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  • 401.
    Titova, Olga E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Metabolic Health and Cognitive Function: The Roles of Lifestyle and Shift Work2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The risk of cognitive impairment and metabolic disturbances increases during aging. Healthy lifestyle habits, such as a regular intake of fatty fish and adherence to the Mediterranean diet (MeDi), have been shown to slow age-related cognitive decline and decrease the risk of metabolic disturbances. Conversely, poor lifestyle habits including habitual short sleep duration as well as irregular work schedules (e.g. night shift work) have been correlated with lower cognitive performance and increased risk of having metabolic syndrome (MetS). However evidence is not conclusive regarding the above mentioned associations. The aim of this thesis was to investigate associations of diet, sleep, and shift work with metabolic health or cognitive performance in two Swedish cohorts.

    In Paper I and II we examined whether the dietary intake of omega-3 fatty acids and adherence to MeDi were related to measures of brain health in elderly subjects. To this aim, we used scores from the 7-minute cognitive screening test (7MS) and brain volume determined by magnetic resonance imaging. In Paper I, self-reported dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at age 70 was positively associated with cognitive performance and global gray matter volume at age 75. In Paper II, the fully-adjusted main analysis revealed that the MeDi score was not linked to measures of brain health. However, low intake of the MeDi component meat and meat products was associated with better performance on the 7MS and larger total brain volume.

    Paper III and IV included subjects aged 45-75 years. In Paper III we demonstrated that current and recent former shift workers (including shifts outside traditional working hours during the past 5 years at the time of the survey) performed worse on the trail making test (TMT) than non-shift workers. The TMT is a test evaluating executive cognitive function, and the performance on this test decreases with age. In Paper IV, sleep duration, sleep disturbances, and sleep-disordered breathing were all linked to an increased prevalence of MetS. Some of the observed associations were age-specific. For example, whereas both short and long sleep durations were linked to a higher prevalence of MetS in younger individuals (<65 years), only long sleep duration did so in the older participants. Collectively, the findings of this thesis suggest that maintaining healthy dietary habits, having high-quality sleep, and following a regular work schedule may be recommended strategies to mitigate age-related morbidities.

  • 402.
    Titova, Olga E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ax, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Brooks, Samantha J
    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.
    Cederholm, Tommy
    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.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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.
    Mediterranean diet habits in older individuals: Associations with cognitive functioning and brain volumes2013In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 48, no 12, p. 1443-1448Article in journal (Refereed)
    Abstract [en]

    To examine the association between dietary habits, cognitive functioning and brain volumes in older individuals, data from 194 cognitively healthy individuals who participated in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort were used. At age 70, participants kept diaries of their food intake for 1week. These records were used to calculate a Mediterranean diet (MeDi) score (comprising dietary habits traditionally found in Mediterranean countries, e.g. high intake of fruits and low intake of meat), with higher scores indicating more pronounced MeDi-like dietary habits. Five years later, participants' cognitive capabilities were examined by the seven minute screening (7MS) (a cognitive test battery used by clinicians to screen for dementia), and their brain volumes were measured by volumetric magnetic resonance imaging. Multivariate linear regression analyses were constructed to examine the association between the total MeDi score and cognitive functioning and brain volumes. In addition, possible associations between MeDi's eight dietary features and cognitive functioning and brain volumes were investigated. From the eight dietary features included in the MeDi score, pertaining to a low consumption of meat and meat products was linked to a better performance on the 7MS test (P=0.001) and greater total brain volume (P=0.03), i.e. the sum of white and gray matter. Integrating all dietary features of MeDi into score did not explain additional variance. These observational findings suggest that keeping to a low meat intake could prove to be an impact-driven public health policy to support healthy cognitive aging, when confirmed by longitudinal studies. Further, they suggest that the MeDi score is a construct that may mask possible associations of single MeDi features with brain health domains in elderly populations.

  • 403.
    Titova, Olga E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ayvazova, Elena A.
    Bichkaeva, Fatima A.
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chumakova, Galina N.
    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.
    The influence of active and passive smoking during pregnancy on umbilical cord blood levels of vitamins A and E and neonatal anthropometric indices2012In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 108, no 8, p. 1341-1345Article in journal (Refereed)
    Abstract [en]

    Smoking during pregnancy has been shown to be detrimental for the developing fetus. The effects of active and passive maternal smoking on umbilical cord serum levels of vitamin A and vitamin E were examined. Secondary measures included anthropometric parameters in the newborn. Maternal and umbilical cord serum levels of vitamins A and E were measured at delivery. The mothers were assigned to three groups: non-smoking (n 12); passive smoking (n 13); active smoking (n 18). Based on multivariate linear regressions, active smoking during pregnancy was associated with increased umbilical cord serum levels of vitamin A and vitamin E. While enhanced circulating levels of vitamin A in cord blood were also found in non-smoking mothers exposed to tobacco smoke during pregnancy, those of vitamin E were not influenced. Further, an inverse association between smoking behaviour during pregnancy and birth length was observed, with shortest length in active smokers followed by passive smoking mothers. Active and passive maternal smoking behaviour during pregnancy increases the fetal demand for antioxidant compounds in order to counteract the oxidative burden by cigarette smoke. Against this background, the observed increase in umbilical cord serum levels of vitamins A and E may subserve antioxidative processes in response to tobacco smoke-induced oxidative stress. This would reduce the availability of vitamins A and E for fetal maturation, which is critical inasmuch as both compounds are indispensable for the developing fetus. However, due to the cross-sectional nature of our observation, this line of reasoning definitely requires validation in cause-effect experiments in the future.

  • 404.
    Titova, Olga E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hjorth, Olof C
    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.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Anorexia nervosa is linked to reduced brain structure in reward and somatosensory regions: a meta-analysis of VBM studies2013In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 13, no 1, p. 110-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Structural imaging studies demonstrate brain tissue abnormalities in eating disorders, yet a quantitative analysis has not been done.

    METHODS

    In global and regional meta-analyses of 9 voxel-based morphometry (VBM) studies, with a total of 228 eating disorder participants (currently ill with anorexia nervosa), and 240 age-matched healthy controls, we compare brain volumes using global and regional analyses.

    RESULTS

    Anorexia nervosa (AN) patients have global reductions in gray (effect size = -0.66) and white matter (effect size = -0.74) and increased cerebrospinal fluid (effect size = 0.98) and have regional decreases in left hypothalamus, left inferior parietal lobe, right lentiform nucleus and right caudate, and no significant increases. No significant difference in hemispheric lateralization was found.

    CONCLUSIONS

    Global and regional meta-analyses suggest that excessive restrained eating as found in those with anorexia nervosa coincides with structural brain changes analogous to clinical symptoms.

  • 405.
    Titova, Olga E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S
    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.
    Feldman, Inna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    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.
    Associations of self-reported sleep disturbance and duration with academic failure in community-dwelling Swedish adolescents: Sleep and academic performance at school2015In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 16, p. 87-93Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine associations of self-reported sleep disturbance and short sleep duration with the risk for academic failure.

    METHODS: A cohort of ~40,000 adolescents (age range: 12-19 years) who were attending high school grades 7, 9, and 2nd year of upper secondary school in the Swedish Uppsala County were invited to participate in the Life and Health Young Survey (conducted between 2005 and 2011 in Uppsala County, Sweden). In addition to the question how many subjects they failed during the school year (outcome variable), subsamples of adolescents also answered questions related to subjective sleep disturbance (n = 20,026) and habitual sleep duration (n = 4736) (exposure variables). Binary logistic regression analysis was utilized to explore if self-reported sleep disturbances and habitual short sleep duration (defined as less than 7-8 h sleep per night) increase the relative risk to fail subjects during the school year (controlled for possible confounders, e.g. body-mass-index).

    RESULTS: Adolescents with self-reported sleep disturbances had an increased risk for academic failure (i.e., they failed at least one subject during the school year; OR: boys, 1.68; girls, 2.05, both P < 0.001), compared to adolescents without self-reported sleep disturbances. In addition, adolescents who reported short sleep duration on both working and weekend days were more likely to fail at least one subject at school than those who slept at least 7-8 h per night (OR: boys, 4.1; girls, 5.0, both P < 0.001).

    CONCLUSION: Our findings indicate that reports of sleep disturbance and short sleep duration are linked to academic failure in adolescents. Based on our data, causality cannot be established.

