| 1. |
- Muscarella, Robert, et al.
(författare)
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The global abundance of tree palms
- 2020
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 29:9, s. 1495-1514
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Tidskriftsartikel (refereegranskat)abstract
- AimPalms are an iconic, diverse and often abundant component of tropical ecosystems that provide many ecosystem services. Being monocots, tree palms are evolutionarily, morphologically and physiologically distinct from other trees, and these differences have important consequences for ecosystem services (e.g., carbon sequestration and storage) and in terms of responses to climate change. We quantified global patterns of tree palm relative abundance to help improve understanding of tropical forests and reduce uncertainty about these ecosystems under climate change.LocationTropical and subtropical moist forests.Time periodCurrent.Major taxa studiedPalms (Arecaceae).MethodsWe assembled a pantropical dataset of 2,548 forest plots (covering 1,191 ha) and quantified tree palm (i.e., ≥10 cm diameter at breast height) abundance relative to co‐occurring non‐palm trees. We compared the relative abundance of tree palms across biogeographical realms and tested for associations with palaeoclimate stability, current climate, edaphic conditions and metrics of forest structure.ResultsOn average, the relative abundance of tree palms was more than five times larger between Neotropical locations and other biogeographical realms. Tree palms were absent in most locations outside the Neotropics but present in >80% of Neotropical locations. The relative abundance of tree palms was more strongly associated with local conditions (e.g., higher mean annual precipitation, lower soil fertility, shallower water table and lower plot mean wood density) than metrics of long‐term climate stability. Life‐form diversity also influenced the patterns; palm assemblages outside the Neotropics comprise many non‐tree (e.g., climbing) palms. Finally, we show that tree palms can influence estimates of above‐ground biomass, but the magnitude and direction of the effect require additional work.ConclusionsTree palms are not only quintessentially tropical, but they are also overwhelmingly Neotropical. Future work to understand the contributions of tree palms to biomass estimates and carbon cycling will be particularly crucial in Neotropical forests.
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| 2. |
- Philippot, Gaetan, et al.
(författare)
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A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)
- 2018
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Ingår i: Toxicological Sciences. - : OXFORD UNIV PRESS. - 1096-6080 .- 1096-0929. ; 166:1, s. 203-212
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Tidskriftsartikel (refereegranskat)abstract
- Acetaminophen (AAP; also known as paracetamol) is the most used and only recommended analgesic and antipyretic among pregnant women and young children. However, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and adverse neurobehavioral effects later in life. We hypothesized that the cannabinoid receptor type 1 (CB1R) may be involved in the developmental neurotoxicity of AAP, owing to its interaction with the endocannabinoid system. Here we test if CB1R agonist WIN 55 212-2 (WIN) and AAP can interact when exposure occurs during a neurodevelopmental stage known for increased growth rate and for its vulnerability to AAP exposure. We exposed male NMRI mice on postnatal day 10 to different combinations of AAP and WIN. Adult mice, neonatally co-exposed to AAP and WIN, displayed a significant lack of habituation in the spontaneous behavior test, when compared with controls and single agent exposed mice. These adult adverse effects may at least in part be explained by a reduction of transcript levels of hippocampal synaptophysin (Syp) and tropomyosin receptor kinase B (Trkb), and cerebral cortical fatty acid amide hydroxylase (Faah), 24h after exposure. These findings are consistent with our hypothesis that AAP and WIN can interact when exposure occurs during early postnatal brain development in mice. Assuming our results are relevant for humans, they raise concerns on AAP safety because it is the only recommended analgesic and antipyretic during pregnancy and early life.
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| 3. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 4. |
- Aggarwal, Tanya, et al.
(författare)
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Knockdown of SLC38 Transporter Ortholog-CG13743 Reveals a Metabolic Relevance in Drosophila
- 2020
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Ingår i: Frontiers in Physiology. - : FRONTIERS MEDIA SA. - 1664-042X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Solute Carrier (SLC) is a cluster of families of membrane bound transporters, of which many members lack defined substrate profile, and many more are poorly characterized. Many play a vital role in regulating metabolic systems, protein synthesis, and post translational modifications. SLC38 is one of the families of SLCs, which are also known as sodium-coupled neutral amino acid transporters (SNATs). In mice, it has 11 members (SNAT1-11) but in Drosophila there are two homologs for the SLC38 family; CG13743 and CG30394. Here, we show characteristics of Drosophila CG13743 which closely resembles SLC38A11 in humans. SLC38A11 still remains an orphan member of the SLC38 family which has not been functionally well studied. We used the UAS-GAL4 system to investigate and control gene expression using RNAi lines for ubiquitous knockdown of the CG13743 gene. It was found to be expressed mainly in salivary gland and brain. Knockdown flies had reduced body weight and consumed less sugar compared with controls. The gene knockdown also affected stored energy pools (lipids and glycogen) and influenced feeding pattern and total activity. In all, this shows novel findings for the characterization of CG13743 in Drosophila and a possible role in maintaining general metabolic pathways and behavior of the fly.
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| 5. |
- Al-Sabri, Mohamed H., et al.
