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  • 151.
    De Felice, Fernanda G.
    et al.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo Meis, Rio De Janeiro, Brazil.;DOr Inst Res & Educ, Rio De Janeiro, Brazil.;Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A Key Role of Insulin Receptors in Memory2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 11, p. 3653-3655Article in journal (Other academic)
  • 152. Drgonova, Jana
    et al.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Han, Joan C.
    Yanovski, Jack A.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Marcus, Claude
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Uhl, George R.
    Involvement of the Neutral Amino Acid Transporter SLC6A15 and Leucine in Obesity-Related Phenotypes2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e68245-Article in journal (Refereed)
    Abstract [en]

    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.

  • 153.
    Dyakova, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Rångtell, Frida H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute sleep loss induces signs of visual discomfort in young men.2019In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, article id e12837Article in journal (Refereed)
    Abstract [en]

    Acute sleep loss influences visual processes in humans, such as recognizing facial emotions. However, to the best of our knowledge, no study till date has examined whether acute sleep loss alters visual comfort when looking at images. One image statistic that can be used to investigate the level of visual comfort experienced under visual encoding is the slope of the amplitude spectrum, also referred to as the slope constant. The slope constant describes the spatial distribution of pixel intensities and deviations from the natural slope constant can induce visual discomfort. In the present counterbalanced crossover design study, 11 young men with normal or corrected-to-normal vision participated in two experimental conditions: one night of sleep loss and one night of sleep. In the morning after each intervention, subjects performed a computerized psychophysics task. Specifically, they were required to adjust the slope constant of images depicting natural landscapes and close-ups with a randomly chosen initial slope constant until they perceived each image as most natural looking. Subjects also rated the pleasantness of each selected image. Our analysis showed that following sleep loss, higher slope constants were perceived as most natural looking when viewing images of natural landscapes. Images with a higher slope constant are generally perceived as blurrier. The selected images were also rated as less pleasant after sleep loss. No such differences between the experimental conditions were noted for images of close-ups. The results suggest that sleep loss induces signs of visual discomfort in young men. Possible implications of these findings are discussed.

  • 154.
    Edvinsson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Bränn, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Freyhult, Eva
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    White, Richard
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Olivier, Jocelien
    Univ Groningen, Groningen Inst Evolutionary Life Sci, Unit Behav Neurosci, Dept Neurobiol, Groningen, Netherlands..
    Bergquist, Jonas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Boström, Adrian E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lower inflammatory markers in women with antenatal depression brings the M1/M2 balance into focus from a new direction2017In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 80, p. 15-25Article in journal (Refereed)
    Abstract [en]

    Background: Antenatal depression and use of serotonin reuptake inhibitors (SSRI) in pregnancy have both been associated with an increased risk of poor pregnancy outcomes, such as preterm birth and impaired fetal growth. While the underlying biological pathways for these complications are poorly understood, it has been hypothesized that inflammation may be a common physiological pathway. The aim of the present study was to assess peripheral inflammatory markers in healthy women, women with antenatal depression, and in women using SSRI during pregnancy.

    Methods: 160 healthy pregnant controls, 59 women with antenatal depression and 39 women on treatment with SSRIs were included. The relative levels of 92 inflammatory proteins were analyzed by proximity extension assay technology.

    Results: Overall, 23 of the inflammatory markers were significantly lower in women with antenatal depression and in women on treatment with SSRIs in comparison with the healthy controls. No difference in any of the inflammatory markers was observed between women with antenatal depression and those who were using SSRI. Top three inflammatory markers that were down-regulated in women with antenatal depression were TNF-related apoptosis-inducing ligand (TRAIL), p = 0.000001, macrophage colony-stimulating factor 1 (CSF-1), p = 0.000004, and fractalkine (CX3CL1), p =0.000005. Corresponding inflammatory markers in SSRI users were CSF-1, p = 0.000011, vascular endothelial growth factor A (VEGF-A), p =0.000016, and IL-15 receptor subunit alpha (IL-15RA), p = 0.000027. The inflammatory markers were negatively correlated with cortisone serum concentrations in controls, but not in the cases. Differential DNA methylation of was found for seven of these inflammatory markers in an independent epigenetics cohort.

    Conclusion: Women with antenatal depression or on SSRI treatment have lower levels of a number of peripheral inflammatory markers than healthy pregnant controls. Hypothetically, this could be due to dysregulated switch to the pro-M2 milieu that characterizes normal third trimester pregnancy. However, longitudinal blood sampling is needed to elucidate whether the presumably dysregulated M2 shift is driving the development of antenatal depression or is a result of the depression.

  • 155.
    Elbere, Ilze
    et al.
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Silamikelis, Ivars
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Ustinova, Monta
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Kalnina, Ineta
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Zaharenko, Linda
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Peculis, Raitis
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Konrade, Ilze
    Riga East Clin Univ Hosp, 2 Hipokrata St, LV-1038 Riga, Latvia.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhukovsky, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gudra, Dita
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Radovica-Spalvina, Ilze
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Fridmanis, Davids
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Pirags, Valdis
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klovins, Janis
    Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
    Significantly altered peripheral blood cell DNA methylation profile as a result of immediate effect of metformin use in healthy individuals2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 156Article in journal (Refereed)
    Abstract [en]

    Background: Metformin is a widely prescribed antihyperglycemic agent that has been also associated with multiple therapeutic effects in various diseases, including several types of malignancies. There is growing evidence regarding the contribution of the epigenetic mechanisms in reaching metformin's therapeutic goals; however, the effect of metformin on human cells in vivo is not comprehensively studied. The aim of our study was to examine metformin-induced alterations of DNA methylation profiles in white blood cells of healthy volunteers, employing a longitudinal study design.

    Results: Twelve healthy metformin-naive individuals where enrolled in the study. Genome-wide DNA methylation pattern was estimated at baseline, 10h and 7days after the start of metformin administration. The whole-genome DNA methylation analysis in total revealed 125 differentially methylated CpGs, of which 11 CpGs and their associated genes with the most consistent changes in the DNA methylation profile were selected: POFUT2, CAMKK1, EML3, KIAA1614, UPF1, MUC4, LOC727982, SIX3, ADAM8, SNORD12B, VPS8, and several differentially methylated regions as novel potential epigenetic targets of metformin. The main functions of the majority of top-ranked differentially methylated loci and their representative cell signaling pathways were linked to the well-known metformin therapy targets: regulatory processes of energy homeostasis, inflammatory responses, tumorigenesis, and neurodegenerative diseases.

    Conclusions: Here we demonstrate for the first time the immediate effect of short-term metformin administration at therapeutic doses on epigenetic regulation in human white blood cells. These findings suggest the DNA methylation process as one of the mechanisms involved in the action of metformin, thereby revealing novel targets and directions of the molecular mechanisms underlying the various beneficial effects of metformin.Trial registrationEU Clinical Trials Register, 2016-001092-74. Registered 23 March 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001092-74/LV.

  • 156.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Functional and Molecular Characterization of Centrally Expressed Genes Associated with Obesity2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Obesity is a complex disorder that has reached epidemic proportions in the Western world, currently affection more than two billion people. The evidence for the genetic influence on obesity has been estimated to be as high as 70% based on twin studies. Subsequent application of genome wide association studies has identified more than 90 genes to be associated with BMI. Despite great efforts the majority of the identified genetic variants have an unknown link to BMI and lack scientific basis explaining how they affect energy balance resulting in altered body weight. This thesis aims to characterize seven BMI-associated genes, Coronin 7, Etv5, Mtch2, Nudt3, Raptor, Sh2b1 and Vps13B by performing a molecular and functional profiling in mouse, zebrafish and fruit fly. A screen analysing the regulation of the selected genes under different dietary conditions revealed altered transcript levels in mouse, zebrafish and fruit fly including a conserved regulation in all species for some of the genes. Using genetic tools the Nudt3 homolog Aps in the Drosophila CNS was knocked down and showed that Aps has a role in the regulation of insulin signaling which could explain the robust association to obesity in humans. A comprehensive in situ hybridization revealed abundant Nudt3 mRNA and protein expression throughout the brain, including in reward and feeding related regions of the hypothalamus while Nudt3 mRNA expression was significantly up-regulated in the same region of food-deprived mice. Furthermore, we were able to identify a novel molecular link between obesity and bipolar disorder. The Drosophila homologue Ets96B regulates the expression of a cellular system with links to obesity and bipolar disorder, including the expression of a conserved endoplasmic reticulum molecular chaperone complex. A connection between the obesity-linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and bipolar disorder at the molecular level. Furthermore, as the BMI associated genetic variants does not fully explain the heritability of obesity we decided to perform a genome wide DNA methylation profile where we compared normal-weight and obese preadolescent children. We found a CpG site located near Coronin 7 to have significantly lower methylation levels in obese children. Further studies showed Coronin 7 to be highly expressed in important brain regions involved in energy balance. Strong immunostaining was also seen in locus coeruleus, the main site for noradrenergic production, and injecting mice with an appetite suppressant increased the number of Coronin 7 neurons within the very same brain region. An evolutionary conserved metabolic function in Drosophila was also demonstrated by knocking down the Coronin 7 homologue Pod1 in the fruit fly adult nervous system.

