| 1. |
- Bagchi, Sonchita, et al.
(författare)
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Histological Analysis of SLC38A6 (SNAT6) Expression in Mouse Brain Shows Selective Expression in Excitatory Neurons with High Expression in the Synapses
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4, s. e95438-
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Tidskriftsartikel (refereegranskat)abstract
- SLC38A6 is one of the newly found members of the solute carrier 38 family consisting of total 11 members, of which only 6 have been characterized so far. Being the only glutamine transporter family expressed in the brain, this family of proteins are most probably involved in the regulation of the glutamate-glutamine cycle, responsible for preventing excitotoxicity. We used immunohistochemistry to show that SLC38A6 is primarily expressed in excitatory neurons and is not expressed in the astrocytes. Using proximity ligation assay, we have quantified the interactions of this SLC38 family protein with other proteins with known localization in the cells, showing that this transporter is expressed at the synapses. Moreover, this study has enabled us to come up with a model suggesting sub-cellular localization of SLC38A6 at the synaptic membrane of the excitatory neurons.
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| 2. |
- Brooks, Samantha J, et al.
(författare)
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BDNF polymorphisms are linked to poorer working memory performance, reduced cerebellar and hippocampal volumes and differences in prefrontal cortex in a Swedish elderly population
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1, s. e82707-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Caruso, Vanni, et al.
(författare)
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The Orphan G Protein-Coupled Receptor Gene GPR178 Is Evolutionary Conserved and Altered in Response to Acute Changes in Food Intake
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating physiological functions fundamental for survival, including energy homeostasis. A few years ago, an amino acid sequence of a novel GPCR gene was identified and named GPR178. In this study, we provide new insights regarding the biological significance of Gpr178 protein, investigating its evolutionary history and tissue distribution as well as examining the relationship between its expression level and feeding status. Our phylogenetic analysis indicated that GPR178 is highly conserved among all animal species investigated, and that GPR178 is not a member of a protein family. Real-time PCR and in situ hybridization revealed wide expression of Gpr178 mRNA in both the brain and periphery, with high expression density in the hypothalamus and brainstem, areas involved in the regulation of food intake. Hence, changes in receptor expression were assessed following several feeding paradigms including starvation and overfeeding. Short-term starvation (12-48h) or food restriction resulted in upregulation of Gpr178 mRNA expression in the brainstem, hypothalamus and prefrontal cortex. Conversely, short-term (48h) exposure to sucrose or Intralipid solutions downregulated Gpr178 mRNA in the brainstem; long-term exposure (10 days) to a palatable high-fat and high-sugar diet resulted in a downregulation of Gpr178 in the amygdala but not in the hypothalamus. Our results indicate that hypothalamic Gpr178 gene expression is altered during acute exposure to starvation or acute exposure to palatable food. Changes in gene expression following palatable diet consumption suggest a possible involvement of Gpr178 in the complex mechanisms of feeding reward.
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| 4. |
- Drgonova, Jana, et al.
(författare)
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Involvement of the Neutral Amino Acid Transporter SLC6A15 and Leucine in Obesity-Related Phenotypes
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9, s. e68245-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Hägglund, Maria G A, et al.
(författare)
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B(0)AT2 (SLC6A15) is localized to neurons and astrocytes, and is involved in mediating the effect of leucine in the brain
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3, s. e58651-
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Tidskriftsartikel (refereegranskat)abstract
- The B(0)AT2 protein is a product of the SLC6A15 gene belonging to the SLC6 subfamily and has been shown to be a transporter of essential branched-chain amino acids. We aimed to further characterize the B(0)AT2 transporter in CNS, and to use Slc6a15 knock out (KO) mice to investigate whether B(0)AT2 is important for mediating the anorexigenic effect of leucine. We used the Slc6a15 KO mice to investigate the role of B(0)AT2 in brain in response to leucine and in particular the effect on food intake. Slc6a15 KO mice show lower reduction of food intake as well as lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to leucine injections compared to wild type mice. We also used RT-PCR on rat tissues, in situ hybridization and immunohistochemistry on mouse CNS tissues to document in detail the distribution of SLC6A15 on gene and protein levels. We showed that B(0)AT2 immunoreactivity is mainly neuronal, including localization in many GABAergic neurons and spinal cord motor neurons. B(0)AT2 immunoreactivity was also found in astrocytes close to ventricles, and co-localized with cytokeratin and diazepam binding inhibitor (DBI) in epithelial cells of the choroid plexus. The data suggest that B(0)AT2 play a role in leucine homeostasis in the brain.
