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1.
Gene ; 581(2): 139-45, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26827797

RESUMO

G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating intercellular interactions of fundamental physiological importance for survival including regulation of food intake, blood pressure, and hormonal sensing signaling, among other roles. Homeostatic alterations in the physiological status of GPCRs are often associated with underlying causes of disease, and to date, several orphan GPCRs are still uncharacterized. Findings from our previous study demonstrate that the Rhodopsin family protein GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in hypothalamus, amygdala, and ventral tegmental area, regions strictly interconnected and involved in the regulation of energy homeostasis and hedonic feeding. In this study, we provide a further anatomical characterization of GPR162 in mouse brain via in situ hybridization as well as detailed mRNA expression in a panel of rat tissues complementing a specie-specific mapping of the receptor. We also provide an attempt to demonstrate a functional implication of GPR162 in food intake-related behavior via antisense knockdown studies. Furthermore, we performed human genetic studies in which for the first time, variants of the GPR162 gene were associated with impairments in glucose homeostasis.


Assuntos
Glucose/metabolismo , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/genética , Adolescente , Animais , Encéfalo/metabolismo , Criança , Ingestão de Alimentos , Feminino , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/metabolismo , Especificidade da Espécie , Suécia , Distribuição Tecidual
2.
Genet Res (Camb) ; 97: e16, 2015 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-26365393

RESUMO

Genome-wide association studies (GWAS) have revealed association of a locus approximately 25b downstream of the TMEM18 gene with body mass and obesity. We utilized targeted re-sequencing of the body mass associated locus in proximity of TMEM18 in a case-control population of severely obese children and adolescents from the Stockholm area. We expanded our study to include the TMEM18 gene itself, with the aim of identifying body mass associated genetic variants. Sequencing was performed on the SOLiD platform, on long-range PCR fragments generated through targeted amplification of the regions of interest. Candidate single nucleotide polymorphisms (SNPs) were validated by TaqMan genotyping. We were able to observe 131 SNPs across the re-sequenced regions. Chi squared tests comparing the allele frequencies between cases and controls revealed 57 SNPs as candidates for association with obesity. Validation and replication genotyping revealed robust associations for SNPs within the haplotype block region located downstream from the TMEM18 gene. This study provides a high resolution map of the genetic variation pattern in the TMEM18 gene, as well as the associated haplotype block, and further strengthens the association of variants within the proximal haplotype block with obesity and body mass.


Assuntos
Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Membrana/genética , Obesidade Infantil/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Técnicas de Genotipagem/métodos , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino
3.
Sleep Med ; 16(1): 87-93, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25441744

RESUMO

OBJECTIVE: To examine associations of self-reported sleep disturbance and short sleep duration with the risk for academic failure. METHODS: A cohort of ~40,000 adolescents (age range: 12-19 years) who were attending high school grades 7, 9, and 2nd year of upper secondary school in the Swedish Uppsala County were invited to participate in the Life and Health Young Survey (conducted between 2005 and 2011 in Uppsala County, Sweden). In addition to the question how many subjects they failed during the school year (outcome variable), subsamples of adolescents also answered questions related to subjective sleep disturbance (n = 20,026) and habitual sleep duration (n = 4736) (exposure variables). Binary logistic regression analysis was utilized to explore if self-reported sleep disturbances and habitual short sleep duration (defined as less than 7-8 h sleep per night) increase the relative risk to fail subjects during the school year (controlled for possible confounders, e.g. body-mass-index). RESULTS: Adolescents with self-reported sleep disturbances had an increased risk for academic failure (i.e., they failed at least one subject during the school year; OR: boys, 1.68; girls, 2.05, both P < 0.001), compared to adolescents without self-reported sleep disturbances. In addition, adolescents who reported short sleep duration on both working and weekend days were more likely to fail at least one subject at school than those who slept at least 7-8 h per night (OR: boys, 4.1; girls, 5.0, both P < 0.001). CONCLUSION: Our findings indicate that reports of sleep disturbance and short sleep duration are linked to academic failure in adolescents. Based on our data, causality cannot be established.


