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      FTO affects hippocampal function by regulation of BDNF processing

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          Abstract

          Initially, the function of the fat mass and obesity associated (Fto) gene seemed to be primarily the regulation of the body weight. Here we show that loss of Fto results in a hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In consequence, Fto -/- mice display an anxiety-like behavior and impairments in working memory. Furthermore, differentiation of neurons is affected in the hippocampus. As a cause of these impairments we identified a processing defect of the neurotrophin BDNF which is most likely the result of a reduced expression of MMP-9. Therefore, we propose FTO as a possible new target to develop novel approaches for the treatment of diseases associated with hippocampal disorders. In parallel, we also would like to make the point that any anti-obesity therapy via blocking FTO function can have negative effects on the proper function of the hippocampus.

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          Most cited references 32

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          Adult hippocampal neurogenesis buffers stress responses and depressive behavior

          Summary Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness 1, 2 . In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis 3 . Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking 4, 5 . Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioral components of the stress response. Using transgenic and radiation methods to specifically inhibit adult neurogenesis, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice compared with intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis 6, 7 . Relative to controls, neurogenesis-deficient mice showed increased food avoidance in a novel environment after acute stress, increased behavioral despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.
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            Inactivation of the Fto gene protects from obesity.

            Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene. Common variants in the first intron define a risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.
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              The involvement of the anterior cingulate cortex in remote contextual fear memory.

              Although the molecular, cellular, and systems mechanisms required for initial memory processing have been intensively investigated, those underlying permanent memory storage remain elusive. We present neuroanatomical, pharmacological, and genetic results demonstrating that the anterior cingulate cortex plays a critical role in remote memory for contextual fear conditioning. Imaging of activity-dependent genes shows that the anterior cingulate is activated by remote memory and that this activation is impaired by a null alpha-CaMKII mutation that blocks remote memory. Accordingly, reversible inactivation of this structure in normal mice disrupts remote memory without affecting recent memory.
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                Author and article information

                Contributors
                Role: InvestigationRole: Writing – original draft
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                7 February 2019
                2019
                : 14
                : 2
                Affiliations
                Institute of Animal Developmental and Molecular Biology, Heinrich Heine University, Düsseldorf, Germany
                Radboud University Medical Centre, NETHERLANDS
                Author notes

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

                [¤]

                Current address: Institute of Cardiovascular Physiology, Heinrich Heine University, Düsseldorf, Germany

                Article
                PONE-D-18-18245
                10.1371/journal.pone.0211937
                6366932
                30730976
                © 2019 Spychala, Rüther

                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.

                Page count
                Figures: 5, Tables: 0, Pages: 14
                Product
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Brain
                Hippocampus
                Medicine and Health Sciences
                Anatomy
                Brain
                Hippocampus
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Rodents
                Mice
                Biology and Life Sciences
                Developmental Biology
                Cell Differentiation
                Neuronal Differentiation
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognitive Neuroscience
                Cognitive Neurology
                Cognitive Impairment
                Biology and Life Sciences
                Neuroscience
                Cognitive Neuroscience
                Cognitive Neurology
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                Medicine and Health Sciences
                Neurology
                Cognitive Neurology
                Cognitive Impairment
                Biology and Life Sciences
                Psychology
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                Animal Behavior
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                Psychology
                Behavior
                Animal Behavior
                Biology and Life Sciences
                Zoology
                Animal Behavior
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognitive Neuroscience
                Working Memory
                Biology and Life Sciences
                Neuroscience
                Cognitive Neuroscience
                Working Memory
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognition
                Memory
                Working Memory
                Biology and Life Sciences
                Neuroscience
                Learning and Memory
                Memory
                Working Memory
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Biology and Life Sciences
                Anatomy
                Brain
                Hippocampal Formation
                Dentate Gyrus
                Medicine and Health Sciences
                Anatomy
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                Hippocampal Formation
                Dentate Gyrus
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