16
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a “Western diet” (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous ( Slc6a4) gene knockout ( Sert −/−: KO), heterozygous ( Sert +/−: HET), or wild-type mice ( Sert +/+: WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 ( Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a ( Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a “rescued” phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert +/− mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.

          Related collections

          Most cited references76

          • Record: found
          • Abstract: found
          • Article: not found

          Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits.

          Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            5-HT(1A) receptor function in major depressive disorder.

            Dysfunction of the serotonin 1A receptor (5-HT(1A)) may play a role in the genesis of major depressive disorder (MDD). Here we review the pharmacological, post-mortem, positron emission tomography (PET), and genetic evidence in support of this statement. We also touch briefly on two MDD-associated phenotypes, cognitive impairment and somatic pain. The results of pharmacological challenge studies with 5-HT(1A) receptor agonists are indicative of blunted endocrine responses in depressed patients. Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other treatment, such as electroconvulsive shock therapy (ECT), all increase post-synaptic 5-HT(1A) receptor signaling through either direct or indirect effects. Reduced somatodendritic and postsynaptic 5-HT(1A) receptor numbers or affinity have been reported in some post-mortem studies of suicide victims, a result consistent with well-replicated PET analyses demonstrating reduced 5-HT(1A) receptor binding potential in diverse regions such as the dorsal raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus. 5-HT(1A) receptor knockout (KO) mice display increased anxiety-related behavior, which, unlike in their wild-type counterparts, cannot be rescued with antidepressant drug (AD) treatment. In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5-HT(1A) receptor gene (HTR1A; rs6295), which abrogates a transcription factor binding site for deformed epidermal autoregulatory factor-1 (Deaf-1) and Hes5, has been reported to be over-represented in MDD cases. Conversely, the C allele has been associated with better response to AD drugs. We raise the possibility that 5-HT(1A) receptor dysfunction represents one potential mechanism underpinning MDD and other stress-related disorders.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Targeting the murine serotonin transporter: insights into human neurobiology.

              Mutations resulting in reduced or completely abrogated serotonin-transporter (SERT) function in mice have led to the identification of more than 50 different phenotypic changes, ranging from increased anxiety and stress-related behaviours to gut dysfunction, bone weakness and late-onset obesity with metabolic syndrome. These multiple effects, which can be amplified by gene-environment and gene-gene interactions, are primarily attributable to altered intracellular and extracellular serotonin concentrations during development and adulthood. Much of the human data relating to altered expression of the gene that encodes SERT are based on genetic-association findings or correlations and are therefore not as robust as the experimental mouse results. Nevertheless, SERT-function-modifying gene variants in humans apparently produce many phenotypes that are similar to those that manifest themselves in mice.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                18 February 2020
                2020
                : 14
                : 24
                Affiliations
                [1] 1Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University , Maastricht, Netherlands
                [2] 2Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University , Moscow, Russia
                [3] 3Faculty of Medicine, Neuroscience Research Center of Lyon, C. Bernard University Lyon 1 , Lyon, France
                [4] 4V.M. Gorbatov Federal Research Center for Food Systems of RAS , Moscow, Russia
                [5] 5Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg , Würzburg, Germany
                [6] 6Institute of General Pathology and Pathophysiology , Moscow, Russia
                [7] 7School of Pharmacy , Southwest University, Chongqing, China
                [8] 8Institute of Translational Biomedicine, St. Petersburg State University , St. Petersburg, Russia
                [9] 9Ural Federal University , Ekaterinburg, Russia
                [10] 10Department of Pharmacology, Oxford University , Oxford, United Kingdom
                Author notes

                Edited by: Dubravka Hranilovic, University of Zagreb, Croatia

                Reviewed by: Francesca Calabrese, University of Milan, Italy; Berend Olivier, Utrecht University, Netherlands; Jose Emilio Mesonero, University of Zaragoza, Spain

                *Correspondence: Tatyana Strekalova, t.strekalova@ 123456maastrichtuniversity.nl

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2020.00024
                7041415
                32132889
                7ed9d674-ec5f-4f19-a6f5-e8569f6b615f
                Copyright © 2020 Veniaminova, Cespuglio, Chernukha, Schmitt-Boehrer, Morozov, Kalueff, Kuznetsova, Anthony, Lesch and Strekalova.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 October 2019
                : 10 January 2020
                Page count
                Figures: 6, Tables: 6, Equations: 0, References: 89, Pages: 18, Words: 0
                Funding
                Funded by: Russian Science Foundation 10.13039/501100006769
                Funded by: Seventh Framework Programme 10.13039/100011102
                Funded by: European Commission 10.13039/501100000780
                Funded by: European Commission 10.13039/501100000780
                Funded by: Horizon 2020 10.13039/501100007601
                Funded by: Horizon 2020 10.13039/501100007601
                Categories
                Neuroscience
                Original Research

                Neurosciences
                sert-deficient mice,western diet,aging,glucose tolerance,toll-like receptor 4 (tlr4),serotonin receptors,obesity,heterosis

                Comments

                Comment on this article

                scite_

                Similar content115

                Cited by7

                Most referenced authors1,007