  • 157.
    Eriksson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hansson, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krishnan, Arunkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Philippot, Gaetan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Yamskova, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Herisson, Florence M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dnyansagar, Rohit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Manios, Yannis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, George P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Frediksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Implication of coronin 7 in body weight regulation in humans, mice and flies2015In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 16, article id 13Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects. Results: We performed genome wide DNA methylation profiling comparing normal-weight and obese 9-13 year old children to investigate possible epigenetic changes correlated with obesity. Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein most likely involved in Golgi complex morphology and function. Anatomical profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions, including the hypothalamus, striatum and locus coeruleus, the main noradrenergic brain site. Interestingly, we found that food deprivation in mice downregulates hypothalamic Coro7 mRNA levels, and injecting ethanol, an appetite stimulant, increased the number of Coro7 expressing cells in the locus coeruleus. Finally, by employing the genetically-tractable Drosophila melanogaster model we were able to demonstrate an evolutionarily conserved metabolic function for the CORO7 homologue pod1. Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression. Conclusion: We conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward.

  • 158. Feld, Gordon B
    et al.
    Wilhem, Ines
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rüdel, Benjamin
    Klameth, Corinna
    Born, Jan
    Hallschmid, Manfred
    Central Nervous Insulin Signaling in Sleep-Associated Memory Formation and Neuroendocrine Regulation2016In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, no 6, p. 1540-1550Article in journal (Refereed)
    Abstract [en]

    The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18-30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information.

  • 159.
    Fredriksson, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hägglund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stephansson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewska, Agnieszka M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain2008In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 5, p. 2062-71Article in journal (Refereed)
    Abstract [en]

    Gene variants of the FTO (fatso) gene have recently been strongly associated with body mass index and obesity. The FTO gene is well conserved and found in a single copy in vertebrate species including fish and chicken, suggesting that the ancestor of this gene was present 450 million years ago. Surprisingly, the FTO gene is present in two species of algae but not in any other invertebrate species. This could indicate that this gene has undergone a horizontal gene transfer. Quantitative real-time PCR showed that the gene is expressed in many peripheral and central rat tissues. Detailed in situ hybridization analysis in the mouse brain showed abundant expression in feeding-related nuclei of the brainstem and hypothalamus, such as the nucleus of the solitary tract, area postrema, and arcuate, paraventricular, and supraoptic nuclei as well as in the bed nucleus of the stria terminalis. Colabeling showed that the FTO gene is predominantly expressed in neurons, whereas it was virtually not found in astrocytes or glia cells. The FTO was significantly up-regulated (41%) in the hypothalamus of rats after 48-h food deprivation. We also found a strong negative correlation of the FTO expression level with the expression of orexigenic galanin-like peptide, which is mainly synthesized in the arcuate nucleus. These results are consistent with the hypothesis that FTO could participate in the central control of energy homeostasis.

  • 160.
    Fredriksson, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordström, Karl J V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stephansson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hägglund, Maria G A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families2008In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 582, no 27, p. 3811-3816Article in journal (Refereed)
    Abstract [en]

    Solute carriers (SLCs) is the largest group of transporters, embracing transporters for inorganic ions, amino acids, neurotransmitters, sugars, purines and fatty acids among other substrates. We mined the finished assembly of the human genome using Hidden Markov Models (HMMs) obtaining a total of 384 unique SLC sequences. Detailed clustering and phylogenetic analysis of the entire SLC family showed that 15 of the families place into four large phylogenetic clusters with the largest containing eight SLC families, suggesting that many of the distinct families of SLCs have a common evolutionary origin. This study represents the first overall genomic roadmap of the SLCs providing large sequence sets and clarifies the phylogenetic relationships among the families of the second largest group of membrane proteins.

  • 161. Freiherr, Jessica
    et al.
    Hallschmid, Manfred
    Frey, William H., II
    Bruenner, Yvonne F.
    Chapman, Colin D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hoelscher, Christian
    Craft, Suzanne
    De Felice, Fernanda G.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Intranasal Insulin as a Treatment for Alzheimer's Disease: A Review of Basic Research and Clinical Evidence2013In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 27, no 7, p. 505-514Article, review/survey (Refereed)
    Abstract [en]

    Research in animals and humans has associated Alzheimer's disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism-such as insulin resistance in obesity, type 2 diabetes and AD-and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.

  • 162.
    Fridmanis, Davids
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Petrovska, Ramona
    Pjanova, Dace
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Replacement of short segments within transmembrane domains of MC2R disrupts retention signal2014In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 53, no 2, p. 201-215Article in journal (Refereed)
    Abstract [en]

    The proteolysis of the pro-opiomelanocortin precursor results in the formation of melanocortins (MCs), a group of peptides that share the conserved -H-F-R-W- sequence, which acts as a pharmacophore for five subtypes of MC receptors (MCRs). MC type 2 receptor (MC2R; also known as ACTHR) is the most specialized of all the MCRs. It is predominantly expressed in the adrenal cortex and specifically binds ACTH. Unlike other MCRs, it requires melanocortin receptor accessory protein 1 (MRAP) for formation of active receptor and for its transport to the cell membrane. The molecular mechanisms underlying this specificity remain poorly understood. In this study, we used directed mutagenesis to investigate the role of various short MC2R sequence segments in receptor membrane trafficking and specific activation upon stimulation with ligands. The strategy of the study was to replace two to five amino acid residues within one MC2R segment with the corresponding residues of MC4R. In total, 20 recombinant receptors C-terminally fused to enhanced green fluorescent protein were generated and their membrane trafficking efficiencies and cAMP response upon stimulation with α-MSH and ACTH(1-24) were estimated during their stand-alone expression and coexpression with MRAP. Our results indicate that both the motif that determines the ligand-recognition specificity and the intracellular retention signal are formed by a specific extracellular structure, which is supported by the correct alignment of the transmembrane domains. Our results also indicate that the aromatic-residue-rich segment of the second extracellular loop is involved in the effects mediated by the second ACTH pharmacophore (-K-K-R-R-).

  • 163.
    Gaston, M. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    De Barioglio, S. R.
    Salvatierra, N. A.
    Gabaergic control of anxiety-like behavior, but not food intake, induced by ghrelin in the intermediate medial mesopallium of the neonatal chick2015In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 67, p. 66-72Article in journal (Refereed)
    Abstract [en]

    Ghrelin (Grh) is an endogenous ligand of the growth hormone secretagogue receptor. In neonatal chicks, central Ghr induces anxiogenic-like behavior but strongly inhibits food intake. The intermediate medial mesopallium (IMM) of the chick forebrain has been identified to be a site of the memory formation, and the modulation of the GABA(A) receptors that are present here modifies the expression of behavior. Thus, the GABAergic system may constitute a central pathway for Ghr action in regulating the processes of food intake and stress-related behaviors. Therefore, we investigated if the effect of systemic administration of bicuculline (GABA(A) receptor antagonist) and diazepam (benzodiazepine receptor agonist) on the anxiety in an Open Field test and inhibition in food intake induced by Grh (30 pmol) when injected into IMM, were mediated by GABAergic transmission. In Open Field test, bicuculline was able to block the anxiogenic-like behavior induced by Ghr, whereas diazepam did not produce it. However, the co-administration of bic-uculline or diazepam plus Ghr did not show any change in food intake at 30,60 and 120 min after injection compared to Ghr alone. Our results indicate for the first time that Ghr, injected into the forebrain IMM area, induces an anxiogenic-like behavior, which was blocked by bicuculline but not diazepam, thus suggesting that Ghr plays an important role in the response pattern to acute stressor, involving the possible participation of the GABAergic system. Nevertheless, as neither drug affected the hypophagia induced by intra-IMM Ghr, this suggests that it may be mediated by different mechanisms.