  • 406.
    Titova, Olga E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Elmstahl, Solve
    Lund Univ, CRC, Dept Hlth Sci, Div Geriatr Med,Skane Univ Hosp, Malmo, Sweden.
    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.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Associations Between the Prevalence of Metabolic Syndrome and Sleep Parameters Vary by Age2018In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 234Article in journal (Refereed)
    Abstract [en]

    Objective: To examine whether the relationship between the metabolic syndrome (MetS) and various sleep parameters [sleep duration, symptoms of sleep-disordered breathing (SDB), and sleep disturbances] varies by age. Methods: Waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose were used to determine MetS status in a cohort (N = 19,691) of middle-aged (aged 45-64 years) and older (aged >= 65 years) subjects. Habitual sleep duration (short, <= 6 h/day; normal, 7-8 h/day; and long >= 9 h/day), sleep disturbances (such as problems with falling and staying asleep), and symptoms of sleep-disordered breathing (SDB, such as snoring and sleep apneas) were measured by questionnaires. Results: Among the participants, 4,941 subjects (25.1%) fulfilled the criteria for MetS. In the entire sample, both short and long sleep durations were associated with higher prevalence of MetS as compared to normal sleep duration. When stratified by age, a similar pattern was observed for middle-aged subjects (<65 years old; prevalence ratio (PR) [95% CI], 1.13 [1.06-1.22] for short sleep and 1.26 [1.06-1.50] for long sleep duration). In contrast, in older individuals (>= 65 years old), only long sleep duration was linked to a higher prevalence of MetS (1.26 [1.12-1.42]; P < 0.01 for sleep duration x age). In the entire cohort, having at least one SDB symptom >= 4 times per week was linked to an increased prevalence of MetS; however, the PR was higher in middle-aged subjects compared with older subjects (1.50 [1.38-1.63] vs. 1.36 [1.26-1.47], respectively; P < 0.001 for SDB x age). Finally, independent of subjects' age, reports of sleep disturbances (i.e., at least one symptom >= 4 times per week) were associated with a higher likelihood of having MetS (1.12 [1.06-1.18]; P > 0.05 for sleep disturbance x age). Conclusion: Our results suggest that age may modify the associations between some sleep parameters and the prevalence of MetS.

  • 407.
    Titova, Olga E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Elmståhl, Solve
    Lund Univ, Skane Univ Hosp, Sweden CRC, Dept Hlth Sci,Div Geriatr Med, Malmo, Sweden..
    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.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association between shift work history and performance on the trail making test in middle-aged and elderly humans: the EpiHealth study2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 45, p. 23-29Article in journal (Refereed)
    Abstract [en]

    Shift work has been proposed to promote cognitive disturbances in humans; however, conflicting evidence is also present. By using data from 7143 middle-aged and elderly humans (45-75 years) who participated in the Swedish EpiHealth cohort study, the present analysis sought to investigate whether self-reported shift work history would be associated with performance on the trail making test (TMT). The TMT has been proposed to be a useful neuropsychological tool to evaluate humans' executive cognitive function, which is known to decrease with age. After adjustment for potential confounders (e.g., age, education, and sleep duration), it was observed that current and recent former shift workers (worked shifts during the past 5 years) performed worse on the TMT than nonshift workers. In contrast, performance on the TMT did not differ between past shift workers (off from shift work for more than 5 years) and nonshift workers. Collectively, our results indicate that shift work history is linked to poorer performance on the TMT in a cohort of middle-aged and elderly humans.

  • 408.
    Titova, Olga E
    et al.
    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.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ax, Erika
    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.
    Riserus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    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.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to gray matter volume and cognitive function in elderly2013In: Age (Omaha), ISSN 0161-9152, E-ISSN 1574-4647, Vol. 35, no 4, p. 1495-1505Article in journal (Refereed)
    Abstract [en]

    In the present study, we tested whether elderly with a high dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) would have higher cognitive test scores and greater brain volume than those with low dietary intake of these fatty acids. Data were obtained from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. The dietary intake of EPA and DHA was determined by a 7-day food protocol in 252 cognitively healthy elderly (122 females) at the age of 70 years. At age 75, participants' global cognitive function was examined, and their brain volumes were measured by magnetic resonance imaging (MRI). Three different multivariate linear regression models were applied to test our hypothesis: model A (adjusted for gender and age), model B (additionally controlled for lifestyle factors, e.g., education), and model C (further controlled for cardiometabolic factors, e.g., systolic blood pressure). We found that the self-reported 7-day dietary intake of EPA and DHA at the age of 70 years was positively associated with global gray matter volume (P < 0.05, except for model C) and increased global cognitive performance score (P < 0.05). However, no significant associations were observed between the dietary intake of EPA and DHA and global white matter, total brain volume, and regional gray matter, respectively. Further, no effects were observed when examining cognitively impaired (n = 27) elderly as separate analyses. These cross-sectional findings suggest that dietary intake of EPA and DHA may be linked to improved cognitive health in late life but must be confirmed in patient studies.

  • 409.
    Torres, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Sociology.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordberg, Camilla
    Helsingfors Univ, Helsinki, Finland.
    Media representations of ethnicity- and migration-related issues within the elderly care in Sweden and Finland2012In: Sociologisk forskning, ISSN 0038-0342, Vol. 49, no 4, p. 283-304Article in journal (Refereed)
    Abstract [en]

    Research on welfare regimes and migration regimes has shown that Sweden and Finland have similar elderly care regimes but different migration regimes. It is against this backdrop that we set out to study what Swedish and Finnish daily press focusing on elderly care has written about ethnic minorities, migrants and migration. The study uses quantitative content analysis to analyze 241 daily newspaper articles published between 1995 and 2008. This article presents the themes that have been discussed, the elderly care actors that have been in focus (i.e. whether the focus has been on elderly care recipients, elderly care providers or informal caregivers), the ethnic backgrounds that these actors have had (i.e. whether the focus has been on the ethnic majority or on ethnic minorities) and the type of explanatory frameworks that the newspaper articles in focus have used. On the basis of this, we problematize the representations of ethnic minorities, migrants and migration that the newspaper articles in question put forth and the fact that the Swedish and Finnish daily press treats the issues at hand as if migration is mostly an issue that can be relegated to the periphery of the elderly care sectors' agenda.

  • 410.
    Uhlén, Staffan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Bergen, Dept Clin Sci, Ctr Pharm, Pharmacol Sect, Bergen, Norway..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jahnsen, Jan Anker
    Univ Bergen, Dept Clin Sci, Ctr Pharm, Pharmacol Sect, Bergen, Norway..
    A new, simple and robust radioligand binding method used to determine kinetic off-rate constants for unlabeled ligands. Application at alpha(2A)- and alpha(2C)-adrenoceptors2016In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 788, p. 113-121Article in journal (Refereed)
    Abstract [en]

    Kinetic on and off rate constants for many receptor ligands are difficult to determine with regular radioligand binding technique since only few of the ligands are available in labeled form. Here we developed a new and simple radioligand binding method for determining the kinetic off-rate constant for unlabeled ligands, using whole cells expressing alpha(2A)- and alpha(2C)-adrenoceptors. The new method involves pre-incubation with unlabeled ligand, centrifugation of microtiter plates in order to adhere the cells to the bottom surface, and then upside-down centrifugation of the plates for few seconds to wash away the non-bound fraction of the pre-incubated ligand. The final on-reaction assay for the radioligand is then started by quick addition of a relatively fast-associating radioligand to the cells. The curve obtained is defined by a fairly simple mathematical formula that reflects the simultaneous dissociation of pre-incubated ligand and association of the radioligand. The method proved to produce highly reproducible results in determining the k(off) constants for various unlabeled ligands. The results show that the alpha(2C)-selectivity of MK912 depends mainly on a very slow off-rate at the alpha(2C)-adrenoceptor subtype. Regarding the markedly alpha(2C)- over alpha(2A)-selective compound spiroxatrine, its much faster on-rate at alpha(2C)- than alpha(2A)-adrenoceptors explains much of its exceptional alpha(2C)-selectivity. Several new techniques for determining the kinetic component of ligand-receptor interactions at molecular level are currently developing. As a reference, based on standard radioligand binding techniques, the present study describes a simple and robust experimental and mathematical procedure for determining k(off) constants of unlabeled drugs.