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| 6. |
- Jacobsson, Josefin A., et al.
(författare)
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Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5, s. e20158-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Krishnan, Arunkumar, et al.
(författare)
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Insights into the Origin of Nematode Chemosensory GPCRs : Putative Orthologs of the Srw Family Are Found across Several Phyla of Protostomes
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3, s. e93048-
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Tidskriftsartikel (refereegranskat)abstract
- Nematode chemosensory GPCRs in Caenorhabditis elegans (NemChRs) are classified into 19 gene families, and are initially thought to have split from the ancestral Rhodopsin family of GPCRs. However, earlier studies have shown that among all 19 NemChR gene families, only the srw family has a clear sequence relationship to the ancestral Rhodopsin GPCR family. Yet, the phylogenetic relationships between the srw family of NemChRs and the Rhodopsin subfamilies are not fully understood. Also, a widespread search was not previously performed to check for the presence of putative srw family-like sequences or the other 18 NemChR families in several new protostome species outside the nematode lineage. In this study, we have investigated for the presence of 19 NemChR families across 26 eukaryotic species, covering basal eukaryotic branches and provide the first evidence that the srw family of NemChRs is indeed present across several phyla of protostomes. We could identify 29 putative orthologs of the srw family in insects (15 genes), molluscs (11 genes) and Schistosoma mansoni (3 genes). Furthermore, using HMM-HMM profile based comparisons and phylogenetic analysis we show that among all Rhodopsin subfamilies, the peptide and SOG (somatostatin/opioid/galanin) subfamilies are phylogenetically the closest relatives to the srw family of NemChRs. Taken together, we demonstrate that the srw family split from the large Rhodopsin family, possibly from the peptide and/or SOG subfamilies, well before the split of the nematode lineage, somewhere close to the divergence of the common ancestor of protostomes. Our analysis also suggests that the srsx family of NemChRs shares a clear sequence homology with the Rhodopsin subfamilies, as well as with few of the vertebrate olfactory receptors. Overall, this study provides further insights into the evolutionary events that shaped the GPCR chemosensory system in protostome species.
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| 8. |
- Krishnan, Arunkumar, et al.
(författare)
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The Origin of GPCRs : Identification of Mammalian like Rhodopsin, Adhesion, Glutamate and Frizzled GPCRs in Fungi
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29817-
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) in humans are classified into the five main families named Glutamate, Rhodopsin, Adhesion, Frizzled and Secretin according to the GRAFS classification. Previous results show that these mammalian GRAFS families are well represented in the Metazoan lineages, but they have not been shown to be present in Fungi. Here, we systematically mined 79 fungal genomes and provide the first evidence that four of the five main mammalian families of GPCRs, namely Rhodopsin, Adhesion, Glutamate and Frizzled, are present in Fungi and found 142 novel sequences between them. Significantly, we provide strong evidence that the Rhodopsin family emerged from the cAMP receptor family in an event close to the split of Opisthokonts and not in Placozoa, as earlier assumed. The Rhodopsin family then expanded greatly in Metazoans while the cAMP receptor family is found in 3 invertebrate species and lost in the vertebrates. We estimate that the Adhesion and Frizzled families evolved before the split of Unikonts from a common ancestor of all major eukaryotic lineages. Also, the study highlights that the fungal Adhesion receptors do not have N-terminal domains whereas the fungal Glutamate receptors have a broad repertoire of mammalian-like N-terminal domains. Further, mining of the close unicellular relatives of the Metazoan lineage, Salpingoeca rosetta and Capsaspora owczarzaki, obtained a rich group of both the Adhesion and Glutamate families, which in particular provided insight to the early emergence of the N-terminal domains of the Adhesion family. We identified 619 Fungi specific GPCRs across 79 genomes and revealed that Blastocladiomycota and Chytridiomycota phylum have Metazoan-like GPCRs rather than the GPCRs specific for Fungi. Overall, this study provides the first evidence of the presence of four of the five main GRAFS families in Fungi and clarifies the early evolutionary history of the GPCR superfamily.
