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      Sex differences in gene expression related to antipsychotic induced weight gain

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          Abstract

          Antipsychotics are crucial for the treatment of schizophrenia and contribute to weight gain in psychosis, particularly during early phases. Antipsychotic Induced Weight Gain (AIWG) might contribute to reduce the quality of life, drug compliance and to increase mortality. To characterize sex differences of gene expression related to AIWG, we sequenced total mRNA from blood samples of schizophrenia patients, before and after 3 months of antipsychotic-treatment. We analyzed schizophrenia patients according to their sex (38 males and 39 females) and their BMI increase after medication, characterizing the differential gene expression before and after medication. Individuals in each group were categorized in patients who gain weight and those whose do not gain weight. The “weight gain” groups included patients with an increase of body mass index (BMI) > 1.0 points (27 males and 23 females with a median BMI increase of 2.68 and 2.32 respectively). The “no weight gain” groups included patients with a change of BMI between < 1.0 and > -1.0 points (11 males and 16 females with a median BMI increase of 0.21 and 0.16 respectively). The males had 331 genes with significant differential expression in the weight gain group and 24 genes in the no weight gain group. The females had 119 genes with significant differential expression in the weight gain group and 75 genes in the no weight gain group. Both weight gain groups were significantly enriched with “obesity” genes (Fisher; p = 1.1E-09 and p = 0.0001 respectively), according to the Gene Reference into Function (GeneRIF) database.In conclusion, we characterized genes with differential expression associated to AIWG that are specific to males, to females and common to both sexes. These genes are good candidates to depict the biological processes involved in AIWG and provide additional evidence of the genetic links between weight gain and the immune system.

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          Rethinking schizophrenia.

          How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects about one per cent of the world's population. After a century of studying schizophrenia, the cause of the disorder remains unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is little evidence that these treatments have substantially improved outcomes for most people with schizophrenia. These current unsatisfactory outcomes may change as we approach schizophrenia as a neurodevelopmental disorder with psychosis as a late, potentially preventable stage of the illness. This 'rethinking' of schizophrenia as a neurodevelopmental disorder, which is profoundly different from the way we have seen this illness for the past century, yields new hope for prevention and cure over the next two decades.
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            Inflammation: the link between insulin resistance, obesity and diabetes.

            Recent data have revealed that the plasma concentration of inflammatory mediators, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), is increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. It is also intriguing that an increase in inflammatory mediators or indices predicts the future development of obesity and diabetes. Two mechanisms might be involved in the pathogenesis of inflammation. Firstly, glucose and macronutrient intake causes oxidative stress and inflammatory changes. Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-alpha and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.
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              Neuregulin 1 and susceptibility to schizophrenia.

              The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SoftwareRole: Writing – review & editing
                Role: Funding acquisitionRole: InvestigationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 April 2019
                2019
                : 14
                : 4
                : e0215477
                Affiliations
                [1 ] Spanish National Research Council (CSIC), Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), Santander, Spain
                [2 ] Bioinformatics Service, Nucleus, University of Salamanca (USAL), Salamanca, Spain
                [3 ] University Hospital Marqués de Valdecilla, IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain
                [4 ] CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Santander, Spain
                [5 ] University Hospital Virgen del Rocio, University of Sevilla, Seville, Spain
                Maastricht University, NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-4018-7175
                Article
                PONE-D-18-35024
                10.1371/journal.pone.0215477
                6464344
                30986260
                8ab62513-3589-4f6c-a791-2520eb063628
                © 2019 Sainz et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 December 2018
                : 2 April 2019
                Page count
                Figures: 1, Tables: 1, Pages: 13
                Funding
                Funded by: Spanish Ministry of Economy
                Award ID: PTA2015-10483-I
                Award Recipient :
                Funded by: Ministerio de Ciencia e Innovación
                Award ID: SAF2010-20840-C02-01/02
                Award Recipient :
                Funded by: Ministerio de Ciencia e Innovación
                Award ID: SAF2010-20840-C02-01/02
                Award Recipient :
                Funded by: Spanish Ministry of Economy, Industry and Competitiveness
                Award ID: SAF2013-46292-R
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 5R01HD056465-07
                Award Recipient :
                CP was supported by the PTA fellowship (PTA2015-10483-I) of the Spanish Ministry of Economy, Industry and Competitiveness (MINECO). BCF was supported by the Ministerio de Ciencia e Innovación (MICINN) in the coordinated project SAF2010-20840-C02-01/02 and by MINECO (SAF2013-46292-R). JS was supported by MICINN (SAF2010-20840-C02-01) and by the NIH (5R01HD056465-07; Sub-award #320793 from The Children’s Hospital of Philadelphia). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Weight Gain
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Weight Gain
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antipsychotics
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Clinical Genetics
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Body Mass Index
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Body Mass Index
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Schizophrenia
                Biology and Life Sciences
                Immunology
                Immune System
                Medicine and Health Sciences
                Immunology
                Immune System
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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                Uncategorized

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