  • 411.
    Valsalan, Ravisankar
    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.
    Almén, Markus Sällman
    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.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Early vertebrate origin of melanocortin 2 receptor accessory proteins (MRAPs)2013In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 188, p. 123-132Article in journal (Refereed)
    Abstract [en]

    The melanocortin 2 receptor (MC2R) accessory proteins, MRAP, along with its homolog, MRAP2, are two among a growing number of G protein-coupled receptor accessory proteins that have been identified in recent years. These proteins interact directly with MC2R and are essential for trafficking of this receptor from the endoplasmic reticulum to the cell surface, where it mediates the effects of ACTH. lthough earlier studies have identified MRAP and MRAP2 subtypes in distant species, an overall evolutionary analysis of these families is still missing. Here, we performed a comprehensive evolutionary analysis of the MRAP and MRAP2 homologs based on whole genome sequences. We systematically mined and analyzed the genomes of metazoans to identify these genes. Overall, we identified 70 sequences of MRAP and MRAP2 from 44 species belonging to several vertebrate lineages, including at least 40 new sequences previously not reported in the literature. Herein, we provide evidence that MRAP2 is likely to be the ancestor of the MRAP family because MRAP2-like protein, but not MRAP, was identified in Petromyzon marinus (sea lamprey), which belong to an ancient basal vertebrate lineage. Later in vertebrate evolution, MRAP2 duplicated and gave rise to MRAP in an event before the emergence of actinopterygii (ray-finned fishes). However, we observed losses of MRAP in sarcopterygii (lobe-finned fish), amphibians and reptiles while both subtypes are present in chicken and most mammals studied. Synteny analysis showed a conserved synteny within same lineages and an inversion of gene order between lineages. An evolutionary rate shift analysis indicated that these genes were under high purifying selection. Overall, this study provides a comprehensive analysis of the evolution and gene repertoire of MRAP and MRAP2.

  • 412.
    Vastermark, Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sawant, Rahul S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Reiter, Jill L.
    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.
    Insulin receptor-like ectodomain genes and splice variants are found in both arthropods and human brain cDNA2013In: Journal of Systematics and Evolution, ISSN 1674-4918, Vol. 51, no 6, p. 664-670Article in journal (Refereed)
    Abstract [en]

    Truncated receptor ectodomains have been described for several classes of cell surface receptors, including those that bind to growth factors, cytokines, immunoglobulins, and adhesion molecules. Soluble receptor isoforms are typically generated by proteolytic cleavage of the cell surface receptor or by alternative splicing of RNA transcripts arising from the same gene encoding the full-length receptor. Both the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR) families produce soluble receptor splice variants in vertebrates and truncated forms of insulin receptor-like sequences have previously been described in Drosophila. The EGFR and INSR ectodomains share significant sequence homology with each other suggestive of a common evolutionary origin. We discovered novel truncated insulin receptor-like variants in several arthropod species. We carried out a phylogenetic analysis of the conserved extracellular receptor L1 and L2 subdomains in invertebrate species. Although the segregation of insulin receptor-like L1 and L2 domains indicated that an internal domain duplication had occurred only once, the generation of truncated insulin receptor-like sequences has occurred multiple times. The significance of this work is the previously unknown and widespread occurrence of truncated isoforms in arthropods, signifying that these isoforms play an important functional role, potentially related to such isoforms in mammals.

  • 413.
    Viereckel, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Konradsson-Geuken, Åsa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Validated multi‐step approach for in vivo recording and analysis of optogenetically evoked glutamate in the mouse globus pallidus2018In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 145, no 2, p. 125-138Article in journal (Refereed)
    Abstract [en]

    Precise quantification of extracellular glutamate concentrations upon neuronal activation is crucial for the understanding of brain function and neurological disorders. While optogenetics is an outstanding method for the correlation between distinct neurons and their role in circuitry and behavior, the electrochemically inactive nature of glutamate has proven challenging for recording upon optogenetic stimulations. This difficulty is due to the necessity for using enzyme-coated microelectrodes and the risk for light-induced artifacts. In this study, we establish a method for the combination of invivo optogenetic stimulation with selective measurement of glutamate concentrations using enzyme-coated multielectrode arrays and amperometry. The glutamatergic subthalamic nucleus (STN), which is the main electrode target site in deep brain stimulation treatment of advanced Parkinsons disease, has recently proven opotogenetically targetable in Pitx2-Cre-transgenic mice and was here used as model system. Upon stereotactic injection of viral Channelrhodopsin2-eYFP constructs into the STN, amperometric recordings were performed at a range of optogenetic stimulation frequencies in the globus pallidus, the main STN target area, in anesthetized mice. Accurate quantification was enabled through a multi-step analysis approach based on self-referencing microelectrodes and repetition of the experimental protocol at two holding potentials, which allowed for the identification, isolation and removal of photoelectric and photoelectrochemical artifacts. This study advances the field of invivo glutamate detection with combined optogenetics and amperometric recordings by providing a validated analysis framework for application in a wide variety of glutamate-based approaches in neuroscience.

  • 414.
    Voisin, Sarah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus S
    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.
    Chrousos, George P
    Manios, Yannis
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dietary fat quality impacts genome-wide DNA methylation patterns in a cross-sectional study of Greek preadolescents2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, p. 654-662Article in journal (Refereed)
    Abstract [en]

    The type and the amount of dietary fat have a significant influence on the metabolic pathways involved in the development of obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases. However, it is unknown to what extent this modulation is achieved through DNA methylation. We assessed the effects of cholesterol intake, the proportion of energy intake derived from fat, the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA), the ratio of monounsaturated fatty acids (MUFA) to SFA, and the ratio of MUFA+PUFA to SFA on genome-wide DNA methylation patterns in normal-weight and obese children. We determined the genome-wide methylation profile in the blood of 69 Greek preadolescents (∼10 years old) as well as their dietary intake for two consecutive weekdays and one weekend day. The methylation levels of one CpG island shore and four sites were significantly correlated with total fat intake. The methylation levels of 2 islands, 11 island shores and 16 sites were significantly correlated with PUFA/SFA; of 9 islands, 26 island shores and 158 sites with MUFA/SFA; and of 10 islands, 40 island shores and 130 sites with (MUFA+PUFA)/SFA. We found significant gene enrichment in 34 pathways for PUFA/SFA, including the leptin pathway, and a significant enrichment in 5 pathways for (MUFA+PUFA)/SFA. Our results suggest that specific changes in DNA methylation may have an important role in the mechanisms involved in the physiological responses to different types of dietary fat.European Journal of Human Genetics advance online publication, 30 July 2014; doi:10.1038/ejhg.2014.139.

  • 415.
    Voisin, Sarah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zheleznyakova, Galina Y.
    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.
    Zarei, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Castillo, Sandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Fia Ence
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Blueher, Matthias
    Univ Leipzig, IFB Adipos Dis, Fac Med, D-04103 Leipzig, Germany..
    Boettcher, Yvonne
    Univ Leipzig, IFB Adipos Dis, Fac Med, D-04103 Leipzig, Germany..
    Kovacs, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Leipzig, IFB Adipos Dis, Fac Med, D-04103 Leipzig, Germany..
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia..
    Rask-Andersen, Mathias
    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.
    Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers2015In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 7, article id 103Article in journal (Refereed)
    Abstract [en]

    Background: The mechanisms by which genetic variants, such as single nucleotide polymorphisms (SNPs), identified in genome-wide association studies act to influence body mass remain unknown for most of these SNPs, which continue to puzzle the scientific community. Recent evidence points to the epigenetic and chromatin states of the genome as having important roles. Methods: We genotyped 355 healthy young individuals for 52 known obesity-associated SNPs and obtained DNA methylation levels in their blood using the Illumina 450 K BeadChip. Associations between alleles and methylation at proximal cytosine residues were tested using a linear model adjusted for age, sex, weight category, and a proxy for blood cell type counts. For replication in other tissues, we used two open-access datasets (skin fibroblasts, n = 62; four brain regions, n = 121-133) and an additional dataset in subcutaneous and visceral fat (n = 149). Results: We found that alleles at 28 of these obesity-associated SNPs associate with methylation levels at 107 proximal CpG sites. Out of 107 CpG sites, 38 are located in gene promoters, including genes strongly implicated in obesity (MIR148A, BDNF, PTPMT1, NR1H3, MGAT1, SCGB3A1, HOXC12, PMAIP1, PSIP1, RPS10-NUDT3, RPS10, SKOR1, MAP2K5, SIX5, AGRN, IMMP1L, ELP4, ITIH4, SEMA3G, POMC, ADCY3, SSPN, LGR4, TUFM, MIR4721, SULT1A1, SULT1A2, APOBR, CLN3, SPNS1, SH2B1, ATXN2L, and IL27). Interestingly, the associated SNPs are in known eQTLs for some of these genes. We also found that the 107 CpGs are enriched in enhancers in peripheral blood mononuclear cells. Finally, our results indicate that some of these associations are not blood-specific as we successfully replicated four associations in skin fibroblasts. Conclusions: Our results strongly suggest that many obesity-associated SNPs are associated with proximal gene regulation, which was reflected by association of obesity risk allele genotypes with differential DNA methylation. This study highlights the importance of DNA methylation and other chromatin marks as a way to understand the molecular basis of genetic variants associated with human diseases and traits.