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| 9. |
- Nilsson, Emil, et al.
(författare)
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Roux-En Y Gastric Bypass Surgery Induces Genome-Wide Promoter-Specific Changes in DNA Methylation in Whole Blood of Obese Patients
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- ContextDNA methylation has been proposed to play a critical role in many cellular and biological processes.ObjectiveTo examine the influence of Roux-en-Y gastric bypass (RYGB) surgery on genome-wide promoter-specific DNA methylation in obese patients. Promoters are involved in the initiation and regulation of gene transcription.MethodsPromoter-specific DNA methylation in whole blood was measured in 11 obese patients (presurgery BMI >35 kg/m2, 4 females), both before and 6 months after RYGB surgery, as well as once only in a control group of 16 normal-weight men. In addition, body weight and fasting plasma glucose were measured after an overnight fast.ResultsThe mean genome-wide distance between promoter-specific DNA methylation of obese patients at six months after RYGB surgery and controls was shorter, as compared to that at baseline (p<0.001). Moreover, postsurgically, the DNA methylation of 51 promoters was significantly different from corresponding values that had been measured at baseline (28 upregulated and 23 downregulated, P<0.05 for all promoters, Bonferroni corrected). Among these promoters, an enrichment for genes involved in metabolic processes was found (n = 36, P<0.05). In addition, the mean DNA methylation of these 51 promoters was more similar after surgery to that of controls, than it had been at baseline (P<0.0001). When controlling for the RYGB surgery-induced drop in weight (-24% of respective baseline value) and fasting plasma glucose concentration (-16% of respective baseline value), the DNA methylation of only one out of 51 promoters (~2%) remained significantly different between the pre-and postsurgery time points.ConclusionsEpigenetic modifications are proposed to play an important role in the development of and predisposition to metabolic diseases, including type II diabetes and obesity. Thus, our findings may form the basis for further investigations to unravel the molecular effects of gastric bypass surgery.Clinical TrialClinicalTrials.gov NCT01730742
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| 10. |
- Perland, Emelie, et al.
(författare)
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Structural prediction of two novel human atypical SLC transporters, MFSD4A and MFSD9, and their neuroanatomical distribution in mice
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Out of the 430 known solute carriers (SLC) in humans, 30% are still orphan transporters regarding structure, distribution or function. Approximately one third of all SLCs belong to the evolutionary conserved and functionally diverse Major Facilitator Superfamily (MFS). Here, we studied the orphan proteins, MFSD4A and MFSD9, which are atypical SLCs of MFS type. Hidden Markov Models were used to identify orthologues in several vertebrates, and human MFSD4A and MFSD9 share high sequence identity with their identified orthologues. MFSD4A and MFSD9 also shared more than 20% sequence identity with other phylogenetically related SLC and MFSD proteins, allowing new family clustering. Homology models displayed 12 transmembrane segments for both proteins, which were predicted to fold into a transporter-shaped structure. Furthermore, we analysed the location of MFSD4A and MFSD9 in adult mouse brain using immunohistochemistry, showing abundant neuronal protein staining. As MFSD4A and MFSD9 are plausible transporters expressed in food regulatory brain areas, we monitored transcriptional changes in several mouse brain areas after 24 hours food-deprivation and eight weeks of high-fat diet, showing that both genes were affected by altered food intake in vivo. In conclusion, we propose MFSD4A and MFSD9 to be novel transporters, belonging to disparate SLC families. Both proteins were located to neurons in mouse brain, and their mRNA expression levels were affected by the diet.
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