  • 164.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha Jane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Riva, Giuseppe
    Nonvisual Multisensory Impairment of Body Perception in Anorexia Nervosa: A Systematic Review of Neuropsychological Studies2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110087-Article in journal (Refereed)
    Abstract [en]

    Background: Body image distortion is a central symptom of Anorexia Nervosa (AN). Even if corporeal awareness is multisensory majority of AN studies mainly investigated visual misperception. We systematically reviewed AN studies that have investigated different nonvisual sensory inputs using an integrative multisensory approach to body perception. We also discussed the findings in the light of AN neuroimaging evidence. Methods: Pub Med and PsycINFO were searched until March, 2014. To be included in the review, studies were mainly required to: investigate a sample of patients with current or past AN and a control group and use tasks that directly elicited one or more nonvisual sensory domains. Results:Thirteen studies were included. They studied a total of 223 people with current or past AN and 273 control subjects. Overall, results show impairment in tactile and proprioceptive domains of body perception in AN patients. lnteroception and multisensory integration have been poorly explored directly in AN patients. A limitation of this review is the relatively small amount of literature available. Conclusions: Our results showed that AN patients had a multisensory impairment of body perception that goes beyond visual misperception and involves tactile and proprioceptive sensory components. Furthermore, impairment of tactile and proprioceptive components may be associated with parietal cortex alterations in AN patients. Interoception and multisensory integration have been weakly explored directly. Further research, using multisensory approaches as well as neuroimaging techniques, is needed to better define the complexity of body image distortion in AN. Key Findings: The review suggests an altered capacity of AN patients in processing and integration of bodily signals: body parts are experienced as dissociated from their holistic and perceptive dimensions. Specifically, it is likely that not only perception but memory, and in particular sensorimotor/proprioceptive memory, probably shapes bodily experience in patients with AN.

  • 165.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dakanalis, Antonios
    Univ Milano Bicocca, Dept Med & Surg, Monza, Italy..
    Personality and eating and weight disorders: an open research challenge2018In: Eating and Weight Disorders, ISSN 1124-4909, E-ISSN 1590-1262, Vol. 23, no 2, p. 143-147Article in journal (Other academic)
  • 166.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dakanalis, Antonios
    Univ Milano Bicocca, Dept Med & Surg, Monza, Italy..
    What about the assessment of personality disturbance in adolescents with eating disorders?2017In: Eating and Weight Disorders, ISSN 1124-4909, E-ISSN 1590-1262, Vol. 22, no 3, p. 551-552Article in journal (Other academic)
  • 167.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Eating Disorders Ctr La Cura Girasole ONLUS, Via Gregorio 7,186-B, I-00165 Rome, Italy;Univ Campus Biomed Roma, Departmental Fac Med & Surg, Area Diagnost Imaging, Via Alvaro del Portillo 200, I-00133 Rome, Italy.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zobel, Bruno Beomonte
    Univ Campus Biomed Roma, Departmental Fac Med & Surg, Area Diagnost Imaging, Via Alvaro del Portillo 200, I-00133 Rome, Italy.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Altered cerebellar-insular-parietal-cingular subnetwork in adolescents in the earliest stages of anorexia nervosa: a network-based statistic analysis2018In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 127Article in journal (Refereed)
    Abstract [en]

    To date, few functional magnetic resonance imaging (fMRI) studies have explored resting-state functional connectivity (RSFC) in long-lasting anorexia nervosa (AN) patients via graph analysis. The aim of the present study is to investigate, via a graph approach (i.e., the network-based statistic), RSFC in a sample of adolescents at the earliest stages of AN (i.e., AN duration less than 6 months). Resting-state fMRI data was obtained from 15 treatment-naive female adolescents with AN restrictive type (AN-r) in its earliest stages and 15 age-matched healthy female controls. A network-based statistic analysis was used to isolate networks of interconnected nodes that differ between the two groups. Group comparison showed a decreased connectivity in a sub-network of connections encompassing the left and right rostral ACC, left paracentral lobule, left cerebellum (10th sub-division), left posterior insula, left medial fronto-orbital gyrus, and right superior occipital gyrus in AN patients. Results were not associated to alterations in intranodal or global connectivity. No sub-networks with an increased connectivity were identified in AN patients. Our findings suggest that RSFC may be specifically affected at the earliest stages of AN. Considering that the altered sub-network comprises areas mainly involved in somatosensory and interoceptive information and processing and in emotional processes, it could sustain abnormal integration of somatosensory and homeostatic signals, which may explain body image disturbances in AN. Further studies with larger samples and longitudinal designs are needed to confirm our findings and better understand the role and consequences of such functional alterations in AN.

  • 168.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Campus Biomed Roma, Dept Fac Med & Surg, Rome, Italy.;Eating Disorders Ctr La Cura Girasole ONLUS, Rome, Italy..
    Quattrocchi, Carlo Cosimo
    Univ Campus Biomed Roma, Dept Fac Med & Surg, Rome, Italy..
    Piervincenzi, Claudia
    Sapienza Univ, Dept Physiol & Pharmacol, Neuroimaging Lab, Rome, Italy..
    Zobel, Bruno Beomonte
    Univ Campus Biomed Roma, Dept Fac Med & Surg, Rome, Italy..
    Montecchi, Francesca Romana
    Eating Disorders Ctr La Cura Girasole ONLUS, Rome, Italy..
    Dakanalis, Antonios
    Univ Pavia, Dept Brain & Behav Sci, Pza Botta 11, I-27100 Pavia, Italy.;Univ Milano Bicocca, Dept Med & Surg, Milan, Italy..
    Riva, Giuseppe
    Ist Auxol Italian, Appl Technol Neuropsychol Lab, Milan, Italy.;Univ Cattolica Sacro Cuore, Dept Psychol, Milan, Italy..
    Carducci, Filippo
    Sapienza Univ, Dept Physiol & Pharmacol, Neuroimaging Lab, Rome, Italy..
    White matter abnormalities in treatment-naive adolescents at the earliest stages of Anorexia Nervosa: A diffusion tensor imaging study2017In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 266, p. 138-145Article in journal (Refereed)
    Abstract [en]

    Few studies have examined white matter (WM) integrity in long-lasting Anorexia Nervosa (AN) patients using Diffusion Tensor Imaging (DTI). In this paper, we investigated WM integrity at the earliest stages of AN (i.e. less than 6 months duration). Fourteen treatment-naive female adolescents with AN restrictive type (AN-r) in its earliest stages and 15 age-matched healthy females received brain MRI. Fractional Anisotropy (FA), Axial Diffusivity (AD), Radial diffusivity (RD), and Mean Diffusivity (MD) maps were computed from DTI data using Tract-Based Spatial Statistics analysis. AN-r patients showed FA decreases compared to controls (p(FwE) < 0.05) mainly in left anterior and superior corona radiata and left superior longitudinal fasciculus. AN-r patients also showed decreased AD in superior longitudinal fasciculus bilaterally and left superior and anterior corona radiata, (p(FwE) < 0.05). No significant differences were found in RD and MD values between the two groups. FA and AD integrity appears to be specifically affected at the earliest stages of AN. Alterations in the microstructural properties of the above mentioned tracts, also involved in cognitive control and visual perception and processing, may be early mechanisms of vulnerability/resilience of WM in AN and sustain the key symptoms of AN, such as impaired cognitive flexibility and body image distortion.

  • 169.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Campus Biomed Roma, Ctr Integrated Res, Area Diagnost Imaging, Via Alvaro Portillo 200, I-00133 Rome, Italy..
    Wiemerslage, Lyle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Cape Town, Dept Psychiat & Mental Hlth, Old Groote Schuur Hosp, Psychiat Neuroimaging Grp, Anzio Rd, ZA-7925 Cape Town, South Africa..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A systematic review of resting-state functional-MRI studies in anorexia nervosa: Evidence for functional connectivity impairment in cognitive control and visuospatial and body-signal integration2016In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 71, p. 578-589Article, review/survey (Refereed)
    Abstract [en]

    This paper systematically reviews the literature pertaining to the use of resting-state functional magnetic resonance imaging (rsfMRI) in anorexia nervosa (AN), classifying studies on the basis of different analysis approaches. We followed PRISMA guidelines. Fifteen papers were included, investigating a total of 294 participants with current or past AN and 285 controls. The studies used seed-based, whole-brain independent component analysis (ICA), network-of-interest ICA based and graph analysis approaches. The studies showed relatively consistent overlap in results, yet little overlap in their analytical approach and/or a-priori assumptions. Functional connectivity alterations were mainly found in the corticolimbic circuitry, involved in cognitive control and visual and homeostatic integration. Some overlapping findings were found in brain areas putatively important in AN, such as the insula. These results suggest altered functional connectivity in networks/areas linked to the main symptom domains of AN, such as impaired cognitive control and body image disturbances. These preliminary evidences suggest that more targeted treatments need to be developed that focus on these two symptom domains. Further studies with multi-approach analyses and longitudinal designs are needed to better understand the complexity of AN.

  • 170.
    Ghersi, Marisa S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gabach, L A
    Buteler, F
    Vilcaes, A A
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perez, M F
    de Barioglio, S R
    Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 10, p. 1843-1857Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Ghrelin (Ghr) is a peptide that participates in the modulation of several biological processes. Ghr administration into the hippocampus improves learning and memory in different memory tests. However, the possible mechanisms underlying this effect on memory have not yet been clarified.

