PMID- 32132889 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 14 DP - 2020 TI - Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity? PG - 24 LID - 10.3389/fnins.2020.00024 [doi] LID - 24 AB - 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. CI - Copyright (c) 2020 Veniaminova, Cespuglio, Chernukha, Schmitt-Boehrer, Morozov, Kalueff, Kuznetsova, Anthony, Lesch and Strekalova. FAU - Veniaminova, Ekaterina AU - Veniaminova E AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands. AD - Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia. FAU - Cespuglio, Raymond AU - Cespuglio R AD - Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia. AD - Faculty of Medicine, Neuroscience Research Center of Lyon, C. Bernard University Lyon 1, Lyon, France. FAU - Chernukha, Irina AU - Chernukha I AD - V.M. Gorbatov Federal Research Center for Food Systems of RAS, Moscow, Russia. FAU - Schmitt-Boehrer, Angelika G AU - Schmitt-Boehrer AG AD - Division of Molecular Psychiatry, Center of Mental Health, University of Wurzburg, Wurzburg, Germany. FAU - Morozov, Sergey AU - Morozov S AD - Institute of General Pathology and Pathophysiology, Moscow, Russia. FAU - Kalueff, Allan V AU - Kalueff AV AD - School of Pharmacy, Southwest University, Chongqing, China. AD - Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia. AD - Ural Federal University, Ekaterinburg, Russia. FAU - Kuznetsova, Oxana AU - Kuznetsova O AD - V.M. Gorbatov Federal Research Center for Food Systems of RAS, Moscow, Russia. FAU - Anthony, Daniel C AU - Anthony DC AD - Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia. AD - Department of Pharmacology, Oxford University, Oxford, United Kingdom. FAU - Lesch, Klaus-Peter AU - Lesch KP AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands. AD - Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia. AD - Division of Molecular Psychiatry, Center of Mental Health, University of Wurzburg, Wurzburg, Germany. FAU - Strekalova, Tatyana AU - Strekalova T AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands. AD - Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia. AD - Division of Molecular Psychiatry, Center of Mental Health, University of Wurzburg, Wurzburg, Germany. AD - Institute of General Pathology and Pathophysiology, Moscow, Russia. LA - eng PT - Journal Article DEP - 20200218 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC7041415 OTO - NOTNLM OT - Sert-deficient mice OT - Toll-like receptor 4 (TLR4) OT - Western diet OT - aging OT - glucose tolerance OT - heterosis OT - obesity OT - serotonin receptors EDAT- 2020/03/07 06:00 MHDA- 2020/03/07 06:01 PMCR- 2020/01/01 CRDT- 2020/03/06 06:00 PHST- 2019/10/14 00:00 [received] PHST- 2020/01/10 00:00 [accepted] PHST- 2020/03/06 06:00 [entrez] PHST- 2020/03/07 06:00 [pubmed] PHST- 2020/03/07 06:01 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fnins.2020.00024 [doi] PST - epublish SO - Front Neurosci. 2020 Feb 18;14:24. doi: 10.3389/fnins.2020.00024. eCollection 2020.