorylation of AMPK and ACC in either line. These data support the premise of a lower threshold for anorexigenic effect of central ghrelin in LWS than HWS chicks, and this difference may be associated with differential hypothalamic AMPK signaling. Additionally, the hypothalamic mRNA level of ghrelin was significantly higher in LWS than HWS, which may have also contributed to the different threshold response to ghrelin in these two lines. The expression of the ghrelin receptor was also higher in the LWS line, but not until 56 days of age. In summary, selection for body weight has resulted in differences in the central ghrelin and obestatin system, and an altered brain AMPK system may contribute to the different neuronal response to ghrelin, but not obestatin.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Peso Corporal/genética , Ingestión de Alimentos/fisiología , Ghrelina/fisiología , Hipotálamo/enzimología , Selección Genética/fisiología , Acetil-CoA Carboxilasa/metabolismo , Factores de Edad , Animales , Regulación del Apetito , Peso Corporal/fisiología , Pollos , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Líquidos/genética , Ingestión de Líquidos/fisiología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/genética , Ghrelina/administración & dosificación , Ghrelina/farmacología , Hipotálamo/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Fosforilación , Receptores de Ghrelina/biosíntesis , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Arginine vasopressin (AVP) and corticotrophin-releasing hormone (CRH) in the parvocellular neurosecretory cells of the paraventricular nucleus (PVN) play a major role in activating the hypothalamic-pituitary-adrenal axis, which is the main neuroendocrine response against the many kinds of stress. We examined the effects of chronic inflammatory/nociceptive stress on the expression of the AVP-enhanced green fluorescent protein (eGFP) fusion gene in the hypothalamus, using the adjuvant arthritis (AA) model. To induce AA, the AVP-eGFP rats were intracutaneously injected heat-killed Mycobacterium butyricum (1 mg/rat) in paraffin liquid at the base of their tails. We measured AVP, oxytocin and corticosterone levels in plasma and changes in eGFP and CRH mRNA in the hypothalamus during the time course of AA development. Then, we examined eGFP fluorescence in the PVN, the supraoptic nucleus (SON), median eminence (ME) and posterior pituitary gland (PP) when AA was established. The plasma concentrations of AVP, oxytocin and corticosterone were significantly increased on days 15 and 22 in AA rats, without affecting the plasma osmolality and sodium. Although CRH mRNA levels in the PVN were significantly decreased, eGFP mRNA levels in the PVN and the SON were significantly increased on days 15 and 22 in AA rats. The eGFP fluorescence in the SON, the PVN, internal and external layers of the ME and PP was apparently increased in AA compared to control rats. These results suggest that the increases in the concentrations of ACTH and corticosterone in AA rats are induced by hypothalamic AVP, based on data from AVP-eGFP transgenic rats.
Asunto(s)
Arginina Vasopresina/genética , Artritis Experimental/genética , Proteínas Fluorescentes Verdes/genética , Hipotálamo/metabolismo , Adyuvantes Inmunológicos , Hormona Adrenocorticotrópica/sangre , Animales , Arginina Vasopresina/sangre , Arginina Vasopresina/metabolismo , Artritis Experimental/sangre , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Peso Corporal/genética , Corticosterona/sangre , Ingestión de Líquidos/genética , Regulación de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Concentración Osmolar , Oxitocina/sangre , Ratas , Ratas Transgénicas , Ratas Wistar , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Sodio/sangre , Fenómenos Fisiológicos del Sistema Urinario/genéticaRESUMEN
RNA interference (RNAi) has become a popular tool to silence gene expression in a variety of in vitro and in vivo systems. However, it has met with limited success in inhibiting gene expression in adult mammals. Here we demonstrate that long double-stranded RNA (dsRNA) can be used to create a "site-specific", transient knockdown of genes in a fashion that is phenotypically akin to genetically manipulated organisms. Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) that regulate a variety of physiological processes including the hypothalamic-pituitary-adrenal axis (HPA axis), energy and water homeostasis were used as model systems. Stereotaxic injections of dsRNA against CRF and AVP in the PVN specifically abolished the expression of these genes in the PVN leaving expression in other loci intact. Control dsRNA did not affect CRF or AVP expression in any brain region, suggesting that dsRNA did not shut down global protein synthesis. ANOVA showed significant main effects of silencing of CRF on dampening of the stress-activated release of adrenocorticotrophin hormone (ACTH) (F(2,7)=4.87; p<0.047). Silencing of AVP resulted in increased water consumption, increased urine output and decreased urine osmolality as compared to control dsRNA-treated rats. Furthermore, dsRNA had no obvious deleterious effects on body weight or food consumption, variables considered essential in ruling out adverse physiologic effects in animal models. Thus, using long dsRNA, we were able to ascertain site-specific roles of CRF and AVP in adult rats without any developmental compensation and in a wild-type background.