(författare)
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Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila. However, the sequential occurrence of mitochondrial phenotypes and myofibril damage remains elusive. To address this, we treated flies with fluvastatin for two and five days and examined their thorax flight muscles using confocal microscopy. In the two-day fluvastatin group, compared to the control, thorax flight muscles exhibited mitochondrial morphological changes, including fragmentation, rounding up and reduced content, while myofibrils remained organized in parallel. In the five-day fluvastatin treatment, not only did mitochondrial morphological changes become more pronounced, but myofibrils became severely disorganized with significantly increased thickness and spacing, along with myofilament abnormalities, suggesting myofibril damage. These findings suggest that fluvastatin-induced mitochondrial changes precede myofibril damage. Moreover, in the five-day fluvastatin group, the mitochondria demonstrated elevated H2O2 and impaired fatty acid oxidation compared to the control group, indicating potential mitochondrial dysfunction. Surprisingly, knocking down Hmgcr (Drosophila homolog of HMGCR) showed normal mitochondrial respiration in all parameters compared to controls or five-day fluvastatin treatment, which suggests that fluvastatin-induced mitochondrial dysfunction might be independent of Hmgcr inhibition. These results provide insights into the sequential occurrence of mitochondria and myofibril damage in statin-induced myopathy for future studies.
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| 6. |
- Al-Sabri, Mohamed H., et al.
(författare)
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Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy : Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes
- 2022
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 11:22
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Tidskriftsartikel (refereegranskat)abstract
- The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, C1C-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle C1C-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored C1C-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered C1C-a expression. Taken together, these results may indicate the potential role of C1C-a inhibition in statinassociated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.
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| 7. |
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| 8. |
- Almén, Markus Sällman, et al.
(författare)
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Genome wide analysis reveals association of a FTO gene variant with epigenetic changes
- 2012
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 99:3, s. 132-137
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Almén, Markus Sällman, et al.
(författare)
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Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity
- 2014
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 548:1, s. 61-67
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Almén, Markus Sällman, et al.
(författare)
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Mapping the human membrane proteome : a majority of the human membrane proteins can be classified according to function and evolutionary origin
- 2009
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Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 7, s. 50-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Membrane proteins form key nodes in mediating the cell's interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins. RESULTS: Here we mined the human proteome and identified the membrane proteome subset using three prediction tools for alpha-helices: Phobius, TMHMM, and SOSUI. This dataset was reduced to a non-redundant set by aligning it to the human genome and then clustered with our own interactive implementation of the ISODATA algorithm. The genes were classified and each protein group was manually curated, virtually evaluating each sequence of the clusters, applying systematic comparisons with a range of databases and other resources. We identified 6,718 human membrane proteins and classified the majority of them into 234 families of which 151 belong to the three major functional groups: receptors (63 groups, 1,352 members), transporters (89 groups, 817 members) or enzymes (7 groups, 533 members). Also, 74 miscellaneous groups with 697 members were determined. Interestingly, we find that 41% of the membrane proteins are singlets with no apparent affiliation or identity to any human protein family. Our results identify major differences between the human membrane proteome and the ones in unicellular organisms and we also show a strong bias towards certain membrane topologies for different functional classes: 77% of all transporters have more than six helices while 60% of proteins with an enzymatic function and 88% receptors, that are not GPCRs, have only one single membrane spanning alpha-helix. Further, we have identified and characterized new gene families and novel members of existing families. CONCLUSION: Here we present the most detailed roadmap of gene numbers and families to our knowledge, which is an important step towards an overall classification of the entire human proteome. We estimate that 27% of the total human proteome are alpha-helical transmembrane proteins and provide an extended classification together with in-depth investigations of the membrane proteome's functional, structural, and evolutionary features.
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| 11. |
- Almén, Markus Sällman, et al.
(författare)
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The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children
- 2010
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 11, s. 58-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 12. |
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| 13. |
- Alsiö, Johan, et al.
(författare)
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Exposure to a high-fat high-sugar diet causes strong up-regulation of proopiomelanocortin and differentially affects dopamine D1 and D2 receptor gene expression in the brainstem of rats
- 2014
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 559, s. 18-23
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Tidskriftsartikel (refereegranskat)abstract
- A strong link between obesity and dopamine (DA) has been established by studies associating body weight status to variants of genes related to DA signalling. Human and animal studies investigating this relationship have so far focused mainly on the role of DA within the mesolimbic pathway. The aim of this study was to investigate potential DA receptor dysregulation in the brainstem, where these receptors play a potential role in meal termination, during high-fat high-sugar diet (HFHS) exposure. Expression of other key genes, including proopiomelanocortin (POMC), was also analyzed. We randomized rats into three groups; ad libitum access to HFHS (n=24), restricted HFHS access (n=10), or controls (chow-fed, n=10). After 5 weeks, brainstem gene expression was investigated by qRT-PCR. We observed an increase in POMC expression in ad libitum HFHS-fed rats compared to chow-fed controls (p<0.05). Further, expression of DA D2 receptor mRNA was down-regulated in the brainstem of the HFHS ad libitum-fed rats (p<0.05), whereas expression of the DA D1 receptor was upregulated (p<0.05) in these animals compared to chow-fed rats. In control experiments, we observed no effect relative to chow-fed controls on DA-receptor or POMC gene expression in the hypothalamus of HFHS diet-exposed rats, or in the brainstem of acutely food deprived rats. The present findings suggest brainstem POMC to be responsive to palatable foods, and that DA dysregulation after access to energy-dense diets occurs not only in striatal regions, but also in the brainstem, which could be relevant for overeating and for the development and maintenance of obesity.
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| 14. |
- Alsiö, Johan, et al.
(författare)
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Inverse association of high-fat diet preference and anxiety-like behavior : a putative role for urocortin 2
- 2009
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Ingår i: Genes, Brain and Behavior. - 1601-1848 .- 1601-183X. ; 8:2, s. 193-202
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.