    OBJECTIVE: The purpose of the present work is to add new insights about the mechanisms by which Ghr modulates long-term memory consolidation in the hippocampus. We examined Ghr effects upon processes related to increased synaptic efficacy as presynaptic glutamate release and changes in the expression of the NR2B-subunits containing n-methyl-d-aspartate receptors (NMDAR), which are critical for LTP induction. We also attempted to determine the temporal window in which Ghr administration induces memory facilitation and if the described effects depend on GHS-R1a stimulation.

    RESULTS: The present research demonstrated that Ghr increased glutamate release from hippocampal synaptosomes; intra-hippocampal Ghr administration increased NR2B-subunits expression in CA1 and DG subareas and also reversed the deleterious effects of the NR2B-subunit-specific antagonist, Ro 25-6981, upon memory consolidation and LTP generation in the hippocampus. These effects are likely to be the consequence of GHS-R1a activation.

    CONCLUSION: According to the results above mentioned and previous findings, we can hypothesize some of the mechanisms by which Ghr modulates memory consolidation. At presynaptic level, Ghr stimulates glutamate release, probably by enhancing [Ca(2+)]i. At postsynaptic level, the glutamate released activates NMDAR while Ghr also mediates effects directly activating its specific receptors and increases NR2B-subunit expression.

  • 171.
    Ghersi, Marisa Soledad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Casas, Sebastian M.
    Escudero, Carla
    Carlini, Valeria P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Buteler, Florencia
    Cabrera, Ricardo J.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Barioglio, Susana R.
    Ghrelin inhibited serotonin release from hippocampal slices2011In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, no 11, p. 2367-2371Article in journal (Refereed)
    Abstract [en]

    Ghrelin (Ghr) is a peptide produced peripherally and centrally. It participates in the modulation of different biological processes. In our laboratory we have shown that (a) Ghr administration, either intracerebroventricular or directly into the hippocampus enhanced memory consolidation in a step down test in rats (b) the effect of Ghr upon memory decreases in animals pretreated with a serotonin (5-HT) reuptake inhibitor, Fluoxetine, suggesting that Ghr effects in the hippocampus could be related to the availability of 5-HT. It has been demonstrated that Ghr inhibits 5-HT release from rat hypothalamic synaptosomes. Taking in mint these evidences, we studied the release of radioactive 5-HT to the superfusion medium from hippocampal slices treated with two doses of Ghr (0.3 and 3 nm/mu l). Ghr inhibited significantly the 5-HT release in relation to those superfused with artificial cerebrospinal fluid (ACSF) (H = 9.48, df = 2, p <= 0.05). In another set of experiments. Ghr was infused into the CA1 area of hippocampus of the rats immediately after training in the step down test and the 5-HT release from slices was studied 24 h after Ghr injection showing that in this condition also the 5-HT release was inhibited (H = 11.72, df = 1, p < 0.05). In conclusion, results provide additional evidence about the neurobiological bases of Ghr action in hippocampus.

  • 172.
    Goergen, Philip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Molecular Mechanism of Aggression and Feeding Behaviour in Drosophila melanogaster2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Obesity is a complex disorder which has become a growing health concern. Twin studies have demonstrated a strong genetic component to the development of obesity and genome wide association studies have identified several genetic loci associated with it. However, most of these loci are still poorly understood in a functional context. Interestingly, many of the hormones and neurobiological messengers responsible for regulating feeding behaviour and metabolism are also linked to controlling aggression, but it is still not understood how they interact to maintain metabolic homeostasis. In this thesis, the model organism Drosophila melanogaster was employed to dissect the molecular mechanisms of the genetic cascades regulating aggressive behaviour and metabolic homeostasis.

    In paper I and II, the role of transcription factor AP-2 (TfAP-2) and Tiwaz Twz, Drosophila homologues of two human obesity-linked genes were investigated in aggression and feeding behaviour. Paper I demonstrated that TfAP-2 and Twz genetically interact in octopaminergic neurons to modulate male aggression by controlling the expression of genes necessary for octopamine (fly analogue of noradrenaline) production and secretion. Moreover, it was revealed that octopamine in turn regulates aggression through the Drosophila cholecystokinin (CCK) satiation hormone homologue Drosulfakinin (Dsk). Paper II revealed that TfAP-2 and Twz also initiate feeding through regulation of octopamine poduction and secretion. Octopamine then induces Dsk expression leading to inhibition of feeding.

    Paper III established that the activity of the small GTPase Ras-related C3 botulinum toxin substrate 2 (Rac2) is required in Drosophila for the proper regulation of metabolic homeostasis, as well as overt behaviours. Rac2 mutants were starvation susceptible, had less lipids and exhibited disrupted feeding behaviour. Moreover, they displayed aberrant aggression and courtship behaviour towards conspecifics.

    Paper IV studied Protein kinase D (PKD), the homologue of a third obesity-linked gene PRKD1, and another kinase Stretchin-Mlck (Strn-Mlck). Reducing PKD transcript levels in the insulin producing cells led to flies with increased starvation susceptibility, decreased levels of lipids and diminished insulin signalling compared to controls. Reduced Strn-Mlck expression resulted in a starvation phenotype and slight reduction in insulin signalling and lipid content. These findings imply a function for PKD and Strn-Mlck in insulin release.

  • 173.
    Goergen, Philip
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kasagiannis, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Drosophila Small GTPase Rac2 is Required for Normal Feeding and Mating Behaviour.2014In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 44, no 2, p. 155-64Article in journal (Refereed)
    Abstract [en]

    All multicellular organisms require the ability to regulate bodily processes in order to maintain a stable condition, which necessitates fluctuations in internal metabolics, as well as modifications of outward behaviour. Understanding the genetics behind this modulation is important as a general model for the metabolic modification of behaviour. This study demonstrates that the activity of the small GTPase Rac2 is required in Drosophila for the proper regulation of lipid storage and feeding behaviour, as well as aggression and mating behaviours. Rac2 mutant males and females are susceptible to starvation and contain considerably less lipids than controls. Furthermore, Rac2 mutants also have disrupted feeding behaviour, eating fewer but larger meals than controls. Intriguingly, Rac2 mutant males rarely initiate aggressive behaviour and display significantly increased levels of courtship behaviour towards other males and mated females. From these results we conclude that Rac2 has a central role in regulating the Drosophila homeostatic system.

  • 174.
    Goergen, Philip
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Khan, Zaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Akber, Mira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The serine/theorine kinases, Protein kinase D and Stretchin-Mlck, are necessary for proper insulin signalling in Drosophila.Manuscript (preprint) (Other academic)
  • 175. Gonzalez, P.
    et al.
    Machado, I.
    Vilcaes, A.
    Caruso, C.
    Roth, G. A.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lasaga, M.
    Scimonelli, T.
    Molecular mechanisms involved in interleukin 1-beta (IL-1 beta)-induced memory impairment. Modulation by alpha-melanocyte-stimulating hormone (alpha-MSH)2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 34, p. 141-150Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory cytokines can affect cognitive processes such as learning and memory. Particularly, interleukin-1 beta (IL-1 beta) influences the consolidation of hippocampus-dependent memories. We previously reported that administration of IL-1 beta in dorsal hippocampus impaired contextual fear memory consolidation. Different mechanisms have been implicated in the action of IL-1 beta on long-term potentiation (LTP), but the processes by which this inhibition occurs in vivo remain to be elucidated. We herein report that intrahippocampal injection of IL-1 beta induced a significant increase in p38 phosphorylation after contextual fear conditioning. Also, treatment with SB203580, an inhibitor of p38, reversed impairment induced by IL-1 beta on conditioned fear behavior, indicating that this MAPK would be involved in the effect of the cytokine. We also showed that IL-1 beta administration produced a decrease in glutamate release from dorsal hippocampus synaptosomes and that treatment with SB203580 partially reversed this effect. Our results indicated that IL-1 beta-induced impairment in memory consolidation could be mediated by a decrease in glutamate release. This hypothesis is sustained by the fact that treatment with D-cycloserine (DCS), a partial agonist of the NMDA receptor, reversed the effect of IL-1 beta on contextual fear memory. Furthermore, we demonstrated that IL-1 beta produced a temporal delay in ERK phosphorylation and that DCS administration reversed this effect. We also observed that intrahippocampal injection of IL-1 beta decreased BDNF expression after contextual fear conditioning. We previously demonstrated that alpha-MSH reversed the detrimental effect of IL-1 beta on memory consolidation. The present results demonstrate that alpha-MSH administration did not modify the decrease in glutamate release induced by IL-1 beta. However, intrahippocampal injection of alpha-MSH prevented the effect on ERR phosphorylation and BDNF expression induced by IL-1 beta after contextual fear conditioning. Therefore, in the present study we determine possible molecular mechanisms involved in the impairment induced by IL-1 beta on fear memory consolidation. We also established how this effect could be modulated by alpha-MSH.