  • 416.
    Västermark, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Evolution of Membrane Bound Proteins and their Ligands: The Melanocortin (MC) Receptor Inverse Agonists AgRP2, ASIP2, Drug/Metabolite Transporters, and SPNS12012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Integral membrane proteins play a key role hormonal and neuronal signaling. Transmembrane helix (TM) proteins form about 27% of the human proteome. Furthermore, 44% of the human drug targets are receptors, and 19% of these are seven-transmembrane domain receptors (GPCRs), which constitute 4% of the entire protein-coding genome. After receptors, solute carriers (SLCs) constitute the second largest superfamily of TM proteins. Three of the largest SLC families contain protein domains that are members of the drug/metabolite transporter clan.

    We present evidence that the drug/metabolite transporter (DMT) families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. We renamed several transporters, and introduced the new HGNC-approved nomenclature of SLC35G1 – 6.

    We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Holocephali. However, we do not find any of these genes in lamprey or lancelet, suggesting that the MCA and MCB receptors function without antagonists in lamprey.

    We report that a venom peptide in Plectreurys tristis has the same cysteine knot structure as fish AgRP2, a higher similarity than previously known. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is likely to be the most ancestral, first splitting from a common ancestor to ASIP and A2. We introduce a new technique for synteny detection, sinusoidal Hough transform.

    We found that the known obesity SNPs in SH2B1, rs4788102 (p=0.0023) and rs7498665 (p=0.0018) were associated with triglyceride levels in the North Swedish Population Health Study (NSPHS) cohort, consisting of 719 individuals from the Karesuando parish in northern Sweden. To account for kinship, the SH2B1 SNPs, and four SNPs in the expanded region were analyzed for association with triglyceride levels using SOLAR. We found a stronger signal (p=0.0009) for a SNP, near SH2B1, rs8045689, located in an intron of SPNS1 which is structurally similar to a sphingolipid transporter.

  • 417.
    Västermark, Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Simmen, Martin W.
    Fredriksson, 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.
    Functional specialization in nucleotide sugar transporters occurred through differentiation of the gene cluster EamA (DUF6) before the radiation of Viridiplantae2011In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 11, p. 123-Article in journal (Refereed)
    Abstract [en]

    Background: The drug/metabolite transporter superfamily comprises a diversity of protein domain families with multiple functions including transport of nucleotide sugars. Drug/metabolite transporter domains are contained in both solute carrier families 30, 35 and 39 proteins as well as in acyl-malonyl condensing enzyme proteins. In this paper, we present an evolutionary analysis of nucleotide sugar transporters in relation to the entire superfamily of drug/metabolite transporters that considers crucial intra-protein duplication events that have shaped the transporters. We use a method that combines the strengths of hidden Markov models and maximum likelihood to find relationships between drug/metabolite transporter families, and branches within families. Results: We present evidence that the triose-phosphate transporters, domain unknown function 914, uracil-diphosphate glucose-N-acetylglucosamine, and nucleotide sugar transporter families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We identify previously unknown branches in the solute carrier 30, 35 and 39 protein families that emerged simultaneously as key physiological developments after the radiation of Viridiplantae, including the "35C/E" branch of EamA, which formed in the lineage of T. adhaerens (Animalia). We identify a second cluster of DMTs, called the domain unknown function 1632 cluster, which has non-cytosolic N- and C-termini, and thus appears to have been formed from a different domain duplication event. We identify a previously uncharacterized motif, G-X(6)-G, which is overrepresented in the fifth transmembrane helix of C-terminal domains. We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. Conclusions: The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.

  • 418.
    Västermark, Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Polymorphisms in sh2b1 and spns1 loci are associated with triglyceride levels in a healthy population in northern Sweden2012In: Journal of Genetics, ISSN 0022-1333, E-ISSN 0973-7731, Vol. 91, no 2, p. 237-240Article in journal (Refereed)
  • 419.
    Västermark, Åke
    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.
    Houle, Michael E.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Miguel Cerda-Reverter, Jose
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Identification of Distant Agouti-Like Sequences and Re-Evaluation of the Evolutionary History of the Agouti-Related Peptide (AgRP)2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e40982-Article in journal (Refereed)
    Abstract [en]

    The Agouti-like peptides including AgRP, ASIP and the teleost-specific A2 (ASIP2 and AgRP2) peptides have potent and diverse functional roles in feeding, pigmentation and background adaptation mechanisms. There are contradictory theories about the evolution of the Agouti-like peptide family as well the nomenclature. Here we performed comprehensive mining and annotation of vertebrate Agouti-like sequences. We identified A2 sequences from salmon, trout, seabass, cod, cichlid, tilapia, gilt-headed sea bream, Antarctic toothfish, rainbow smelt, common carp, channel catfish and interestingly also in lobe-finned fish. Moreover, we surprisingly found eight novel homologues from the kingdom of arthropods and three from fungi, some sharing the characteristic C-x(6)-C-C motif which are present in the Agouti-like sequences, as well as approximate sequence length (130 amino acids), positioning of the motif sequence and sharing of exon-intron structures that are similar to the other Agouti-like peptides providing further support for the common origin of these sequences. Phylogenetic analysis shows that the AgRP sequences cluster basally in the tree, suggesting that these sequences split from a cluster containing both the ASIP and the A2 sequences. We also used a novel approach to determine the statistical evidence for synteny, a sinusoidal Hough transform pattern recognition technique. Our analysis shows that the teleost AgRP2 resides in a chromosomal region that has synteny with Hsa 8, but we found no convincing synteny between the regions that A2, AgRP and ASIP reside in, which would support that the Agouti-like peptides were formed by whole genome tetraplodization events. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is the most distantly related to the three other members of that group, first splitting from a common ancestor to ASIP and A2, and then later the A2 split from ASIP followed by a split resulting in ASIP2 and AgRP2.

  • 420.
    Västermark, Åke
    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.
    The early origin of melanocortin receptors, agouti-related peptide, agouti signalling peptide, and melanocortin receptor-accessory proteins, with emphasis on pufferfishes, elephant shark, lampreys, and amphioxus2011In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 660, no 1, p. 61-69Article in journal (Refereed)
    Abstract [en]

    There are conflicting theories about the evolution of melanocortin MC receptors while only few studies have addressed the evolution of agouti-related peptide (AgRP) and agouti signalling peptide (ASIP), which are antagonists at the melanocortin receptors (MCRs), or the melanocortin MC(2) receptor accessory proteins (MRAP1 and MRAP2). Previously we have cloned melanocortin MC receptors (MC(a) and MC(b)) genes in river lamprey and here we identify orthologues to these melanocortin MC receptor sequences in the sea lamprey. We investigate the putative presence of the melanocortin MC receptor genes in lancelet (amphioxus; Branchiostoma floridae) but we find it unlikely that such gene exists, due to a sharp drop in sequence similarity beyond sequence clusters of known receptors. We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Elasmobranchii. However, we do not find any of these genes in lamprey or lancelet after detailed analysis of both targeted and whole proteome regular expression scans. We found MRAP2, but not MRAP1, to be present in elephant shark and sea lamprey while Fugu (T. rubripes) has both genes. This study shows that the most ancient presence of these melanocortin-related sequences is found in elephant shark and lampreys considering the current available sequence data.

  • 421.
    Wallen-Mackenzie, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arvidsson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Restrepo, Ernesto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Johann, Stefano Pupe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leao, Richardson Naves
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Targeting VGLUT2 in dopamine neurons affects the brain reward system2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S128-S129Article in journal (Other academic)
  • 422.
    Wallén-Mackenzie, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fejgin, Kim
    Lagerström, Malin C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wass, Caroline
    Andersson, Daniel
    Egecioglu, Emil
    Andersson, My
    Strandberg, Joakim
    Lindhe, Örjan
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chergui, Karima
    Hanse, Eric
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Svensson, Lennart
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 7, p. 2238-2251Article in journal (Refereed)
    Abstract [en]

    A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.