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| 15. |
- Andersen, Sören M., et al.
(författare)
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A scalable route to 5-substituted 3-isoxazolol fibrinolysis inhibitor AZD6564
- 2014
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 18:8, s. 952-959
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Tidskriftsartikel (refereegranskat)abstract
- A practical and chromatography-free multikilogram synthesis of a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been developed in eight steps and 7% overall yield starting from methyl 2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling and an enzymatic resolution of a racemic ester.
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| 16. |
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| 17. |
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| 18. |
- 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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| 19. |
- Bagchi, Sonchita, et al.
(författare)
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In Situ Proximity Ligation Assay (PLA)
- 2015
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Ingår i: ELISA. - New York, NY : Springer-Verlag New York. - 9781493927425 - 9781493927418 ; , s. 149-159
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Bokkapitel (refereegranskat)abstract
- In situ proximity ligation assay (PLA) is a method to identify physical closeness of proteins, where a signal will only be produced if the two proteins are closer than 40 nm, in tissue section or cell cultures. Modifications of the PLA method can also be used to increase specificity or sensitivity of standard immunohistochemistry protocols.
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| 20. |
- Bagchi, Sonchita, 1978-, et al.
(författare)
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Probable role for major facilitator superfamily domain containing 6 (MFSD6) in the brain during variable energy consumption
- 2020
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Ingår i: International Journal of Neuroscience. - : Informa UK Limited. - 0020-7454 .- 1563-5279 .- 1543-5245. ; 130:5, s. 476-489
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The major facilitator superfamily (MFS) is known as the largest and most diverse superfamily containing human transporters, and these transporters are essential as they sustain the homeostasis within cellular compartments by moving substances over lipid membranes.Methods: We have identified a novel MFS protein, named Major facilitator superfamily domain containing 6 (MFSD6), and confirmed that it is phylogenetically related to the human Solute Carrier (SLC) transporter family. A homology model of MFSD6 revealed 12 predicted transmembrane segments (TMS) with the classical MFS fold between TMS 6 and 7.Results: Immunohistological analyses showed specific MFSD6 staining in neurons of wildtype mouse brain tissue, but no expression in astrocytes. Furthermore, we explored expression and probable function(s) of MFSD6 in relation to its phylogenetically related proteins, major facilitator superfamily domain containing 8 (MFSD8) and 10 (MFSD10), which is of interest as both these proteins are involved in diseases.Conclusions: We showed that expression levels of Mfsd6 and Mfsd10 were decreased with elevated or depleted energy consumption, while that of Mfsd8 remained unaffected.
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| 21. |
- Benedict, Christian, et al.
(författare)
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The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men
- 2011
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 32:6, s. 1159.e1-1159.e5
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 22. |
- Bjarnadóttir, Thóra K., et al.
(författare)
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Comprehensive repertoire and phylogenetic analysis of the G-protein-coupled receptors in human and mouse
- 2006
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 88:3, s. 263-273
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Tidskriftsartikel (refereegranskat)abstract
- Understanding differences in the repertoire of orthologous gene pairs is vital for interpretation of pharmacological and physiological experiments if conclusions are conveyed between species. Here we present a comprehensive dataset for G protein-coupled receptors (GPCRs) in both human and mouse with a phylogenetic road map. We performed systematic searches applying several search tools such as BLAST, BLAT, and Hidden Markov models and searches in literature data. We aimed to gather a full-length version of each human or mouse GPCR in only one copy referring to a single chromosomal position. Moreover, we performed detailed phylogenetic analysis of the transmembrane regions of the receptors to establish accurate orthologous pairs. The results show the identity of 495 mouse and 400 human functional nonolfactory GPCRs. Overall, 329 of the receptors are found in one-to-one orthologous pairs, while 119 mouse and 31 human receptors originate from species-specific expansions or deletions. The average percentage similarity of the orthologue pairs is 85%, while it varies between the main GRAFS families from an average of 59 to 94%. The orthologous pairs for the lipid-binding GPCRs had the lowest levels of conservation, while the biogenic amines had highest levels of conservation. Moreover, we searched for expressed sequence tags (ESTs) and identified more than 17,000 ESTs matching GPCRs in mouse and human, providing information about their expression patterns. On the whole, this is the most comprehensive study of the gene repertoire that codes for human and mouse GPCRs. The datasets are available for downloading.
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| 23. |
- Bjarnadóttir, Thóra K., et al.
(författare)
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Identification of novel splice variants of Adhesion G protein-coupled receptors
- 2007
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 387:1-2, s. 38-48
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Tidskriftsartikel (refereegranskat)abstract
- Alternative splicing is an important mechanism to generate proteome diversity in higher eukaryotic organisms. We searched for splice variants of the human Adhesion family of G protein-coupled receptors (GPCRs) using mRNA sequences and expressed sequence tags. The results presented here describe 53 human splice variants among the 33 Adhesion GPCRs. Many of these variants appear to be coding for “functional” proteins (29) while the others are seemingly “non-functional” (24). Novel functional splice variants were found for: CD97, CELR3, EMR2, EMR3, GPR56, GPR110, GPR112–GPR114, GPR116, GPR123–GPR126, GPR133, HE6, and LEC1–LEC3. Splice variants for GPR116, GPR125, GPR126, and HE6 were found conserved in other species. Several of the functional splice variants lack one or more of the functional domains that are found in the N-termini of these receptors. These functional domains are likely to affect ligand binding or interaction with other proteins and these novel splice variants may have important roles for the specificity of interactions between these receptors and extracellular molecules. Another type of splice variants found here lacks a GPCR proteolytic site (GPS). The GPS domain has been shown to be essential for the proteolytic cleavage of the receptors N-termini and for cellular surface expression. We suggest that these alternative splice variants may be crucial for the function of the receptors while the seemingly non-functional splice variants may be a part of a regulative mechanism.