Assuntos
Escolaridade , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/psicologia , Adolescente , Comportamento do Adolescente , Criança , Estudos de Coortes , Feminino , Hábitos , Humanos , Masculino , Fatores de Risco , Autorrelato , Fatores Sexuais , Suécia , Adulto Jovem
4.
Psychiatry Res ; 224(3): 246-53, 2014 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-25456522

RESUMO

The role of rumination at the beginning of eating disorder (ED) is not well understood. We hypothesised that impulsivity, rumination and restriction could be associated with neural activity in response to food stimuli in young individuals with eating disorders (ED). We measured neural responses with functional magnetic resonance imaging (fMRI), tested working memory (WM) and administered the eating disorders examination questionnaire (EDE-Q), Barratt impulsivity scale (BIS-11) and obsessive-compulsive inventory (OCI-R) in 15 adolescent females with eating disorder not otherwise specified (EDNOS) (mean age 15 years) and 20 age-matched healthy control females. We found that EDNOS subjects had significantly higher scores on the BIS 11, EDE-Q and OCI-R scales. Significantly increased neural responses to food images in the EDNOS group were observed in the prefrontal circuitry. OCI-R scores in the EDNOS group also significantly correlated with activity in the prefrontal circuitry and the cerebellum. Significantly slower WM responses negatively correlated with bilateral superior frontal gyrus activity in the EDNOS group. We conclude that ruminations, linked to WM, are present in adolescent females newly diagnosed with EDNOS. These may be risk factors for the development of an eating disorder and may be detectable before disease onset.


Assuntos
Córtex Cerebral/fisiopatologia , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Comportamento Impulsivo/fisiologia , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiopatologia , Adolescente , Feminino , Humanos , Imageamento por Ressonância Magnética , Transtorno Obsessivo-Compulsivo/fisiopatologia
5.
Gene ; 548(1): 61-7, 2014 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-25010727

RESUMO

The combination of the obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylated with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.


Assuntos
Envelhecimento/genética , Metilação de DNA , Marcadores Genéticos , Obesidade/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Ilhas de CpG , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Proteínas/genética , Telomerase/genética
6.
PLoS One ; 9(1): e82707, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24465375

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking. METHODS: 367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF. RESULTS: The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes. CONCLUSIONS: The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Cerebelo/anatomia & histologia , Hipocampo/anatomia & histologia , Memória de Curto Prazo , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/anatomia & histologia , Idoso , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cerebelo/fisiologia , Função Executiva , Feminino , Neuroimagem Funcional , Expressão Gênica , Estudos de Associação Genética , Hipocampo/fisiologia , Humanos , Desequilíbrio de Ligação , Masculino , Tamanho do Órgão , Córtex Pré-Frontal/fisiologia , Estudos Prospectivos
7.
PLoS One ; 8(9): e68245, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24023709

RESUMO

Brain pathways, including those in hypothalamus and nucleus of the solitary tract, influence food intake, nutrient preferences, metabolism and development of obesity in ways that often differ between males and females. Branched chain amino acids, including leucine, can suppress food intake, alter metabolism and change vulnerability to obesity. The SLC6A15 (v7-3) gene encodes a sodium-dependent transporter of leucine and other branched chain amino acids that is expressed by neurons in hypothalamus and nucleus of the solitary tract. We now report that SLC6A15 knockout attenuates leucine's abilities to reduce both: a) intake of normal chow and b) weight gain produced by access to a high fat diet in gender-selective fashions. We identify SNPs in the human SLC6A15 that are associated with body mass index and insulin resistance in males. These observations in mice and humans support a novel, gender-selective role for brain amino acid compartmentalization mediated by SLC6A15 in diet and obesity-associated phenotypes.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Leucina/metabolismo , Leucina/farmacologia , Obesidade/metabolismo , Adolescente , Sistemas de Transporte de Aminoácidos Neutros/genética , Animais , Criança , Pré-Escolar , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Genótipo , Humanos , Masculino , Camundongos , Camundongos Knockout , Obesidade/induzido quimicamente , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
8.
Gene ; 527(2): 462-8, 2013 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-23860325