  • 423.
    Wang, Ludi
    et al.
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China..
    Zhou, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Xing, Ying
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China..
    Zhou, Xiaoguang
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China..
    A Novel Neural Network Model for Blood Pressure Estimation Using Photoplethesmography without Electrocardiogram2018In: Journal of Healthcare Engineering, ISSN 2040-2295, E-ISSN 2040-2309, article id 7804243Article in journal (Refereed)
    Abstract [en]

    The prevention, evaluation, and treatment of hypertension have attracted increasing attention in recent years. As photoplethysmography (PPG) technology has been widely applied to wearable sensors, the noninvasive estimation of blood pressure (BP) using the PPG method has received considerable interest. In this paper, a method for estimating systolic and diastolic BP based only on a PPG signal is developed. The multitaper method (MTM) is used for feature extraction, and an artificial neural network (ANN) is used for estimation. Compared with previous approaches, the proposed method obtains better accuracy; the mean absolute error is 4.02 +/- 2.79mmHg for systolic BP and 2.27 +/- 1.82mmHg for diastolic BP.

  • 424.
    Wiemerslage, L
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Islam, R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    van der Kamp, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cao, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ence-Eriksson, F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Castillo, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Larsen, A L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dahlberg, L S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perland, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gustavsson, V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, H
    Schürmann, A
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Rask-Andersen, Mathias
    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.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels2017In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 41, no 6, p. 990-994Article in journal (Refereed)
    Abstract [en]

    We investigated five methylation markers recently linked to body-mass index, for their role in the neuropathology of obesity. In neuroimaging experiments, our analysis involving 23 participants showed that methylation levels for the cg07814318 site, which lies within the KLF13 gene, correlated with brain activity in the claustrum, putamen, cingulate gyrus, and frontal gyri, some of which have been previously associated to food signaling, obesity, or reward. Methylation levels at cg07814318 also positively correlated with ghrelin levels. Moreover, expression of KLF13 was augmented in the brains of obese and starved mice. Our results suggest the cg07814318 site could be involved in orexigenic processes, and also implicate KLF13 in obesity. Our findings are the first to associate methylation levels in blood with brain activity in obesity-related regions, and further support previous findings between ghrelin, brain activity, and genetic differences.

  • 425.
    Wiemerslage, Lyle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gohel, Priya A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Maestri, Giulia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hilmarsson, Torfi G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mickael, Michel
    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.
    Williams, Michael J.
    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 Drosophila ortholog of TMEM18 regulates insulin and glucagon-like signaling2016In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 229, no 3, p. 233-243Article in journal (Refereed)
    Abstract [en]

    Transmembrane protein 18 (TMEM18) is an ill-described, obesity-related gene, but few studies have explored its molecular function. We found single-nucleotide polymorphism data, suggesting that TMEM18 may be involved in the regulation/physiology of metabolic syndrome based on associations with insulin, homeostatic model assessment-beta (HOMA beta), triglycerides, and blood sugar. We then found an ortholog in the Drosophila genome, knocked down Drosophila Tmem18 specifically in insulin-producing cells, and tested for its effects on metabolic function. Our results suggest that TMEM18 affects substrate levels through insulin and glucagon signaling, and its downregulation induces a metabolic state resembling type 2 diabetes. This work is the first to experimentally describe the metabolic consequences of TMEM18 knockdown, and further supports its association with obesity.

  • 426.
    Wiemerslage, Lyle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ismael, Sazan
    Ohio Univ, Dept Biol Sci, Neurosci Program, Athens, OH 45701 USA..
    Lee, Daewoo
    Ohio Univ, Dept Biol Sci, Neurosci Program, Athens, OH 45701 USA..
    Early alterations of mitochondrial morphology in dopaminergic neurons from Parkinson's disease-like pathology and time-dependent neuroprotection with D2 receptor activation2016In: Mitochondrion (Amsterdam. Print), ISSN 1567-7249, E-ISSN 1872-8278, Vol. 30, p. 138-147Article in journal (Refereed)
    Abstract [en]

    Neuroprotection, to prevent vulnerable cell populations from dying, is perhaps the main strategy for treating Parkinson's disease (PD). Yet in clinical practice, therapy is introduced after the disease is well established and many neurons have already disappeared, while experimentally, treatment is typically added at the same time that PD pathology is instigated. This study uses an already established Drosophila melanogaster model of PD to test for early markers of neurodegeneration and if those markers are reversible following neuroprotective treatment. Specifically, we treat primary neuronal cultures with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and track neuritic, dopaminergic mitochondria over time, observing a fragmenting change in their morphology before cell death. We then add a neuroprotective treatment (quinpirole, a D2 receptor agonist) at different timepoints to determine if the changes in mitochondrial morphology are reversible. We find that neuroprotective treatment must be added concomitantly to prevent changes in mitochondrial morphology and subsequent cell death. This work further supports Drosophila's use as a model organism and mitochondria's use as a biomarker for neurodegenerative disease. But mainly, this work highlights an import factor for experiments in neuroprotection - time of treatment. Our results highlight the problem that current neuroprotective treatments for PD may not be used the same way that they are tested experimentally.

  • 427.
    Wiemerslage, Lyle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lee, Daewoo
    Ohio Univ, Dept Biol Sci, Neurosci Program, Athens, OH 45701 USA.
    Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters.2016In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 262, p. 56-65Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies of mitochondrial morphology vary in techniques. Most use one morphological parameter while others describe mitochondria qualitatively. Because mitochondria are so dynamic, a single parameter does not capture the true state of the network and may lead to erroneous conclusions. Thus, a gestalt method of analysis is warranted.

    NEW METHOD: This work describes a method combining immunofluorescence assays with computerized image analysis to measure the mitochondrial morphology within neuritic projections of a specific population of neurons. Six parameters of mitochondrial morphology were examined utilizing ImageJ to analyze colocalized signals.

    RESULTS: Using primary neuronal cultures from Drosophila, we tested mitochondrial morphology in neurites of dopaminergic (DA) neurons. We validate our model using mutants with known defects in mitochondrial morphology. Furthermore, we show a difference in mitochondrial morphology between cells treated as control or with a neurotoxin inducing PD (Parkinson's Disease in humans)-like pathology. We also show interactions between morphological parameters and experimental treatment.

    COMPARISON WITH EXISTING METHODS: Our method is a significant improvement of previously described methods. Six morphometric parameters are quantified, providing a gestalt analysis of mitochondrial morphology. Also it can target specific populations of mitochondria using immunofluorescence assay and image analysis.

    CONCLUSIONS: We found that our method adequately detects differences in mitochondrial morphology between treatment groups. We conclude that some parameters may be unique to a mutation or a disease state, and the relationship between parameters is altered by experimental treatment. We suggest at least four variables should be considered when using mitochondrial structure as an experimental endpoint.

  • 428.
    Wiemerslage, Lyle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dahlberg, Linda Solstrand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ence-Eriksson, Fia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Castillo, Sandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Larsen, Anna L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bylund, Simon B. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Titova, Olga E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Benedict, Christian
    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, Old Groote Schuur Hosp, 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.
    An obesity-associated risk allele within the FTO gene affects human brain activity for areas important for emotion, impulse control and reward in response to food images2016In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 43, no 9, p. 1173-1180Article in journal (Refereed)
    Abstract [en]

    Understanding how genetics influences obesity, brain activity and eating behaviour will add important insight for developing strategies for weight-loss treatment, as obesity may stem from different causes and as individual feeding behaviour may depend on genetic differences. To this end, we examined how an obesity risk allele for the FTO gene affects brain activity in response to food images of different caloric content via functional magnetic resonance imaging (fMRI). Thirty participants homozygous for the rs9939609 single nucleotide polymorphism were shown images of low-or high-calorie food while brain activity was measured via fMRI. In a whole-brain analysis, we found that people with the FTO risk allele genotype (AA) had increased activity compared with the non-risk (TT) genotype in the posterior cingulate, cuneus, precuneus and putamen. Moreover, higher body mass index in the AA genotype was associated with reduced activity to food images in areas important for emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and lentiform nucleus). Lastly, we corroborate our findings with behavioural scales for the behavioural inhibition and activation systems. Our results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing.