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| 24. |
- Bjarnadóttir, T K, et al.
(författare)
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The adhesion GPCRs : a unique family of G protein-coupled receptors with important roles in both central and peripheral tissues
- 2007
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 64:16, s. 2104-2119
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Forskningsöversikt (refereegranskat)abstract
- Gprotein-coupled receptors (GPCRs) are adiverse superfamily of membrane-bound receptors.The second largest subgroup of GPCRs, the AdhesionGPCRs, has 33 members in humans. Phylogeneticanalysis of the entire repertoire of the seven transmembrane-domain (7TM) regions of GPCRs showsthat the Adhesion GPCRs form a distinct family.Adhesion GPCRs are characterised by (1) long Ntermini with multiple functional domains often foundin other proteins such as tyrosine kinases, integrinsand cadherins, (2) highly complex genomic structurewith multiple introns and splice variants and (3) a7TMregion that has no clear similarities with 7TM fromother GPCRs. Several AdhesionGPCRs are known tohave a role in the immune system but it is becomingmore evident that many have important roles in theCNS. We speculate that the overall structural constructionof the Adhesion GPCRs allows them toparticipate in different types of cell guidance.
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| 25. |
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| 26. |
- Bjarnadóttir, Thóra K., et al.
(författare)
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The human and mouse repertoire of the adhesion family of G-protein-coupled receptors
- 2004
-
Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 84:1, s. 23-33
-
Tidskriftsartikel (refereegranskat)abstract
- The adhesion G-protein-coupled receptors (GPCRs) (also termed LN-7TM or EGF-7TM receptors) are membrane-bound proteins with long N-termini containing multiple domains. Here, 2 new human adhesion-GPCRs, termed GPR133 and GPR144, have been found by searches done in the human genome databases. Both GPR133 and GPR144 have a GPS domain in their N-termini, while GPR144 also has a pentraxin domain. The phylogenetic analyses of the 2 new human receptors show that they group together without close relationship to the other adhesion-GPCRs. In addition to the human genes, mouse orthologues to those 2 and 15 other mouse orthologues to human were identified (GPR110, GPR111, GPR112, GPR113, GPR114, GPR115, GPR116, GPR123, GPR124, GPR125, GPR126, GPR128, LEC1, LEC2, and LEC3). Currently the total number of human adhesion-GPCRs is 33. The mouse and human sequences show a clear one-to-one relationship, with the exception of EMR2 and EMR3, which do not seem to have orthologues in mouse. EST expression charts for the entire repertoire of adhesion-GPCRs in human and mouse were established. Over 1600 ESTs were found for these receptors, showing widespread distribution in both central and peripheral tissues. The expression patterns are highly variable between different receptors, indicating that they participate in a number of physiological processes.
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| 27. |
- Bjarnadóttir, Þóra Kristín, 1978-
(författare)
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The Gene Repertoire of G protein-coupled Receptors : New Genes, Phylogeny, and Evolution
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The superfamily of G protein-coupled receptors (GPCRs) is one of the largest protein families of mammalian genomes and can be divided into five main families; Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin. GPCRs participate in most major physiological functions, contributing to the fact that they are important targets in drug discovery. In paper I we mined the human and mouse genomes for new Adhesion GPCR genes. We found two new human genes (GPR133 and GPR144) and 17 mouse Adhesion genes, bringing the number up to 33 human and 31 mouse genes. In paper II we describe 53 new splice variants for human Adhesion receptors supported by expressed sequence tags (EST) data. 29 of these variants seem to code for functional proteins, several of which lack one or more functional domains in the N-termini. Lack of certain domains is likely to affect ligand binding or interaction with other proteins. Paper III describes the Glutamate GPCR in human, mouse, Fugu, and zebrafish. We gathered a total of 22 human, 79 mouse, 30 Fugu, and 32 zebrafish sequences and grouped these into eight clans using phylogenetic methods. The report provides an overview of the expansion or deletions among the different branches of the Glutamate receptor family. Paper IV focuses on the trace amine (TA) clan of Rhodopsin GPCRs. We identified 18 new rodent genes, 57 zebrafish genes, and eight Fugu genes belonging to the clan. Chromosomal mapping together with phylogenetic relationships suggests that the family arose through several mechanisms involving tetraploidisation, block duplications, and local duplication events. Paper V provides a comprehensive dataset of the GPCR superfamily of human and mouse containing 495 mouse and 400 human non-olfactory GPCRs. Phylogenetic analyses showed that 329 of the receptors are found in one-to-one orthologous pairs, whereas other receptors may have originated from species-specific expansions.
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| 28. |
- Bromée, Torun, et al.