RESUMO

Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, but have also been linked with type 2 diabetes (T2D). Our aim was to investigate the contribution of these variants to risk of T2D in a population in Latvia. Four single nucleotide polymorphisms (SNP) in the first and fourth intronic regions of FTO and one close to TMEM18 were genotyped in 987 patients with T2D and 1080 controls selected from the Latvian Genome Data Base (LGDB). We confirmed association of SNPs in the first intron (rs11642015, rs62048402 and rs9939609) of FTO and rs7561317 representing the TMEM18 locus with T2D. Association between SNP in FTO and T2D remained significant after correction for body mass index (BMI). The rs57103849 located in the fourth intron of FTO and rs7561317 in TMEM18 showed BMI independent association with younger age at diagnosis of T2D. Our results add to the evidence that BMI related variants in and near FTO and TMEM18 may increase the risk for T2D not only through secondary effects of obesity. The influence of variants in the fourth intron of the FTO gene on development of T2D may be mediated by mechanisms other than those manifested by SNPs in the first intron of the same gene.


Assuntos
Fatores Etários , Diabetes Mellitus Tipo 2/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Idade de Início , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Humanos
10.
BMC Med Genet ; 13: 36, 2012 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-22594783

RESUMO

BACKGROUND: Recent genome-wide association studies have identified a single nucleotide polymorphism within the last intron of MAP2K5 associated with a higher body mass index (BMI) in adults. MAP2K5 is a component of the MAPK-family intracellular signaling pathways, responding to extracellular growth factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). In this study, we examined the association of this variant in two cohorts of children from Sweden and Greece. METHODS: We examine the association of rs2241423 to BMI in a cohort of 474 Swedish children admitted for treatment of childhood obesity and 519 children matched for gender, ethnicity and socioeconomic background from the Stockholm area, as well as a cross-sectional cohort of 2308 Greek school children (Healthy Growth Study). Children were genotyped using a predesigned TaqMan polymorphism assay. Logistic regression was used to test for an association of rs2241423 to obesity in the cohort of Swedish children. Linear regression was used to test for an association of rs2241423 to BMI z-score and phenotypic measurements of body adiposity in the cohort of Greek children. Models were adjusted for age and gender. In the cohort of Greek children the model was also adjusted for stage of pubertal development. RESULTS: The minor allele of rs2241423, allele A, was associated with a protective effect against obesity in the cohort of Swedish children (p = 0.029, OR = 0.79 (95% CI: 0.64-0.98)), and with a lower BMI z-score in the cohort of Greek children (p = 0.028, ß = -0.092). No association to phenotypic measurements of body fat distribution could be observed in our study. CONCLUSIONS: rs2241423 was associated with BMI and obesity in two independent European cohorts suggesting a role for MAP2K5 in early weight regulation.


Assuntos
Índice de Massa Corporal , Predisposição Genética para Doença , MAP Quinase Quinase 5/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Genótipo , Grécia/epidemiologia , Humanos , Desequilíbrio de Ligação , Masculino , Obesidade/epidemiologia , Fenótipo , Prognóstico , Fatores de Risco , Suécia/epidemiologia , Adulto Jovem
11.
PLoS Genet ; 8(3): e1002568, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22438821

RESUMO

Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/- mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.


Assuntos
Índice de Massa Corporal , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Comportamento Alimentar , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Obesidade/genética , Tecido Adiposo/metabolismo , Adolescente , Animais , Tronco Encefálico/metabolismo , Criança , Privação de Alimentos , Regulação da Expressão Gênica/genética , Estudos de Associação Genética , Humanos , Hipotálamo/metabolismo , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Genomics ; 99(3): 132-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22234326

RESUMO

Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1, STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Our findings suggest that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, these sites might prove to be valuable biomarkers for the understanding of obesity and its comorbidites.