  • 429.
    Wiemerslage, Lyle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhou, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stark, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A resting-state fMRI study of obese females between pre- and postprandial states before and after bariatric surgery.2017In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 45, no 3, p. 333-341Article in journal (Refereed)
    Abstract [en]

    Past studies utilizing resting-state functional MRI (rsfMRI), have shown that obese humans exhibit altered activity in brain areas related to reward compared to normal-weight controls. However, to what extent bariatric surgery-induced weight loss alters resting-state brain activity in obese humans is less well-studied. Thus, we measured the fractional amplitude of low-frequency fluctuations (fALFF) from eyes-closed, rsfMRI in obese females (n = 11, mean age = 42 years, mean BMI = 41 kg/m(2) ) in both a pre- and post-prandial state at two time points: four weeks before, and four weeks after bariatric surgery. Several brain areas showed altered resting-state activity following bariatric surgery, including the putamen, insula, cingulate, thalamus, and frontal regions. Activity augmented by surgery was also dependent on prandial state. For example, in the fasted state, activity in the middle frontal, and pre- and postcentral gyri was found to be decreased after surgery. In the sated state, activity within the insula was increased before, but not after surgery. Collectively, our results suggest that resting-state neural functions are rapidly affected following bariatric surgery and the associated weight loss and change in diet. 

  • 430.
    Williams, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Shaik, Muksheed
    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.
    Yamskova, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Paulsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Thombare, Ketan
    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.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The obesity-linked Nudt3 Drosophila homolog Aps is associated with insulin signalling2015In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 29, no 9, p. 1303-1319Article in journal (Refereed)
    Abstract [en]

    Several genome-wide association studies have linked the Nudix hydrolase family member nucleoside diphosphate-linked moiety X motif 3 (NUDT3) to obesity. However, the manner of NUDT3 involvement in obesity is unknown, and NUDT3 expression, regulation, and signaling in the central nervous system has not been studied. We performed an extensive expression analysis in mice, as well as knocked down the Drosophila NUDT3 homolog Aps in the nervous system, to determine its effect on metabolism. Detailed in situ hybridization studies in the mouse brain revealed abundant Nudt3 mRNA and protein expression throughout the brain, including reward- and feeding-related regions of the hypothalamus and amygdala, whereas Nudt3 mRNA expression was significantly up-regulated in the hypothalamus and brainstem of food-deprived mice. Knocking down Aps in the Drosophila central nervous system, or a subset of median neurosecretory cells, known as the insulin-producing cells (IPCs), induces hyperinsulinemia-like phenotypes, including a decrease in circulating trehalose levels as well as significantly decreasing all carbohydrate levels under starvation conditions. Moreover, lowering Aps IPC expression leads to a decreased ability to recruit these lipids during starvation. Also, loss of neuronal Aps expression caused a starvation susceptibility phenotype while inducing hyperphagia. Finally, the loss of IPC Aps lowered the expression of Akh, llp6, and llp3, genes known to be inhibited by insulin signaling. These results point toward a role for this gene in the regulation of insulin signaling, which could explain the robust association with obesity in humans.

  • 431.
    Williams, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Goergen, Philip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rajendran, Jayasimman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zheleznyakova, Galina
    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.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bagchi, Sonchita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kalogeropoulou, Argyro
    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.
    Fredriksson, Robert
    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.
    Obesity-linked homologues TfAP-2 and Twz establish meal frequency in Drosophila melanogaster2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 9, p. e1004499-Article in journal (Refereed)
    Abstract [en]

    In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.

  • 432.
    Williams, Michael J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus Sällman
    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.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    What model organisms and interactomics can reveal about the genetics of human obesity2012In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 69, no 22, p. 3819-3834Article, review/survey (Refereed)
    Abstract [en]

    Genome-wide association studies have identified a number of genes associated with human body weight. While some of these genes are large fields within obesity research, such as MC4R, POMC, FTO and BDNF, the majority do not have a clearly defined functional role explaining why they may affect body weight. Here, we searched biological databases and discovered 33 additional genes associated with human obesity (CADM2, GIPR, GPCR5B, LRP1B, NEGR1, NRXN3, SH2B1, FANCL, GNPDA2, HMGCR, MAP2K5, NUDT3, PRKD1, QPCTL, TNNI3K, MTCH2, DNAJC27, SLC39A8, MTIF3, RPL27A, SEC16B, ETV5, HMGA1, TFAP2B, TUB, ZNF608, FAIM2, KCTD15, LINGO2, POC5, PTBP2, TMEM18, TMEM160). We find that the majority have orthologues in distant species, such as D. melanogaster and C. elegans, suggesting that they are important for the biology of most bilateral species. Intriguingly, signalling cascade genes and transcription factors are enriched among these obesity genes, and several of the genes show properties that could be useful for potential drug discovery. In this review, we demonstrate how information from several distant model species, interactomics and signalling pathway analysis represents an important way to better understand the functional diversity of the surprisingly high number of molecules that seem to be important for human obesity.

  • 433.
    Williams, Michael J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Goergen, Philip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Phad, Ganesh
    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.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Drosophila Kctd-family homologue Kctd12-like modulates male aggression and mating behaviour2014In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 40, no 3, p. 2513-2526Article in journal (Refereed)
    Abstract [en]

    In Drosophila, serotonin (5-HT) regulates aggression, mating behaviour and sleep/wake behaviour through different receptors. Currently, how these various receptors are themselves regulated is still not completely understood. The KCTD12-family of proteins, which have been shown to modify G-protein-coupled receptor (GPCR) signalling in mammals, are one possibility of auxiliary proteins modulating 5-HT receptor signalling. The KCTD12-family was found to be remarkably conserved and present in species from C. elegans to humans. The Drosophila KCTD12 homologue Kctd12-like (Ktl) was highly expressed in both the larval and adult CNS. By performing behavioural assays in male Drosophila, we now reveal that Ktl is required for proper male aggression and mating behaviour. Previously, it was shown that Ktl is in a complex with the Drosophila 5-HT receptor 5-HT7, and we observed that both Ktl and the 5-HT1A receptor are required in insulin-producing cells (IPCs) for proper adult male behaviour, as well as for hyperaggressive activity induced by the mammalian 5-HT1A receptor agonist 8-hydroxy-2-dipropylaminotetralin-hydrobromide. Finally, we show that Ktl expression in the IPCs is necessary to regulate locomotion and normal sleep/wake patterns in Drosophila, but not the 5-HT1A receptor. Similar to what was observed with mammalian KCTD12-family members that interact physically with a GPCR receptor to regulate desensitization, in Drosophila Ktl may function in GPCR 5-HT receptor pathways to regulate their signalling, which is required for proper adult male behaviour.

  • 434.
    Williams, Michael J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Goergen, Philip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rajendran, Jayasimman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klockars, Anica
    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.
    Fredriksson, 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.
    Regulation of aggression by obesity-linked genes TfAP-2 and Twz through octopamine signaling in Drosophila2014In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 196, no 1, p. 349-362Article in journal (Refereed)
    Abstract [en]

    In Drosophila, the monoamine octopamine, through mechanisms that are not completely understood, regulates both aggression and mating behavior. Interestingly, our study demonstrates that the Drosophila obesity-linked homologs Transcription factor AP-2 (TfAP-2; TFAP2B in humans) and Tiwaz (Twz; KCTD15 in humans) interact to modify male behavior by controlling the expression of Tyramine β-hydroxylase and Vesicular monanime transporter, genes necessary for octopamine production and secretion. Furthermore, we reveal that octopamine in turn regulates aggression through the Drosophila cholecystokinin satiation hormone homolog Drosulfakinin (Dsk). Finally, we establish that TfAP-2 is expressed in octopaminergic neurons known to control aggressive behavior and that TfAP-2 requires functional Twz for its activity. We conclude that genetically manipulating the obesity-linked homologs TfAP-2 and Twz is sufficient to affect octopamine signaling, which in turn modulates Drosophila male behavior through the regulation of the satiation hormone Dsk.

  • 435.
    Williams, Michael J.
    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.
    Eriksson, Mikaela M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Carlsson, Josef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Erlandsson, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Laan, Loora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mahebali, Tabusi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Potter, Ella
    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.
    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.
    Recurrent Sleep Fragmentation Induces Insulin and Neuroprotective Mechanisms in Middle-Aged Flies2016In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 8, article id 180Article in journal (Refereed)
    Abstract [en]

    Lack of quality sleep increases central nervous system oxidative stress and impairs removal of neurotoxic soluble metabolites from brain parenchyma. During aging poor sleep quality, caused by sleep fragmentation, increases central nervous system cellular stress. Currently, it is not known how organisms offset age-related cytotoxic metabolite increases in order to safeguard neuronal survival. Furthermore, it is not understood how age and sleep fragmentation interact to affect oxidative stress protection pathways. We demonstrate sleep fragmentation increases systems that protect against oxidative damage and neuroprotective endoplasmic reticulum molecular chaperones, as well as neuronal insulin and dopaminergic expression in middle-aged Drosophila males. Interestingly, even after sleep recovery the expression of these genes was still upregulated in middle-aged flies. Finally, sleep fragmentation generates higher levels of reactive oxygen species (ROS) in middle-aged flies and after sleep recovery these levels remain significantly higher than in young flies. The fact that neuroprotective pathways remain upregulated in middle-aged flies beyond sleep fragmentation suggests it might represent a strong stressor for the brain during later life.