(författare)
-
Neuropeptide Y-family receptors Y6 and Y7 in chicken : Cloning, pharmacological characterization, tissue distribution and conserved synteny with human chromosome region
- 2006
-
Ingår i: The FEBS Journal. - : Federation of European Biochemical Societies. - 1742-464X .- 1742-4658. ; 273:9, s. 2048-2063
-
Tidskriftsartikel (refereegranskat)abstract
- The peptides of the neuropeptide Y (NPY) family exert their functions, including regulation of appetite and circadian rhythm, by binding to G-protein coupled receptors. Mammals have five subtypes, named Y1, Y2, Y4, Y5 and Y6, and recently Y7 has been discovered in fish and amphibians. In chicken we have previously characterized the first four subtypes and here we describe Y6 and Y7. The genes for Y6 and Y7 are located 1 megabase apart on chromosome 13, which displays conserved synteny with human chromosome 5 that harbours the Y6 gene. The porcine PYY radioligand bound the chicken Y6 receptor with a Kd of 0.80 ± 0.36 nm. No functional coupling was demonstrated. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue. Porcine PYY bound chicken Y7 with a Kd of 0.14 ± 0.01 nm (mean ± SEM), whereas chicken PYY surprisingly had a much lower affinity, with a Ki of 41 nm, perhaps as a result of its additional amino acid at the N terminus. Truncated peptide fragments had greatly reduced affinity for Y7, in agreement with its closest relative, Y2, in chicken and fish, but in contrast to Y2 in mammals. This suggests that in mammals Y2 has only recently acquired the ability to bind truncated PYY. Chicken Y7 has a much more restricted tissue distribution than other subtypes and was only detected in adrenal gland. Y7 seems to have been lost in mammals. The physiological roles of Y6 and Y7 remain to be identified, but our phylogenetic and chromosomal analyses support the ancient origin of these Y receptor genes by chromosome duplications in an early (pregnathostome) vertebrate ancestor.
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| 29. |
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| 30. |
- Brooks, Samantha J, et al.
(författare)
-
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
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1, s. e82707-
-
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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| 31. |
- Brooks, Samantha J., et al.
(författare)
-
Exposure to subliminal arousing stimuli induces robust activation in the amygdala, hippocampus, anterior cingulate, insular cortex and primary visual cortex : A systematic meta-analysis of fMRI studies
- 2012
-
Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 59:3, s. 2962-2973
-
Forskningsöversikt (refereegranskat)abstract
- Functional Magnetic Resonance Imaging (fMRI) demonstrates that the subliminal presentation of arousing stimuli can activate subcortical brain regions independently of consciousness-generating top-down cortical modulation loops. Delineating these processes may elucidate mechanisms for arousal, aberration in which may underlie some psychiatric conditions. Here we are the first to review and discuss four Activation Likelihood Estimation (ALE) meta-analyses of fMRI studies using subliminal paradigms. We find a maximum of 9 out of 12 studies using subliminal presentation of faces contributing to activation of the amygdala, and also a significantly high number of studies reporting activation in the bilateral anterior cingulate, bilateral insular cortex, hippocampus and primary visual cortex. Subliminal faces are the strongest modality, whereas lexical stimuli are the weakest. Meta-analyses independent of studies using Regions of Interest (ROI) revealed no biasing effect Core neuronal arousal in the brain, which may be at first independent of conscious processing, potentially involves a network incorporating primary visual areas, somatosensory, implicit memory and conflict monitoring regions. These data could provide candidate brain regions for the study of psychiatric disorders associated with aberrant automatic emotional processing.
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| 32. |
- Bäckström, Daniel, 1985, et al.
(författare)
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On the use of alternative fuels in rotary kiln burners - An experimental and modelling study of the effect on the radiative heat transfer conditions
- 2015
-
Ingår i: Fuel processing technology. - : Elsevier. - 0378-3820 .- 1873-7188. ; 138, s. 210-220
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract In this work, the radiative heat transfer conditions in a 400 kWfuel test furnace were studied. The test furnace is a scaled pilot of a rotary kiln furnace used in iron ore pellet production. In particular, the study focuses on the choice of fuel and the subsequent effect on temperature and radiative conditions in the flame. Several co-firing flames of coal and biomass were investigated and also other fuels such as heavy fuel oil and natural gas. The test furnace was used in the experiments, and radiative intensity was measured with a narrow angle radiometer. Detailed radiation modelling was performed using spectral models for gas and particle properties. The results show that all co-firing flames give a shorter radiating flame length. Based on the radiation modelling, it was also shown that the particle radiation dominates the heat transfer from the flames. Due to the high pre-heating temperature of the combustion air (1100°C), the flame temperatures were generally very high. The flame temperature in the natural gas flame was likely around 2000°C while the coal flame temperatures were estimated to 1500-1600°C. The two coals tested, having almost identical fuel specifications, resulted in a substantial difference in the radiation intensity emitted by the flame. This emphasizes the need of direct radiation measurements to evaluate fuel changes in industrial processes that are highly dependent on the heat transfer conditions.
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| 33. |
- Caruso, Vanni, et al.
(författare)
-
mRNA GPR162 changes are associated with decreased food intake in rat, and its human genetic variants with impairments in glucose homeostasis in two Swedish cohorts
- 2016
-
Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 581:2, s. 139-145
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 34. |
- Caruso, Vanni, et al.
(författare)
-
Synaptic changes induced by melanocortin signalling
- 2014
-
Ingår i: Nature Reviews Neuroscience. - : Springer Science and Business Media LLC. - 1471-003X .- 1471-0048. ; 15:2, s. 98-110
-
Forskningsöversikt (refereegranskat)abstract
- The melanocortin system has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction. In this Review, we focus on the role of the melanocortin 4 receptor and provide an integrative view of the molecular mechanisms that lead to melanocortin-induced changes in synaptic plasticity within these diverse physiological systems. We also highlight the importance of melanocortin peptides and receptors in chronic pain syndromes, memory impairments, depression and drug abuse, and the possibility of targeting them for therapeutic purposes.