  • 176. Gonzalez, Patricia Verónica
    et al.
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lasaga, Mercedes
    Scimonelli, Teresa Nieves
    Memory impairment induced by IL-1beta is reversed by alpha-MSH through central melanocortin-4 receptors2009In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 23, no 6, p. 817-822Article in journal (Refereed)
    Abstract [en]

    Interleukin-1beta (IL-1beta) significantly influences memory consolidation. Treatments that raise the level of IL-1beta in the brain, given after training, impair contextual fear conditioning. The melanocortin alpha-MSH exerts potent anti-inflammatory actions by physiologically antagonizing the effect of pro-inflammatory cytokines. Five subtypes of melanocortin receptors (MC1R-MC5R) have been identified, with MC3R and MC4R predominating in the central nervous system. The present experiments show that injection of IL-1beta (5 ng/0.25 microl) in dorsal hippocampus up to 15 min after training decreased freezing during the contextual fear test. The treatment with IL-1beta (5 ng/0.25 microl) 12h after conditioning cause amnesia when animals were tested 7 days post training. Thus, our results also demonstrated that IL-1beta can influence persistence of long-term memory. We determined that animals previously injected with IL-1beta can acquire a new contextual fear memory, demonstrating that the hippocampus was not damaged. Treatment with alpha-MSH (0.05 microg/0.25 microl) blocked the effect of IL-1beta on contextual fear memory. Administration of the MC4 receptor antagonist HS014 (0.5 microg/0.25 microl) reversed the effect of alpha-MSH. However, treatment with gamma-MSH (0.5 microg/0.25 microl), an MC3 agonist, did not affect IL-1beta-induced impairment of memory consolidation. These results suggest that alpha-MSH, through central MC4R can inhibit the effect of IL-1beta on memory consolidation.

  • 177.
    Gremel, Gabriela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fagerberg, Linn
    Hallström, Björn
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling.2015In: Journal of gastroenterology, ISSN 0944-1174, E-ISSN 1435-5922, Vol. 50, no 1, p. 46-57Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The gastrointestinal tract (GIT) is subdivided into different anatomical organs with many shared functions and characteristics, but also distinct differences. We have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to describe the gene and protein expression patterns that define the human GIT.

    METHODS: RNA sequencing data derived from stomach, duodenum, jejunum/ileum and colon specimens were compared to gene expression levels in 23 other normal human tissues analysed with the same method. Protein profiling based on immunohistochemistry and tissue microarrays was used to sub-localize the corresponding proteins with GIT-specific expression into sub-cellular compartments and cell types.

    RESULTS: Approximately 75 % of all human protein-coding genes were expressed in at least one of the GIT tissues. Only 51 genes showed enriched expression in either one of the GIT tissues and an additional 83 genes were enriched in two or more GIT tissues. The list of GIT-enriched genes with validated protein expression patterns included various well-known but also previously uncharacterised or poorly studied genes. For instance, the colon-enriched expression of NXPE family member 1 (NXPE1) was established, while NLR family, pyrin domain-containing 6 (NLRP6) expression was primarily found in the human small intestine.

    CONCLUSIONS: We have applied a genome-wide analysis based on transcriptomics and antibody-based protein profiling to identify genes that are expressed in a specific manner within the human GIT. These genes and proteins constitute important starting points for an improved understanding of the normal function and the different states of disease associated with the GIT.

  • 178.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Foord, Steven M.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gloriam, David E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The G protein-coupled receptor subset of the dog genome is more similar to that in humans than rodents2009In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 10, p. 24-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    The dog is an important model organism and it is considered to be closer to humans than rodents regarding metabolism and responses to drugs. The close relationship between humans and dogs over many centuries has lead to the diversity of the canine species, important genetic discoveries and an appreciation of the effects of old age in another species. The superfamily of G protein-coupled receptors (GPCRs) is one of the largest gene families in most mammals and the most exploited in terms of drug discovery. An accurate comparison of the GPCR repertoires in dog and human is valuable for the prediction of functional similarities and differences between the species.

    RESULTS

    We searched the dog genome for non-olfactory GPCRs and obtained 353 full-length GPCR gene sequences, 18 incomplete sequences and 13 pseudogenes. We established relationships between human, dog, rat and mouse GPCRs resolving orthologous pairs and species-specific duplicates. We found that 12 dog GPCR genes are missing in humans while 24 human GPCR genes are not part of the dog GPCR repertoire. There is a higher number of orthologous pairs between dog and human that are conserved as compared with either mouse or rat. In almost all cases the differences observed between the dog and human genomes coincide with other variations in the rodent species. Several GPCR gene expansions characteristic for rodents are not found in dog.

    CONCLUSION

    The repertoire of dog non-olfactory GPCRs is more similar to the repertoire in humans as compared with the one in rodents. The comparison of the dog, human and rodent repertoires revealed several examples of species-specific gene duplications and deletions. This information is useful in the selection of model organisms for pharmacological experiments.

  • 179.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stephansson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat2008In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 9, p. 43-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    The Adhesion G protein-coupled receptors (GPCRs) are membrane-bound receptors with long N termini. This family has 33 members in humans. Several Adhesion GPCRs are known to have important physiological functions in CNS development and immune system response mediated by large cell surface ligands. However, the majority of Adhesion GPCRs are still poorly studied orphans with unknown functions.

    RESULTS

    In this study we performed the extensive tissue localization analysis of the entire Adhesion GPCR family in rat and mouse. By applying the quantitative real-time PCR technique we have produced comparable expression profile for each of the members in the Adhesion family. The results are compared with literature data and data from the Allen Brain Atlas project. Our results suggest that the majority of the Adhesion GPCRs are either expressed in the CNS or ubiquitously. In addition the Adhesion GPCRs from the same phylogenetic group have either predominant CNS or peripheral expression, although each of their expression profile is unique.

    CONCLUSION

    Our findings indicate that many of Adhesion GPCRs are expressed, and most probably, have function in CNS. The related Adhesion GPCRs are well conserved in their structure and interestingly have considerable overlap in their expression profiles, suggesting similarities among the physiological roles for members within many of the phylogenetically related clusters.

  • 180. Hamann, Joerg
    et al.
    Aust, Gabriela
    Arac, Demet
    Engel, Felix B.
    Formstone, Caroline
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hall, Randy A.
    Harty, Breanne L.
    Kirchhoff, Christiane
    Knapp, Barbara
    Krishnan, Arunkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Liebscher, Ines
    Lin, Hsi-Hsien
    Martinelli, David C.
    Monk, Kelly R.
    Peeters, Miriam C.
    Piao, Xianhua
    Proemel, Simone
    Schoeneberg, Torsten
    Schwartz, Thue W.
    Singer, Kathleen
    Stacey, Martin
    Ushkaryov, Yuri A.
    Vallon, Mario
    Wolfrum, Uwe
    Wright, Mathew W.
    Xu, Lei
    Langenhan, Tobias
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors2015In: Pharmacological Reviews, ISSN 0031-6997, E-ISSN 1521-0081, Vol. 67, no 2, p. 338-367Article, review/survey (Refereed)
    Abstract [en]

    The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.

  • 181.
    Harty, Breanne L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krishnan, Arunkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sanchez, Nicholas E.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Monk, Kelly R.
    Defining the gene repertoire and spatiotemporal expression profiles of adhesion G protein-coupled receptors in zebrafish2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 62Article in journal (Refereed)
    Abstract [en]

    Background: Adhesion G protein-coupled receptors (aGPCRs) are the second largest of the five GPCR families and are essential for a wide variety of physiological processes. Zebrafish have proven to be a very effective model for studying the biological functions of aGPCRs in both developmental and adult contexts. However, aGPCR repertoires have not been defined in any fish species, nor are aGPCR expression profiles in adult tissues known. Additionally, the expression profiles of the aGPCR family have never been extensively characterized over a developmental time-course in any species. Results: Here, we report that there are at least 59 aGPCRs in zebrafish that represent homologs of 24 of the 33 aGPCRs found in humans; compared to humans, zebrafish lack clear homologs of GPR110, GPR111, GPR114, GPR115, GPR116, EMR1, EMR2, EMR3, and EMR4. We find that several aGPCRs in zebrafish have multiple paralogs, in line with the teleost-specific genome duplication. Phylogenetic analysis suggests that most zebrafish aGPCRs cluster closely with their mammalian homologs, with the exception of three zebrafish-specific expansion events in Groups II, VI, and VIII. Using quantitative real-time PCR, we have defined the expression profiles of 59 zebrafish aGPCRs at 12 developmental time points and 10 adult tissues representing every major organ system. Importantly, expression profiles of zebrafish aGPCRs in adult tissues are similar to those previously reported in mouse, rat, and human, underscoring the evolutionary conservation of this family, and therefore the utility of the zebrafish for studying aGPCR biology. Conclusions: Our results support the notion that zebrafish are a potentially useful model to study the biology of aGPCRs from a functional perspective. The zebrafish aGPCR repertoire, classification, and nomenclature, together with their expression profiles during development and in adult tissues, provides a crucial foundation for elucidating aGPCR functions and pursuing aGPCRs as therapeutic targets.