Assuntos
Metilação de DNA/genética , Obesidade/genética , Proteínas/genética , Alelos , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Peso Corporal , Criança , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos
13.
Eur J Hum Genet ; 20(2): 192-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21952719

RESUMO

Genome-wide association studies have shown a strong association of single-nucleotide polymorphisms (SNPs) in the near vicinity of the TMEM18 gene. The effects of the TMEM18-associated variants are more readily observed in children. TMEM18 encodes a 3TM protein, which locates to the nuclear membrane. The functional context of TMEM18 and the effects of its associated variants are as of yet undetermined. To further explore the effects of near-TMEM18 variants, we have genotyped two TMEM18-associated SNPs, rs6548238 and rs4854344, in a cohort of 2352 Greek children (Healthy Growth Study). Included in this study are data on anthropomorphic traits body weight, BMI z-score and waist circumference. Also included are dietary energy and macronutrient intake as measured via 24-h recall interviews. Major alleles of rs6548238 and rs4854344 were significantly associated with an increased risk of obesity (odds ratio = 1.489 (1.161-1.910) and 1.494 (1.165-1.917), respectively), and positively correlated to body weight (P = 0.017, P = 0.010) and waist circumference (P = 0.003, P = 0.003). An association to energy and macronutrient intake was not observed in this cohort. We also correlated food intake and body weight in a food choice model in rats to Tmem18 expression in central regions involved in feeding behavior. We observed a strong positive correlation between TMEM18 expression and body weight in the prefrontal cortex (PFC) (r = 0.5694, P = 0.0003) indicating a potential role for TMEM18 in higher functions related to feeding involving the PFC.


Assuntos
Índice de Massa Corporal , Peso Corporal/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/genética , Circunferência da Cintura/genética , Alelos , Animais , Criança , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Obesidade/genética , Ratos , Ratos Wistar
14.
PLoS One ; 6(5): e20158, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21637715

RESUMO

BACKGROUND: The rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution. OBJECTIVE: To examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans. DESIGN: Cross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. RESULTS: Neither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women. CONCLUSIONS: Due to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender.


Assuntos
Composição Corporal/genética , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Antropometria , Estudos de Coortes , Ingestão de Energia/genética , Feminino , Marcadores Genéticos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Fenótipo , Análise de Regressão
15.
Neurobiol Aging ; 32(6): 1159.e1-5, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21458110

RESUMO

Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.


Assuntos
Predisposição Genética para Doença , Obesidade/complicações , Sobrepeso/complicações , Polimorfismo Genético/genética , Proteínas/genética , Distúrbios da Fala/etiologia , Distúrbios da Fala/genética , Idoso de 80 Anos ou mais , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Frequência do Gene , Genótipo , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Testes Neuropsicológicos , Obesidade/genética , Sobrepeso/genética , Comportamento Verbal/fisiologia , População Branca/genética
16.
BMC Med Genet ; 11: 58, 2010 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-20380707

RESUMO

BACKGROUND: TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure. METHODS: The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131). RESULTS: TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002). CONCLUSION: We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.


Assuntos
Encéfalo/metabolismo , Proteínas de Membrana/genética , Neurônios/metabolismo , Obesidade/genética , Adolescente , Sequência de Aminoácidos , Animais , Índice de Massa Corporal , Peso Corporal , Encéfalo/citologia , Criança , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Proteínas de Membrana/classificação , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Dados de Sequência Molecular , Filogenia , Polimorfismo de Nucleotídeo Único , Ratos , Alinhamento de Sequência , Distribuição Tecidual , Adulto Jovem
17.
J Mol Neurosci ; 41(2): 230-42, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19697161

RESUMO

About one third of all known human proteins are membrane proteins, which constitute several large families. The solute carriers with over 300 known members are probably the second largest family with additional members frequently being identified. We recently found a new putative solute carrier, C6ORF192, belonging to the major facilitator superfamily type of proteins. The gene is evolutionary highly conserved with a single copy present in each of the genomes from mouse, rat, chicken, zebrafish, tetraodon, Caenorhabditis elegans, and Drosophila melanogaster. C6ORF192 forms a novel evolutionary branch of solute carriers and is most closely related to the solute carrier families 16, 17, and 18, all members of the major facilitator superfamily. Ten of the 25 members of these families show amino acid identity with C6ORF192 ranging from 21% to 27%. C6ORF192 differs however, structurally from these families and does not share key motifs in the transmembrane domains. Expression profiling by quantitative real-time polymerase chain reaction and in situ hybridization showed that C6ORF192 transcript can be detected in several tissues, both in the central nervous system and the periphery.