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| 35. |
- Caruso, Vanni, et al.
(författare)
-
The G protein-coupled receptor GPR162 is widely distributed in the CNS and highly expressed in the hypothalamus and in hedonic feeding areas
- 2014
-
Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 553:1, s. 1-6
-
Tidskriftsartikel (refereegranskat)abstract
- The Rhodopsin family is a class of integral membrane proteins belonging to G protein-coupled receptors (GPCRs). To date, several orphan GPCRs are still uncharacterized and in this study we present an anatomical characterization of the GPR162 protein and an attempt to describe its functional role. Our results show that GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in areas related to energy homeostasis and hedonic feeding such as hypothalamus, amygdala and ventral tegmental area, regions known to be involved in the regulation of palatable food consumption.
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| 36. |
- Caruso, Vanni, et al.
(författare)
-
The Orphan G Protein-Coupled Receptor Gene GPR178 Is Evolutionary Conserved and Altered in Response to Acute Changes in Food Intake
- 2015
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6
-
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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| 37. |
- Ceder, Mikaela, 1991-
(författare)
-
Characterization of Novel Solute Carriers in Humans, Mice and Flies : Solute Carriers in a Broad and Narrow Perspective
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The solute carrier family is the largest family of membrane-bound transporters in humans, with 430 members divided into 65 subfamilies. They transport various substrates across lipid barriers and are vital for absorption, distribution, metabolism and excretion in all cell types in the body. Despite being involved in vital functions, and their effect on both physiology and pathophysiology, many transporters are not characterized. The aim of this thesis was to study newly identified putative solute carriers of which little is known. In Paper I, the relationship of solute carriers in humans and fruit flies was studied. The study revealed that 54 of the 65 subfamilies in humans have one or more orthologues in fruit flies, and a total of 381 orthologues were identified in fruit flies. In Paper II, a comprehensive study of the putative solute carriers and their response to different sugar concentrations were performed. Several, but not all, putative solute carriers were altered in cell cultures maintained in media containing low or no glucose, and the expression normalized upon refeeding with glucose. Similar results were observed in fruit flies subjected to complete starvation or diets with varying sugar concentrations. Last, in Paper III and IV, characterization of one putative solute carrier, UNC93A, was performed. The studies revealed that UNC93A was a conserved protein with an abundant expression in the body of mice but with a restricted expression in fruit flies. The protein was found to possibly be expressed at, or close to, the plasma membrane of cells and to co-localize with Twik-Acid sensitive potassium channels. UNC93A was found to be important for the renal function in fruit flies and to affect survival and membrane potentials in cells. The findings of this thesis establish a high conservation of several putative solute carriers and that they have a highly dynamic regulation during fluctuating energy and glucose availability. Further, while several clear biological aspects of UNC93A was identified, the exact function of transporter proteins is cumbersome to find and more research about these transporters is needed to fully understand their mechanistic role and their association and/or involvement in health and sickness.
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| 38. |
- Ceder, Mikaela M., et al.
(författare)
-
A phylogenetic analysis between humans and D. melanogaster : A repertoire of solute carriers in humans and flies
- 2022
-
Ingår i: Gene. - : Elsevier. - 0378-1119 .- 1879-0038. ; 809
-
Tidskriftsartikel (refereegranskat)abstract
- The solute carrier (SLC) superfamily is the largest group of transporters in humans, with the role to transport solutes across plasma membranes. The SLCs are currently divided into 65 families with 430 members. Here, we performed a detailed mining of the SLC superfamily and the recent annotated family of “atypical” SLCs in human and D. melanogaster using Hidden Markov Models and PSI-BLAST. Our analyses identified 381 protein sequences in D. melanogaster and of those, 55 proteins have not been previously identified in flies. In total, 11 of the 65 human SLC families were found to not be conserved in flies, while a few families are highly conserved, which perhaps reflects the families’ functions and roles in cellular pathways. This study provides the first collection of all SLC sequences in D. melanogaster and can serve as a SLC database to be used for classification of SLCs in other phyla.
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| 39. |
- Ceder, Mikaela M., et al.
(författare)
-
CG4928 is vital for renal function in fruit flies and membrane potential in cells : A first in-depth characterization of the putative Solute Carrier UNC93A
- 2020
-
Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK(1) channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.
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| 40. |
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| 41. |
- Ceder, Mikaela M., et al.
(författare)
-
Glucose Availability Alters Gene and Protein Expression of Several Newly Classified and Putative Solute Carriers in Mice Cortex Cell Culture and D. melanogaster
- 2020
-
Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Many newly identified solute carriers (SLCs) and putative transporters have the possibility to be intricately involved in glucose metabolism. Here we show that many transporters of this type display a high degree of regulation at both mRNA and protein level following no or low glucose availability in mouse cortex cultures. We show that this is also the case in Drosophila melanogaster subjected to starvation or diets with different sugar content. Interestingly, re-introduction of glucose to media, or refeeding flies, normalized the gene expression of a number of the targets, indicating a fast and highly dynamic control. Our findings demonstrate high conservation of these transporters and how dependent both cell cultures and organisms are on gene and protein regulation during metabolic fluctuations. Several transporter genes were regulated simultaneously maybe to initiate alternative metabolic pathways as a response to low glucose levels, both in the cell cultures and in D. melanogaster. Our results display that newly identified SLCs of Major Facilitator Superfamily type, as well as the putative transporters included in our study, are regulated by glucose availability and could be involved in several cellular aspects dependent of glucose and/or its metabolites. Recently, a correlation between dysregulation of glucose in the central nervous system and numerous diseases such as obesity, type 2 diabetes mellitus as well as neurological disease such as Alzheimer’s and Parkinson’s diseases indicate a complex regulation and fine tuning of glucose levels in the brain. The fact that almost one third of transporters and transporter-related proteins remain orphans with unknown or contradictive substrate profile, location and function, pinpoint the need for further research about them to fully understand their mechanistic role and their impact on cellular metabolism.