  • 182. Hauser, Alexander S
    et al.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gloriam, David E
    Trends in GPCR drug discovery: new agents, targets and indications2017In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 16, no 12, p. 829-842Article in journal (Refereed)
    Abstract [en]

    G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

  • 183.
    Heany, Sarah J.
    et al.
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa..
    van Honk, Jack
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa.;Univ Utrecht, Dept Psychol, Utrecht, Netherlands.;Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa..
    Stein, Dan J.
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa..
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa..
    A quantitative and qualitative review of the effects of testosterone on the function and structure of the human social-emotional brain2016In: Metabolic brain disease, ISSN 0885-7490, E-ISSN 1573-7365, Vol. 31, no 1, p. 157-167Article in journal (Refereed)
    Abstract [en]

    Social and affective research in humans is increasingly using functional and structural neuroimaging techniques to aid the understanding of how hormones, such as testosterone, modulate a wide range of psychological processes. We conducted a meta-analysis of functional magnetic resonance imaging (fMRI) studies of testosterone administration, and of fMRI studies that measured endogenous levels of the hormone, in relation to social and affective stimuli. Furthermore, we conducted a review of structural MRI i.e. voxel based morphometry (VBM) studies which considered brain volume in relation to testosterone levels in adults and in children. In the included testosterone administration fMRI studies, which consisted of female samples only, bilateral amygdala/parahippocampal regions as well as the right caudate were significantly activated by social-affective stimuli in the testosterone condition. In the studies considering endogenous levels of testosterone, stimuli-invoked activations relating to testosterone levels were noted in the bilateral amygdala/parahippocampal regions and the brainstem. When the endogenous testosterone studies were split by sex, the significant activation of the brain stem was seen in the female samples only. Significant stimuli-invoked deactivations relating to endogenous testosterone levels were also seen in the right and left amygdala/parahippocampal regions studies. The findings of the VBM studies were less consistent. In adults larger volumes in the limbic and temporal regions were associated with higher endogenous testosterone. In children, boys showed a positive correlation between testosterone and brain volume in many regions, including the amygdala, as well as global grey matter volume, while girls showed a neutral or negative association between testosterone levels and many brain volumes. In conclusion, amygdalar and parahippocampal regions appear to be key target regions for the acute actions of testosterone in response to social and affective stimuli, while neurodevelopmentally the volumes of a broader network of brain structures are associated with testosterone levels in a sexually dimorphic manner.

  • 184.
    Hellsten, Sofie V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hägglund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The neuronal and astrocytic protein SLC38A10 transports glutamine, glutamate, and aspartate, suggesting a role in neurotransmission2017In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 6, p. 730-746Article in journal (Refereed)
    Abstract [en]

    In brain cells, glutamine transporters are vital to monitor and control the levels of glutamate and GABA. There are 11 members of the SLC38 family of amino acid transporters of which eight have been functionally characterized. Here, we report the first histological and functional characterization of the previously orphan member, SLC38A10. We used pairwise global sequence alignments to determine the sequence identity between the SLC38 family members. SLC38A10 was found to share 20-25% transmembrane sequence identity with several family members, and was predicted to have 11 transmembrane helices. SLC38A10 immunostaining was abundant in mouse brain using a custom-made anti-SLC38A10 antibody and colocalization of SLC38A10 immunoreactivity with markers for neurons and astrocytes was detected. Using Xenopus laevis oocytes overexpressing SLC38A10, we show that SLC38A10 mediates bidirectional transport of L-glutamine, L-alanine, L-glutamate, and D-aspartate, and efflux of L-serine. This profile mostly resembles system A members of the SLC38 family. In conclusion, the bidirectional transport of glutamine, glutamate, and aspartate by SLC38A10, and the immunostaining detected in neurons and astrocytes, suggest that SLC38A10 plays a role in pathways involved in neurotransmission.

  • 185.
    Hellsten, Sofie V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ahmad, Tauseef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The gene expression of numerous SLC transporters is altered in the immortalized hypothalamic cell line N25/2 following amino acid starvation2017In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 2, p. 249-264Article in journal (Refereed)
    Abstract [en]

    Amino acids are known to play a key role in gene expression regulation,and in mammalian cells, amino acid signaling is mainly mediated via twopathways, the mammalian target of rapamycin complex 1 (mTORC1) pathwayand the amino acid responsive (AAR) pathway. It is vital for cells tohave a system to sense amino acid levels, in order to control protein andamino acid synthesis and catabolism. Amino acid transporters are crucialin these pathways, due to both their sensing and transport functions. Inthis large-scale study, an immortalized mouse hypothalamic cell line (N25/2)was used to study the gene expression changes following 1, 2, 3, 5 or 16 hof amino acid starvation. We focused on genes encoding solute carriers(SLCs) and putative SLCs, more specifically on amino acid transporters.The microarray contained 28 270 genes and 86.2% of the genes wereexpressed in the cell line. At 5 h of starvation, 1001 genes were upregulatedand 848 genes were downregulated, and among these, 47 genes from theSLC superfamily or atypical SLCs were found. Of these, 15 were genesencoding amino acid transporters and 32 were genes encoding other SLCsor atypical SLCs. Increased expression was detected for genes encodingamino acid transporters from system A, ASC, L, N, T, xc-, and y+. UsingGO annotations, genes involved in amino acid transport and amino acidtransmembrane transporter activity were found to be most upregulated at3 h and 5 h of starvation.

  • 186.
    Hellsten, Sofie Victora
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    SLC38A9 is expressed in inhibitory and excitatory neurons and the gene expression changes in mouse brain after starvation and high-fat dietManuscript (preprint) (Other academic)
  • 187.
    Hellsten, Sofie Victora
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ahmad, Tauseef
    Yamskova, Olga
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Amino acid deprivation of neuronal cells changes expression levels of numerous transporters from the SLC family, including several members of the SLC38 family2016Article in journal (Refereed)
  • 188.
    Herisson, F. M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Waikato, Dept Biol Sci, Fac Sci & Engn, Private Bag 3105, Hamilton, New Zealand..
    Waas, J. R.
    Univ Waikato, Dept Biol Sci, Fac Sci & Engn, Private Bag 3105, Hamilton, New Zealand..
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, A. S.
    Univ Minnesota, Dept Food Sci & Nutr, 1334 Eckles Ave, St Paul, MN USA..
    Olszewski, P. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Waikato, Dept Biol Sci, Fac Sci & Engn, Private Bag 3105, Hamilton, New Zealand.;Univ Minnesota, Dept Food Sci & Nutr, 1334 Eckles Ave, St Paul, MN USA..
    Oxytocin Acting in the Nucleus Accumbens Core Decreases Food Intake2016In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 28, no 4Article in journal (Refereed)
    Abstract [en]

    Central oxytocin (OT) promotes feeding termination in response to homeostatic challenges, such as excessive stomach distension, salt loading and toxicity. OT has also been proposed to affect feeding reward by decreasing the consumption of palatable carbohydrates and sweet tastants. Because the OT receptor (OTR) is expressed in the nucleus accumbens core (AcbC) and shell (AcbSh), a site regulating diverse aspects of eating behaviour, we investigated whether OT acts there to affect appetite in rats. First, we examined whether direct AcbC and AcbSh OT injections affect hunger- and palatability-driven consumption. We found that only AcbC OT infusions decrease deprivation-induced chow intake and reduce the consumption of palatable sucrose and saccharin solutions in nondeprived animals. These effects were abolished by pretreatment with an OTR antagonist, L-368,899, injected in the same site. AcbC OT at an anorexigenic dose did not induce a conditioned taste aversion, which indicates that AcbC OT-driven anorexia is not caused by sickness/malaise. The appetite-specific effect of AcbC OT is supported by the real-time polymerase chain reaction analysis of OTR mRNA in the AcbC, which revealed that food deprivation elevates OTR mRNA expression, whereas saccharin solution intake decreases OTR transcript levels. We also used c-Fos immunohistochemistry as a marker of neuronal activation and found that AcbC OT injection increases activation of the AcbC itself, as well as of two feeding-related sites: the hypothalamic paraventricular and supraoptic nuclei. Finally, considering the fact that OT plays a significant role in social behaviour, we examined whether offering animals a meal in a social setting would modify their hypophagic response to AcbC OT injections. We found that a social context abolishes the anorexigenic effects of AcbC OT. We conclude that OT acting via the AcbC decreases food intake driven by hunger and reward in rats offered a meal in a nonsocial setting.