  • 436.
    Williams, Michael J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wang, Yi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klockars, Anica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Fredriksson, 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.
    Exposure to Bisphenol A Affects Lipid Metabolism in Drosophila melanogaster2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 114, no 5, p. 414-420Article in journal (Refereed)
    Abstract [en]

    Exposure to bisphenol A (BPA) in rodents was shown to induce obesity, yet the mechanism by which BPA might induce obesity is still unclear. We employed the genetically tractable model organism, Drosophila melanogaster, to test the effects of raising them on food containing various concentrations of BPA. Of note, raising males on food containing BPA were susceptible to starvation, possibly by inhibiting their ability to perform lipolysis during starvation, leading to significantly increased lipid content after 24 hr of fasting. Furthermore, feeding males with BPA significantly inhibited the expression of insulin-like peptides. From these results, we conclude that BPA may inhibit lipid recruitment during starvation in Drosophila.

  • 437.
    Williams, Michael J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wiemerslage, Lyle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gohel, Priya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala Univ, Dept Neurosci, Funct Pharmacol, S-75124 Uppsala, Sweden..
    Kheder, Sania
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kothegala, Lakshmi V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala Univ, Dept Neurosci, Funct Pharmacol, S-75124 Uppsala, Sweden..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dibutyl Phthalate Exposure Disrupts Evolutionarily Conserved Insulin and Glucagon-Like Signaling in Drosophila Males2016In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 157, no 6, p. 2309-2321Article in journal (Refereed)
    Abstract [en]

    Phthalate diesters are commonly used as industrial plasticisers, as well as in cosmetics and skin care products, as a result people are constantly exposed to these xenobiotics. Recent epidemiological studies have found a correlation between circulating phthalate levels and type 2 diabetes, whereas animal studies indicate that phthalates are capable of disrupting endocrine signaling. Nonetheless, how phthalates interfere with metabolic function is still unclear. Here, we show that feeding Drosophila males the xenobiotic dibutyl phthalate (DBP) affects conserved insulin- and glucagon-like signaling. We report that raising flies on food containing DBP leads to starvation resistance, increased lipid storage, hyperglycemia, and hyperphagia. We go on to show that the starvation-resistance phenotype can be rescued by overexpression of the glucagon analogue adipokinetic hormone (Akh). Furthermore, although acute DBP exposure in adult flies is able to affect insulin levels, only chronic feeding influences Akh expression. We establish that raising flies on DBP-containing food or feeding adults DBP food affects the expression of homologous genes involved in xenobiotic and lipid metabolism (AHR [Drosophila ss], NR1I2 [Hr96], ABCB1 [MDR50], ABCC3 [MRP], and CYP3A4 [Cyp9f2]). Finally, we determined that the expression of these genes is also influenced by Akh. Our results provide comprehensive evidence that DBP can disrupt metabolism in Drosophila males, by regulating genes involved in glucose, lipid, and xenobiotic metabolism.

  • 438.
    Williams, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klockars, Anica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Anders
    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.
    Dnyansagar, Rohit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wiemerslage, Lyle
    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.
    Akram, Mehwish
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kheder, Sania
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ambrosi, Valerie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hallqvist, Emilie
    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.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Drosophila ETV5 homologue Ets96B: Molecular link between obesity and bipolar disorder2016In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 6, article id e1006104Article in journal (Refereed)
    Abstract [en]

    Several reports suggest obesity and bipolar disorder (BD) share some physiological and behavioural similarities. For instance, obese individuals are more impulsive and have heightened reward responsiveness, phenotypes associated with BD, while bipolar patients become obese at a higher rate and earlier age than people without BD; however, the molecular mechanisms of such an association remain obscure. Here we demonstrate, using whole transcriptome analysis, that Drosophila Ets96B, homologue of obesity-linked gene ETV5, regulates cellular systems associated with obesity and BD. Consistent with a role in obesity and BD, loss of nervous system Ets96B during development increases triacylglyceride concentration, while inducing a heightened startle-response, as well as increasing hyperactivity and reducing sleep. Of notable interest, mouse Etv5 and Drosophila Ets96B are expressed in dopaminergic-rich regions, and loss of Ets96B specifically in dopaminergic neurons recapitulates the metabolic and behavioural phenotypes. Moreover, our data indicate Ets96B inhibits dopaminergic-specific neuroprotective systems. Additionally, we reveal that multiple SNPs in human ETV5 link to body mass index (BMI) and BD, providing further evidence for ETV5 as an important and novel molecular intermediate between obesity and BD. We identify a novel molecular link between obesity and bipolar disorder. The Drosophila ETV5 homologue Ets96B regulates the expression of cellular systems with links to obesity and behaviour, including the expression of a conserved endoplasmic reticulum molecular chaperone complex known to be neuroprotective. Finally, a connection between the obesity- linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and BD at the molecular level.

  • 439.
    Xu, Jiayue
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Boström, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Saeed, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dubey, Raghvendra K.
    Univ Hosp Zurich, Clin Reprod Endocrinol, Dept Obstet & Gynecol, Zurich, Switzerland..
    Waeber, Gerard
    Univ Lausanne, Univ Hosp Lausanne, Dept Internal Med, Lausanne, Switzerland..
    Vollenweider, Peter
    Univ Lausanne, Univ Hosp Lausanne, Dept Internal Med, Lausanne, Switzerland..
    Marques-Vidal, Pedro
    Univ Lausanne, Univ Hosp Lausanne, Dept Internal Med, Lausanne, Switzerland..
    Mwinyi, Jessica
    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.
    A genetic variant in the catechol-O-methyl transferase (COMT) gene is related to age-dependent differences in the therapeutic effect of calcium-channel blockers2017In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 96, no 30, article id e7029Article in journal (Refereed)
    Abstract [en]

    Hypertension is the leading risk factor for cardiovascular disease and one of the major health concerns worldwide. Genetic factors impact both the risk for hypertension and the therapeutic effect of antihypertensive drugs. Sex- and age-specific variances in the prevalence of hypertension are partly induced by estrogen. We investigated 6 single nucleotide polymorphisms in genes encoding enzymes involved in estrogen metabolism in relation to sex- and age-specific differences in the systolic and diastolic blood pressure (SBP and DBP) outcome under the treatment of diuretics, calcium-channel blockers (CCBs), angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers (ARBs). We included 5064 subjects (age: 40-82) from the population-based CoLaus cohort. Participants were genotyped for the catechol-O-methyltransferase gene (COMT) variants rs4680, rs737865, and rs165599; the uridine-diphospho-glucuronosyltransferase 1A gene family (UGT1A) variants rs2070959 and rs887829; and the aromatase gene (CYP19A1) variant rs10046. Binomial and linear regression analyses were performed correcting for age, sex, body mass index, smoking, diabetes, and antihypertensive therapy to test whether the variants in focus are significantly associated with BP. All investigated COMT variants were strongly associated with the effect of diuretics, CCBs, and ARBs on SBP or DBP (P<.05), showing an additive effect when occurring in combination. After Bonferroni correction the polymorphism rs4680 (Val(158)Met) in COMT was significantly associated with lower SBP in participants treated with CCBs (P=.009) with an especially strong impact in elderly individuals (age >= 70) alone (Delta=-14.08 mm Hg, P=.0005). These results underline the important role of estrogens and catecholamines in hypertension and the importance of genotype dependent, age-related adjustments of calcium-channel blocker treatment.