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| 42. |
- Ceder, Mikaela M., et al.
(författare)
-
The Fly Homologue of MFSD11 Is Possibly Linked to Nutrient Homeostasis and Has a Potential Role in Locomotion : A First Characterization of the Atypical Solute Carrier CG18549 in Drosophila Melanogaster
- 2021
-
Ingår i: Insects. - : MDPI. - 2075-4450. ; 12:11
-
Tidskriftsartikel (refereegranskat)abstract
- Cellular transport and function are dependent on substrate influx and efflux of various compounds. In humans, the largest superfamily of transporters is the SoLute Carriers (SLCs). Many transporters are orphans and little to nothing is known about their expression and/or function, yet they have been assigned to a cluster called atypical SLCs. One of these atypical SLCs is MFSD11. Here we present a first in-depth characterization of the MFSD11, CG18549. By gene expression and behavior analysis on ubiquitous and brain-specific knockdown flies. CG18549 knockdown flies were found to have altered adipokinetic hormone and adipokinteic hormone receptor expression as well as reduced vesicular monoamine transporter expression; to exhibit an altered locomotor behavior, and to have an altered reaction to stress stimuli. Furthermore, the gene expression of CG18549 in the brain was visualized and abundant expression in both the larvae and adult brain was observed, a result that is coherent with the FlyAtlas Anatomy microarray. The exact mechanism behind the observed behaviors is not fully understood, but this study provides new insights into the expression and function of CG18549. Clearly, these results provide a strong example as to why it is vital to fully characterize orphan transporters and through that gain knowledge about the body during normal condition and disease.
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| 43. |
- Ceder, Mikaela, et al.
(författare)
-
The Neuronal and Peripheral Expressed Membrane-Bound UNC93A Respond to Nutrient Availability in Mice
- 2017
-
Ingår i: Frontiers in Molecular Neuroscience. - : FRONTIERS MEDIA SA. - 1662-5099. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Many transporters such as the solute carriers belonging to the Major facilitator superfamily Pfam clan are orphans in that their tissue and cellular localization as well as substrate profile and function are still unknown. Here we have characterized the putative solute carrier UNC93A. We aimed to investigate the expression profile on both protein and mRNA level of UNC93A in mouse since it has not been clarified. UNC93A staining was found in cortex, hippocampus and cerebellum. It was found to be expressed in many neurons, but not all, with staining located in close proximity to the plasma membrane. Furthermore, we aimed to extend the starvation data available for Unc93a in hypothalamic cell cultures from mouse. We investigated the Unc93a alterations with focus on amino acid deprivation in embryonic cortex cells from mice as well as 24 h starvation in adult male mice and compared it to recently studied putative and known solute carriers. Unc93a expression was found both in the brain and peripheral organs, in low to moderate levels in the adult mice and was affected by amino acid deprivation in embryonic cortex cultures and starvation in in vivo samples. In conclusion, the membrane-bound UNC93A is expressed in both the brain and peripheral tissues and responds to nutrient availability in mice.
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| 44. |
- Cedernaes, Jonathan, et al.
(författare)
-
Comprehensive analysis of localization of 78 solute carrier genes throughout the subsections of the rat gastrointestinal tract
- 2011
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 411:4, s. 702-707
-
Tidskriftsartikel (refereegranskat)abstract
- Solute carriers (SLCs), the second largest super-family of membrane proteins in the human genome, transport amino acids, sugars, fatty acids, inorganic ions, essential metals and drugs over membranes. To date no study has provided a comprehensive analysis of SLC localization along the entire GI tract. The aim of the present study was to provide a comprehensive, segment-specific description of the localization of SLC genes along the rat Cl tract by employing bioinformatics and molecular biology methods. The Unigene database was screened for rat SLC entries in the intestinal tissue. Using qPCR we measured expression of the annotated genes in the Cl tract divided into the following segments: the esophagus, the corpus and the antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum. Our Unigene-derived gene pool was expanded with data from in-house tissue panels and a literature search. We found 44 out of 78 (56%) of gut SLC transcripts to be expressed in all Cl tract segments, whereas the majority of remaining SLCs were detected in more than five segments. SLCs are predominantly expressed in gut regions with absorptive functions although expression was also found in segments unrelated to absorption. The proximal jejunum had the highest number of differentially expressed SLCs. In conclusion, SLCs are a crucial molecular component of the Cl tract, with many of them expressed along the entire GI tract. This work presents the first overall road map of localization of transporter genes in the Cl tract.