  • 189. Herzog, N.
    et al.
    Friedrich, A.
    Richter, A.
    Hyzy, F.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Oltmanns, K. M.
    A bad night's sleep impairs morning glucose tolerance in humans: Role of slow wave sleep2012In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 27, no S1Article in journal (Other academic)
  • 190. Herzog, Nina
    et al.
    Friedrich, Alexia
    Fujita, Naoko
    Gais, Steffen
    Jauch-Chara, Kamila
    Oltmanns, Kerstin M.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Effects of Daytime Food Intake on Memory Consolidation during Sleep or Sleep Deprivation2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e40298-Article in journal (Refereed)
    Abstract [en]

    Sleep enhances memory consolidation. Bearing in mind that food intake produces many metabolic signals that can influence memory processing in humans (e.g., insulin), the present study addressed the question as to whether the enhancing effect of sleep on memory consolidation is affected by the amount of energy consumed during the preceding daytime. Compared to sleep, nocturnal wakefulness has been shown to impair memory consolidation in humans. Thus, a second question was to examine whether the impaired memory consolidation associated with sleep deprivation (SD) could be compensated by increased daytime energy consumption. To these aims, 14 healthy normal-weight men learned a finger tapping sequence (procedural memory) and a list of semantically associated word pairs (declarative memory). After the learning period, standardized meals were administered, equaling either similar to 50% or similar to 150% of the estimated daily energy expenditure. In the morning, after sleep or wakefulness, memory consolidation was tested. Plasma glucose was measured both before learning and retrieval. Polysomnographic sleep recordings were performed by electroencephalography (EEG). Independent of energy intake, subjects recalled significantly more word pairs after sleep than they did after SD. When subjects stayed awake and received an energy oversupply, the number of correctly recalled finger sequences was equal to those seen after sleep. Plasma glucose did not differ among conditions, and sleep time in the sleep conditions was not influenced by the energy intake interventions. These data indicate that the daytime energy intake level affects neither sleep's capacity to boost the consolidation of declarative and procedural memories, nor sleep's quality. However, high energy intake was followed by an improved procedural but not declarative memory consolidation under conditions of SD. This suggests that the formation of procedural memory is not only triggered by sleep but is also sensitive to the fluctuations in the energy state of the body.

  • 191. Herzog, Nina
    et al.
    Jauch-Chara, Kamila
    Hyzy, Franziska
    Richter, Annekatrin
    Friedrich, Alexia
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Oltmanns, Kerstin M.
    Selective slow wave sleep but not rapid eye movement sleep suppression impairs morning glucose tolerance in healthy men2013In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 10, p. 2075-2082Article in journal (Refereed)
    Abstract [en]

    Shortened nocturnal sleep impairs morning glucose tolerance. The underlying mechanism of this effect is supposed to involve a reduced fraction of slow wave sleep (SWS). However, it remains unanswered if impaired glucose tolerance occurs due to specific SWS reduction or a general disturbance of sleep. Sixteen healthy men participated in three experimental conditions in a crossover design: SWS suppression, rapid eye movement (REM)-sleep disturbance, and regular sleep. Selective sleep stage disturbance was performed by means of an acoustic tone (532 Hz) with gradually rising sound intensity. Blood concentrations of glucoregulatory parameters were measured upon an oral glucose tolerance test the next morning. Our data show that morning plasma glucose and serum insulin responses were significantly increased after selective SWS suppression. Moreover, SWS suppression reduced postprandial insulin sensitivity up to 20%, as determined by Matsuda Index. Contrastingly, disturbed REM-sleep did not affect glucose homeostasis. We conclude that specifically SWS reduction is critically involved in the impairment of glucose tolerance associated with disturbed sleep. Therefore, glucose metabolism in subjects predisposed to reduced SWS (e.g. depression, aging, obstructive sleep apnea, pharmacological treatment) should be thoroughly monitored.

  • 192. Herzog, Nina
    et al.
    Jauch-Chara, Kamila
    Oltmanns, Kerstin M.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Compromised sleep increases food intake in humans:: two sexes, same response?2012In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 95, no 2, p. 531-531Article in journal (Refereed)
  • 193.
    Hoeber, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    König, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhou, Chunfang
    Nanologica AB , Södertälje, Sweden.
    Pankratova, Stanislava
    Univ Copenhagen, Inst Neurosci & Pharmacol, Copenhagen, Denmark.
    Åkesson, Elisabet
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord2017In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 14, p. 1065-1077Article in journal (Refereed)
    Abstract [en]

    Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

  • 194.
    Hogenkamp, Pleunie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The effect of sensory-nutrient congruency on food intake after repeated exposure: Do texture and/or energy density matter?2014In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 136, no SI, p. 86-90Article in journal (Refereed)
    Abstract [en]

    Sensory properties guide the amount that people eat. In particular, food texture plays an important role in a food's 'expected satiation', which in turn affects the food-related decision making process. One hypothesis is that incongruent pairing of a textural cue with a post-ingestive outcome compromises this process, leading to poor energy compensation. Several studies examined the effect of both energy density and sensory characteristics (i.e. increased creaminess and thickness) on expectations, subjective appetite and food intake. To add to this literature, a re-analysis of data assessed whether the effect of sensory-nutrient pairings on energy intake compensation persisted after repeated exposure to a food. In this cross-over design, 27 participants consumed two preloads with 'congruent' (low-energy/liquid; high-energy/semi-solid) and two preloads with 'incongruent' (low-energy/semi-solid; high-energy/liquid) texture-nutrient combinations for nine subsequent meals, during which ad libitum intake was measured. Intake at first exposure did not differ between the low-energy (280±150kcal) and high-energy preloads (292±183kcal) in the incongruent conditions. By contrast, it was greater after the low-energy (332±203kcal) than after the high-energy (236±132kcal) preload in the congruent conditions (energyincongruent/congruent, p=0.04). Post-exposure, this pattern changed: intake depended on the energy density of the preloads in all conditions, and was greater after low-energy preloads (dayenergyincongruent/congruent-interaction for breakfast: p=0.02). Thus, manipulating the sensory properties of a food influenced energy compensation and meal size, but only at initial exposure. Repeated exposure 'corrected' the initial lack of compensation observed in conditions with incongruent sensory-nutrient pairings.

  • 195.
    Hogenkamp, Pleunie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chapman, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    Department of Physiology/Endocrinology, The Sahlgrenska Academy at the University of Gothenburg.
    Hjorth, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zarei, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lundberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dickson, Suzanne
    Department of Physiology/Endocrinology, The Sahlgrenska Academy at the University of Gothenburg.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Calorie anticipation alters food intake after low-caloric but not high-caloric preloads2013In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, no 8, p. 1548-1553Article in journal (Refereed)
    Abstract [en]

    Objective: Cognitive factors and anticipation are known to influence food intake. The current study examined the effect of anticipation and actual consumption of food on hormone (ghrelin, cortisol, insulin) and glucose levels, appetite and ad libitum intake, to assess whether changes in hormone levels might explain the predicted differences in subsequent food intake.

    Design and Methods: During four breakfast sessions, participants consumed a yogurt preload that was either low-caloric (LC; 180 kcal/300 g) or high-caloric (HC; 530 kcal/300 g), and were provided with either consistent or inconsistent calorie information (i.e. stating the caloric content of the preload was low or high). Appetite ratings and hormone and glucose levels were measured at baseline (t=0), after providing the calorie information about the preload (t=20), after consumption of the preload (t=40) and just before ad libitum intake (t=60).

    Results: Ad libitum intake was lower after HC preloads (as compared to LC preloads; p<0.01). Intake after LC preloads was higher when provided with (consistent) LC-information (467±254 kcal) as compared to (inconsistent) HC-information (346±210 kcal), but intake after the HC preloads did not depend on the information provided (LC-info: 290±178 kcal, HC-info: 333±179 kcal; caloric load*information p=0.03). Hormone levels did not respond in an anticipatory manner, and the post-prandial responses depended on actual calories consumed.

    Conclusions: These results suggest that both cognitive and physiological information determine food intake. When actual caloric intake was sufficient to produce physiological satiety, cognitive factors played no role; however, when physiological satiety was limited, cognitively-induced satiety reduced intake to comparable levels.