  • 440.
    Zan, Yanjun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg, Simon K. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Princeton Univ, Ecol & Evolutionary Biol Dept, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08540 USA.
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    On the Relationship Between High-Order Linkage Disequilibrium and Epistasis2018In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 8, no 8, p. 2817-2824Article in journal (Refereed)
    Abstract [en]

    A plausible explanation for statistical epistasis revealed in genome wide association analyses is the presence of high order linkage disequilibrium (LD) between the genotyped markers tested for interactions and unobserved functional polymorphisms. Based on findings in experimental data, it has been suggested that high order LD might be a common explanation for statistical epistasis inferred between local polymorphisms in the same genomic region. Here, we empirically evaluate how prevalent high order LD is between local, as well as distal, polymorphisms in the genome. This could provide insights into whether we should account for this when interpreting results from genome wide scans for statistical epistasis. An extensive and strong genome wide high order LD was revealed between pairs of markers on the high density 250k SNP-chip and individual markers revealed by whole genome sequencing in the Arabidopsis thaliana 1001-genomes collection. The high order LD was found to be more prevalent in smaller populations, but present also in samples including several hundred individuals. An empirical example illustrates that high order LD might be an even greater challenge in cases when the genetic architecture is more complex than the common assumption of bi-allelic loci. The example shows how significant statistical epistasis is detected for a pair of markers in high order LD with a complex multi allelic locus. Overall, our study illustrates the importance of considering also other explanations than functional genetic interactions when genome wide statistical epistasis is detected, in particular when the results are obtained in small populations of inbred individuals.

  • 441.
    Zhang, Linyu
    et al.
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Dong, Hao
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Si, Youwen
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Wu, Nan
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Cao, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mei, Bing
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Meng, Bo
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    miR-125b promotes tau phosphorylation by targeting the neural cell adhesion molecule in neuropathological progression2019In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 73, p. 41-49Article in journal (Refereed)
    Abstract [en]

    MicroRNAs, small noncoding RNAs, not only regulate gene expression at the post-transcriptional level in a variety of physiological processes but also accompany the initiation and progression of a vast number of diseases, including dementia. While miR-125b has been shown to be aberrantly expressed in some dementia patients, its role in the pathological process remains ambiguous. Presenilin-1/2 conditional double knockout mice exhibit a range of symptoms, including impaired cognition and memory, increased tau phosphorylation, neuroinflammation, and apoptosis, and are therefore regarded as a useful dementia model. In the prefrontal cortices of double knockout mice, miR-125b was found to be abnormally increased in an age-dependent manner. We further verified the neural cell adhesion molecule (NCAM) as an miR-125b target using the dual luciferase reporter assay. The NCAM protein level was decreased when miR-125b was overexpressed (OE) in neuronal growth factor-induced differentiated PC12 cells, which further inhibited the neuronal growth factor-induced phosphorylation of glycogen synthase kinase 3 beta (GSK beta) at the Ser9 site and ultimately increased the GSK3 beta activity and tau phosphorylation. Moreover, on serum deprivation, high GSK3 beta activity in differentiated miR-125b-OE PC12 cells induced increased caspase-3 activation. Finally, adeno-associated virus-mediated miR-125b overexpression in the prefrontal cortexes of wild-type C57B/L6 mice resulted in decreased dendritic spine density. In addition, similar to the in vitro data, elevated GSK3 beta activity and hyperphosphorylation of the tau protein were confirmed. Taken together, our findings reveal a direct regulation of miR-125b on NCAM, which leads to further effects on downstream GSK3 beta activity and tau phosphorylation and may contribute to the generation of neurofibrillary tangles in neuropathological progression. 

  • 442.
    Zheleznyakova, Galina Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Karolinska Inst, Karolinska Univ Hosp, Dept Clin Neurosci, CMM L8-04, S-17176 Stockholm, Sweden..
    Cao, Hao
    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.
    BDNF DNA methylation changes as a biomarker of psychiatric disorders: literature review and open access database analysis2016In: Behavioral and Brain Functions, ISSN 1744-9081, E-ISSN 1744-9081, Vol. 12, article id 17Article, review/survey (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor (BDNF) plays an important role in nervous system development and function and it is well established that BDNF is involved in the pathogenesis of a wide range of psychiatric disorders. Recently, numerous studies have associated the DNA methylation level of BDNF promoters with certain psychiatric phenotypes. In this review, we summarize data from current literature as well as from our own analysis with respect to the correlation of BDNF methylation changes with psychiatric disorders and address questions about whether DNA methylation related to the BDNF can be useful as biomarker for specific neuropsychiatric disorders.

  • 443.
    Zheleznyakova, Galina Y.
    et al.
    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.
    Kiselev, Anton V.
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Xavier, Miguel J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Maretina, Marianna A.
    Tishchenko, Lyudmila I.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Baranov, Vladislav S.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 9, p. 988-993Article in journal (Refereed)
    Abstract [en]

    Spinal muscular atrophy (SMA) is a monogenic disorder that is subdivided into four different types and caused by survival motor neuron gene 1 (SMN1) deletion. Discordant cases of SMA suggest that there exist additional severity modifying factors, apart from the SMN2 gene copy number. Here we performed the first genome-wide methylation profiling of SMA patients and healthy individuals to study the association of DNA methylation status with the severity of the SMA phenotype. We identified strong significant differences in methylation level between SMA patients and healthy controls in CpG sites close to the genes CHML, ARHGAP22, CYTSB, CDK2AP1 and SLC23A2. Interestingly, the CHML and ARHGAP22 genes are associated with the activity of Rab and Rho GTPases, which are important regulators of vesicle formation, actin dynamics, axonogenesis, processes that could be critical for SMA development. We suggest that epigenetic modifications may influence the severity of SMA and that these novel genetic positions could prove to be valuable biomarkers for the understanding of SMA pathogenesis.

  • 444.
    Zheleznyakova, Galina Yu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kiselev, Anton V.
    Vakharlovsky, Viktor G.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chavan, Rohit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Egorova, Anna A.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Baranov, Vladislav S.
    Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III2011In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 12, p. 96-Article in journal (Refereed)
    Abstract [en]

    Background: Spinal muscular atrophy (SMA type I, II and III) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron gene (SMN1). SMN2 is a centromeric copy gene that has been characterized as a major modifier of SMA severity. SMA type I patients have one or two SMN2 copies while most SMA type II patients carry three SMN2 copies and SMA III patients have three or four SMN2 copies. The SMN1 gene produces a full-length transcript (FL-SMN) while SMN2 is only able to produce a small portion of the FL-SMN because of a splice mutation which results in the production of abnormal SMN Delta 7 mRNA. Methods: In this study we performed quantification of the SMN2 gene copy number in Russian patients affected by SMA type II and III (42 and 19 patients, respectively) by means of real-time PCR. Moreover, we present two families consisting of asymptomatic carriers of a homozygous absence of the SMN1 gene. We also developed a novel RT-qPCR-based assay to determine the FL-SMN/SMN Delta 7 mRNA ratio as SMA biomarker. Results: Comparison of the SMN2 copy number and clinical features revealed a significant correlation between mild clinical phenotype (SMA type III) and presence of four copies of the SMN2 gene. In both asymptomatic cases we found an increased number of SMN2 copies in the healthy carriers and a biallelic SMN1 absence. Furthermore, the novel assay revealed a difference between SMA patients and healthy controls. Conclusions: We suggest that the SMN2 gene copy quantification in SMA patients could be used as a prognostic tool for discrimination between the SMA type II and SMA type III diagnoses, whereas the FL-SMN/SMN Delta 7 mRNA ratio could be a useful biomarker for detecting changes during SMA pharmacotherapy.

  • 445.
    Zheleznyakova, Galina Yu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kiselev, Anton V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Maretina, Marianna A.
    Tishchenko, Lyudmila I.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Baranov, Vladislav S.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Methylation Levels of SLC23A2 and NCOR2 Genes Correlate with Spinal Muscular Atrophy Severity2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0121964Article in journal (Refereed)
    Abstract [en]

    Spinal muscular atrophy (SMA) is a monogenic neurodegenerative disorder subdivided into four different types. Whole genome methylation analysis revealed 40 CpG sites associated with genes that are significantly differentially methylated between SMA patients and healthy individuals of the same age. To investigate the contribution of methylation changes to SMA severity, we compared the methylation level of found CpG sites, designed as "targets", as well as the nearest CpG sites in regulatory regions of ARHGAP22, CDK2AP1, CHML, NCOR2, SLC23A2 and RPL9 in three groups of SMA patients. Of notable interest, compared to type I SMA male patients, the methylation level of a target CpG site and one nearby CpG site belonging to the 5'UTR of SLC23A2 were significantly hypomethylated 19-22% in type III-IV patients. In contrast to type I SMA male patients, type III-IV patients demonstrated a 16% decrease in the methylation levels of a target CpG site, belonging to the 5'UTR of NCOR2. To conclude, this study validates the data of our previous study and confirms significant methylation changes in the SLC23A2 and NCOR2 regulatory regions correlates with SMA severity.

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