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| 45. |
- Cedernaes, Jonathan
(författare)
-
Intestinal Gene Expression Profiling and Fatty Acid Responses to a High-fat Diet
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The gastrointestinal tract (GIT) regulates nutrient uptake, secretes hormones and has a crucial gut flora and enteric nervous system. Of relevance for these functions are the G protein-coupled receptors (GPCRs) and the solute carriers (SLCs). The Adhesion GPCR subfamily is known to mediate neural development and immune system functioning, whereas SLCs transport e.g. amino acids, fatty acids (FAs) and drugs over membranes. We aimed to comprehensively characterize Adhesion GPCR and SLC gene expression along the rat GIT. Using qPCR we measured expression of 78 SLCs as well as all 30 Adhesion GPCRs in a twelve-segment GIT model. 21 of the Adhesion GPCRs had a widespread (≥5 segments) or ubiquitous (≥11 segments) expression. Restricted expression patterns were characteristic for most group VII members. Of the SLCs, we found the majority (56 %) of these transcripts to be expressed in all GIT segments. SLCs were predominantly found in the absorption-responsible gut regions. Both Adhesion GPCRs and SLCs were widely expressed in the rat GIT, suggesting important roles. The distribution of Adhesion GPCRs defines them as a potential pharmacological target.FAs constitute an important energy source and have been implicated in the worldwide obesity increase. FAs and their ratios – indices for activities of e.g. the desaturase enzymes SCD-1 (SCD-16, 16:1n-7/16:0), D6D (18:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6) – have been associated with e.g. overall mortality and BMI. We examined whether differences in FAs and their indices in five lipid fractions contributed to obesity susceptibility in rats fed a high fat diet (HFD), and the associations of desaturase indices between lipid fractions in animals on different diets. We found that on a HFD, obesity-prone (OP) rats had a higher SCD-16 index and a lower linoleic acid (LA) proportions in subcutaneous adipose tissue (SAT) than obesity-resistant rats. Desaturase indices were significantly correlated between many of the lipid fractions. The higher SCD-16 may indicate higher SCD-1 activity in SAT in OP rats, and combined with lower LA proportions may provide novel insights into HFD-induced obesity. The associations between desaturase indices show that plasma measurements can serve as proxies for some lipid fractions, but the correlations seem to be affected by diet and weight gain.
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| 46. |
- Chatzikyriakidou, Yurie, 1991-
(författare)
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Determining Ligand- and Lipid- Interactions of SLC Transporters
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Solute carrier transporters (SLCs) mediate the inter- and intra- cellular trafficking of a plethora of substrates and are essential to cell homeostasis. Despite their importance to human physiology and their potential as therapeutic targets, many SLCs are considered orphans as the physiological substrate has not been experimentally determined. Furthermore, SLCs remain understudied and underutilized, partly due to the inherent difficulties in working with SLC transporters. In this thesis, I present the development of the GFP-based thermostability assay (GFP-TS), which enables the detection of ligand-SLC interactions using un-purified material, but with the same high-throughput screening capability as dye-based thermal-shift assays. We highlight how GFP-TS is an excellent complement to native mass spectrometry approaches for analyzing lipid-protein interactions, by demonstrating how specific lipids modulate oligomerization in Na+/H+ exchangers. GFP-TS was combined with other biochemical approaches to show that not all SLC35 members transport nucleotide-sugars, as currently believed. Specifically, we unequivocally demonstrate that SLC35B1 is a strict ADP/ATP exchanger, which is critical for cell homeostasis, as it supplies the endoplasmic reticulum (ER) with ATP. Finally, I outline the progress towards elucidating the function of the synaptic vesicle protein 2A (SV2A), an enigmatic brain SLC transporter that is the receptor for clinically-used anti-epileptic drugs. In summary, my research contributes to the growing body of knowledge of SLC function, and outlines how a simple thermal stability can be utilised for determining ligand- and lipid-interactions of SLC transporters.
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| 47. |
- Civelli, Olivier, et al.
(författare)
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G Protein-Coupled Receptor Deorphanizations
- 2013
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Ingår i: Annual Review of Pharmacology and Toxicology. - : Annual Reviews. - 0362-1642 .- 1545-4304. ; 53, s. 127-146
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Forskningsöversikt (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) are major regulators of intercellular interactions. They initiate these actions by being activated by a wide variety of natural ligands. Historically, ligands were discovered first, but the advent of molecular biology reversed this trend. Most GPCRs are identified on the basis of their DNA sequences and thus are initially unmatched to known natural ligands. They are termed orphan GPCRs. Discovering their ligands-i.e., "deorphanizing" the GPCRs-gave birth to the field of reverse pharmacology. This review discusses the present status of GPCR deorphanization, presents a few examples of successes and surprises, and highlights difficulties encountered in these efforts.
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| 48. |
- Corell, Mikael, et al.
(författare)
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GABA and its B-receptor are present at the node of Ranvier in a small population of sensory fibers, implicating a role in myelination
- 2015
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 93:2, s. 285-295
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Tidskriftsartikel (refereegranskat)abstract
- The γ-aminobutyric acid (GABA) type B receptor has been implicated in glial cell development in the peripheral nervous system (PNS), although the exact function of GABA signaling is not known. To investigate GABA and its B receptor in PNS development and degeneration, we studied the expression of the GABAB receptor, GABA, and glutamic acid decarboxylase GAD65/67 in both development and injury in fetal dissociated dorsal root ganglia (DRG) cell cultures and in the rat sciatic nerve. We found that GABA, GAD65/67, and the GABAB receptor were expressed in premyelinating and nonmyelinating Schwann cells throughout development and after injury. A small population of myelinated sensory fibers displayed all of these molecules at the node of Ranvier, indicating a role in axon-glia communication. Functional studies using GABAB receptor agonists and antagonists were performed in fetal DRG primary cultures to study the function of this receptor during development. The results show that GABA, via its B receptor, is involved in the myelination process but not in Schwann cell proliferation. The data from adult nerves suggest additional roles in axon-glia communication after injury.
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| 49. |
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| 50. |
- 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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