  • 196.
    Hogenkamp, Pleunie S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Late-life alcohol consumption and cognitive function in elderly men2014In: Age (Omaha), ISSN 0161-9152, E-ISSN 1574-4647, Vol. 36, no 1, p. 243-249Article in journal (Refereed)
    Abstract [en]

    Moderate alcohol consumption (one to two drinks per day) has been associated with better cognitive function and lower risk of developing dementia in the elderly. In light of alcohol's well-known neurotoxic properties, more evidence from well-controlled population-based studies is required. The objective of this study was to examine whether self-reported alcohol intake at age 70 is linked to cognitive function (assessed by trail making tests (TMTs) A and B, which are measures of attention, mental speed, and flexibility) in a population-based cohort consisting of 652 cognitively healthy elderly men. Linear regression models were used to assess both cross-sectional (i.e., age 70) and prospective (i.e., age 77) associations between alcohol intake and cognitive function. The analyses were adjusted for education, body mass index, energy intake, self-reported physical activity, smoking, a history of hypertension or diabetes, apolipoprotein E epsilon 4 status, and cholesterol levels at the age of 70. Baseline data were obtained from 1990 to 1996. Self-reported alcohol intake (mean 6.9 +/- 7.1 g/day) was associated with better performance on TMT-B at ages 70 and 77 (beta = -0.87, p < 0.001). In contrast, alcohol intake was not predictive of the difference in performance on these tests between ages 70 and 77. Despite cross-sectional associations with performance in a test of executive functioning, moderate intake of alcohol was not linked to differences in cognitive performance between ages 70 and 77 in the present study. Thus, our findings do not support the view that daily moderate alcohol consumption is a recommendable strategy to slow cognitive aging in elderly populations.

  • 197.
    Hogenkamp, Pleunie S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chapman, C D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, H
    Dickson, S L
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sweet taste perception not altered after acute sleep deprivation in healthy young men2013In: Somnologie, ISSN 1432-9123, E-ISSN 1439-054X, Vol. 17, no 2, p. 111-114Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    We hypothesized that acutely sleep-deprived participants would rate ascending concentrations of sucrose as more intense and pleasant, than they would do after one night of normal sleep. Such a finding would offer a potential mechanism through which acute sleep loss could promote overeating in humans.

    METHOD:

    A total of 16 healthy normal-weight men participated in 2 conditions: sleep (permitted between 22:30 and 06:30 h) and total sleep deprivation (TSD) respectively. On the morning after regular sleep and TSD, circulating concentrations of ghrelin and glucose were measured. In addition, participants hunger level was assessed by means of visual analogue scales, both before and after a caloric preload. Finally, following the preload, participants rated both intensity and pleasantness of six orally presented yogurt probes with varying sucrose concentrations (2-29 %).

    RESULTS:

    Feelings of hunger were significantly more intense under both fasted and sated conditions when subjects were sleep-deprived. In contrast, the change in hunger induced by the preload was similar between the sleep and TSD conditions. Plasma concentrations of ghrelin were significantly higher under conditions of TSD, whereas plasma glucose did not differ between the conditions. No effects were found either on sweet taste intensity or on pleasantness after TSD.

    CONCLUSION:

    One night of TSD increases morning plasma concentrations of the hunger-promoting hormone ghrelin in healthy young men. In contrast, sweet taste perception was not affected by nocturnal wakefulness. This suggests that an altered sweet taste perception is an unlikely mechanism by which TSD enhances food intake.

  • 198.
    Hogenkamp, Pleunie S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Victor C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chapman, Colin D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    Lundberg, Lina S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zarei, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rångtell, Frida H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Dickson, Suzanne L
    Brunström, Jeffrey M
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute sleep deprivation increases portion size and affects food choice in young men2013In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 9, p. 1668-1674Article in journal (Refereed)
    Abstract [en]

    Acute sleep loss increases food intake in adults. However, little is known about the influence of acute sleep loss on portion size choice, and whether this depends on both hunger state and the type of food (snack or meal item) offered to an individual. The aim of the current study was to compare portion size choice after a night of sleep and a period of nocturnal wakefulness (a condition experienced by night-shift workers, e.g. physicians and nurses). Sixteen men (age: 23 ± 0.9 years, BMI: 23.6 ± 0.6 kg/m2) participated in a randomized within-subject design with two conditions, 8-h of sleep and total sleep deprivation (TSD). In the morning following sleep interventions, portion size, comprising meal and snack items, was measured using a computer-based task, in both fasted and sated state. In addition, hunger as well as plasma levels of ghrelin were measured. In the morning after TSD, subjects had increased plasma ghrelin levels (13%, p = 0.04), and chose larger portions (14%, p = 0.02), irrespective of the type of food, as compared to the sleep condition. Self-reported hunger was also enhanced (p < 0.01). Following breakfast, sleep-deprived subjects chose larger portions of snacks (16%, p = 0.02), whereas the selection of meal items did not differ between the sleep interventions (6%, p = 0.13). Our results suggest that overeating in the morning after sleep loss is driven by both homeostatic and hedonic factors. Further, they show that portion size choice after sleep loss depend on both an individual's hunger status, and the type of food offered.

  • 199.
    Hogenkamp, Pleunie S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Effect of oral processing behaviour on food intake and satiety2013In: Trends in Food Science & Technology, ISSN 0924-2244, E-ISSN 1879-3053, Vol. 34, no 1, p. 67-75Article in journal (Refereed)
    Abstract [en]

    Many foods can be consumed quickly or with a little chewing. An overview of 33 experiments suggests that oral processing plays a role in food intake by affecting satiation (assessed by the measurement of ad libitum intake) and satiety (assessed by measurement of subjective appetite ratings, subsequent intake, and/or release of hormones, such as CCK and GLP-1). An increase in oral processing may result in an increased timespan for satiety signals to induce meal termination or evoke satiety. Determinants of oral processing (e.g. bite size, chewing, texture) are modifiable factors that may be considered to contribute to food intake regulation.

  • 200.
    Hogenkamp, Pleunie S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Columbia Univ, Med Ctr, New York Obes Nutr Res Ctr, Russ Berrie Pavil 1150 St Nicholas Ave, New York, NY 10032 USA..
    Shechter, A.
    Columbia Univ, Med Ctr, New York Obes Nutr Res Ctr, Russ Berrie Pavil 1150 St Nicholas Ave, New York, NY 10032 USA.;Columbia Univ, Inst Human Nutr, New York, NY 10032 USA.;Columbia Univ, Med Ctr, Dept Med, New York, NY USA..
    St-Onge, M-P
    Columbia Univ, Med Ctr, New York Obes Nutr Res Ctr, Russ Berrie Pavil 1150 St Nicholas Ave, New York, NY 10032 USA.;Columbia Univ, Inst Human Nutr, New York, NY 10032 USA.;Columbia Univ, Med Ctr, Dept Med, New York, NY USA..
    Sciafani, A.
    CUNY Brooklyn Coll, Dept Psychol, Brooklyn, NY 11210 USA..
    Kissileff, H. R.
    Columbia Univ, Med Ctr, New York Obes Nutr Res Ctr, Russ Berrie Pavil 1150 St Nicholas Ave, New York, NY 10032 USA.;Columbia Univ, Inst Human Nutr, New York, NY 10032 USA.;Columbia Univ, Med Ctr, Dept Med, New York, NY USA..
    A sipometer for measuring motivation to consume and reward value of foods and beverages in humans: Description and proof of principle2017In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 171, p. 216-227Article in journal (Refereed)
    Abstract [en]

    New methods, derived from animal work, for measuring food reward value (i.e. reinforcing value of food), and motivation (i.e. strength of desire) to consume, in humans are described and validated. A sipping device (sipometer) was developed that permits access to a liquid food or beverage on two reward schedules: continuous reinforcement (CR) and progressively increasing time spent exerting pressure on a straw (PR-schedule). In addition, a pictorial scale showing a cup, from which the 'amount wanted' could be marked was used to pre-test potential consumption. Intake, time spent sipping, breakpoint, and pressure exerted were the main dependent variables measured. Three pilot experiments were conducted. In Experiment 1, participants (n = 8) consumed yogurt shakes after a 1-h or 21-h food deprivation period on both schedules. In Experiment 2, participants (n = 8) sham-consumed (Le. spit out) sweet and non-sweet beverages, utilizing both schedules. In Experiment 3, sham-consuming sweet and non-sweet beverages on both schedules and working for shake on the PR schedule were repeated, after three nights of either habitual sleep or short sleep duration (n = 7) in a crossover design. In Experiment 1, participants sipped longer after 21-h vs. 1-h of food deprivation (13 +/- 3.0 vs. 8.0 +/- 2.1 s; p = 0.04), on the PR schedule. In Experiment 2, sham-intake (p = 0.01) and sipping time (p = 0.04) were greater for sweet than non-sweet beverages on the PR schedule and a similar, though not conventionally significant, effect was observed for exerted pressure (p = 0.09). In both Experiment 2 and Experiment 3 after habitual sleep, on the PR schedule, cumulative pressure difference between sweet and non-sweet beverage increased with difference in amount wanted in the taste test. In contrast, after short sleep participants were less willing to work for sweet taste as their wanting increased, suggesting that sleep deprivation raises desire, but lowers behavioral output. Taken together these results demonstrate that the sipometer and associated ratings are reliable and useful measures of motivation to consume and reward value in humans. Participants were more motivated to obtain access to sweet beverages, especially when these were better liked than to obtain access to non-sweet beverages.

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