Assuntos
Evolução Biológica , Encéfalo/metabolismo , Proteínas de Membrana Transportadoras , Fases de Leitura Aberta , Sequência de Aminoácidos , Animais , Encéfalo/anatomia & histologia , Perfilação da Expressão Gênica , Humanos , Hibridização In Situ , Masculino , Proteínas de Membrana Transportadoras/classificação , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase , Conformação Proteica , Ratos , Alinhamento de Sequência , Distribuição Tecidual
18.
BMC Med Genet ; 10: 131, 2009 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-20003232

RESUMO

BACKGROUND: Common FTO (fat mass and obesity associated) gene variants have recently been strongly associated with body mass index and obesity in several large studies. Here we set out to examine the association of the FTO variant rs9939609 with BMI in a 32 year follow up study of men born 1920-1924. Moreover, we analyzed the effect of physical activity on the different genotypes. METHODS: The FTO rs9936609 was genotyped using an Illumina golden gate assay. BMI was calculated using standard methods and body fat was estimated by measuring skinfold thickness using a Harpenden caliper. Physical activity was assessed using a four question medical questionnaire. RESULTS: FTO rs9939609 was genotyped in 1153 elderly Swedish men taking part of a population-based cohort study, the ULSAM cohort. The risk of obesity and differences in BMI according to genotype at the ages of 50, 60, 70, 77 and 82 were investigated. We found no increased risk of obesity and no association with BMI at any age with the FTO rs9939609 variant. We found however interaction between physical activity at the age of 50 years and genotype on BMI levels (p = 0.039) and there was a clear trend towards larger BMI differences between the TT and AA carriers as well as between AT and AA carriers in the less physically active subjects. CONCLUSION: Here we found that the well established obesity risk allele for a common variant in FTO does not associate with increased BMI levels in a Swedish population of adult men which reached adulthood before the appearance of today's obesogenic enviroment. There is an interaction between physical activity and the effect of the FTO genotype on BMI levels suggesting that lack of physical activity is a requirement for an association of FTO gene variants to obesity.


Assuntos
Índice de Massa Corporal , Obesidade/genética , Proteínas/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Estudos de Associação Genética , Variação Genética , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Atividade Motora , Obesidade/fisiopatologia , Fatores de Risco , Suécia
19.
J Mol Neurosci ; 35(2): 179-93, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18418736

RESUMO

Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the beta-group of SLCs, are known to transport neutral amino acids. In this paper, we show that these three families were present before the split of the animal lineage and that they are likely to share a common decent. We also show that the APF transporters found in plants are most likely homologous to the mammalian beta-group, suggesting that this type of transporters arouse early in the evolution of eukaryotes. We performed detailed tissue expression analysis of all the members of the beta-group in rat and found several examples of highly specific expression patterns, with SLC38A7 being exclusively found in liver, SLC38A5 in blood, and SLC38A4 in muscle and liver. Moreover, we found that SLC38A10 is expressed in several endocrine organs. We also found that SLC38A1 is highly up regulated in the cortex from rats treated with diazepam and that SLC38A2 is significantly down regulated in the same tissue. In addition, we performed a detailed expression analysis of SLC38A1 and SLC38A6 in mouse brain using in situ hybridization, which showed that both these transporters are widely expressed in the brain.


Assuntos
Sistema A de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos/genética , Evolução Molecular , Proteínas do Tecido Nervoso/genética , Filogenia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Animais , Anticonvulsivantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Diazepam/farmacologia , Dopaminérgicos/farmacologia , Sistema Endócrino/fisiologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Hibridização In Situ , Levodopa/farmacologia , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Músculo Esquelético/fisiologia , Ratos , Ratos Wistar
20.
Biochem Biophys Res Commun ; 368(3): 476-82, 2008 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-18249188

RESUMO

Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P=0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.


Assuntos
Resistência à Insulina/genética , Obesidade/epidemiologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Medição de Risco/métodos , Adolescente , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Criança , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética/genética , Humanos , Fenótipo , Prevalência , Fatores de Risco , Distribuição por Sexo , Fatores Sexuais , Suécia/epidemiologia
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