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Consuming a \u201cWestern diet\u201d (WD), which is high in saturated fats, cholesterol, and sugars, can induce metabolic syndrome. Previous research indicated that mice carrying a targeted inactivation of the Sert gene (knockout, KO) and fed a WD display significant metabolic disturbances and behaviors reminiscent of ADHD. These abnormalities might be mediated via a dysfunction in insulin receptor (IR) signaling, which is also associated with adult ADHD. However, the impact of Sert deficiency on IR signaling and systemic metabolic changes has not been thoroughly explored. In this study, we conducted a detailed analysis of locomotor behavior in wild-type (WT) and KO mice fed a WD or control diet. We investigated changes in the blood metabolome and examined, via PCR, the expression of insulin receptor A and B isoforms and key regulators of their function in the brain. Twelve-month-old KO mice and their WT littermates were fed a WD for three weeks. Nuclear magnetic resonance spectroscopy analysis of plasma samples showed that KO mice on a WD had higher levels of lipids and lipoproteins and lower levels of glucose, lactate, alanine, valine, and isoleucine compared to other groups. SERT-KO mice on the control diet exhibited increased brain levels of both IR A and B isoforms, accompanied by a modest increase in the negative regulator ENPP. The KO mice also displayed anxiety-like behavior and reduced exploratory activity in an open field test. However, when the KO animals were fed a WD, the aberrant expression levels of IR isoforms in the KO mice and locomotor behavior were ameliorated indicating a complex interaction between genetic and dietary factors that might contribute to ADHD-like symptoms. Overall, our findings suggest that the lack of Sert leads to a unique metabolic phenotype in aged mice, characterized by dysregulated IR-related pathways. These changes are exacerbated by WD in the blood metabolome and are associated with behavioral abnormalities.<\/jats:p>","DOI":"10.3390\/biom14080884","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T14:26:50Z","timestamp":1721744810000},"page":"884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Impact of Serotonin Transporter Absence on Brain Insulin Receptor Expression, Plasma Metabolome Changes, and ADHD-like Behavior in Mice fed a Western Diet"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-6655","authenticated-orcid":false,"given":"Daniel C.","family":"Anthony","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fay","family":"Probert","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK"},{"name":"Department of Chemistry, Oxford University, Oxford OX1 2JD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Gorlova","sequence":"additional","affiliation":[{"name":"Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenna","family":"Hebert","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8781-7459","authenticated-orcid":false,"given":"Daniel","family":"Radford-Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zlata","family":"Nefedova","sequence":"additional","affiliation":[{"name":"Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksei","family":"Umriukhin","sequence":"additional","affiliation":[{"name":"Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5915-7999","authenticated-orcid":false,"given":"Andrey","family":"Nedorubov","sequence":"additional","affiliation":[{"name":"Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-8643","authenticated-orcid":false,"given":"Raymond","family":"Cespuglio","sequence":"additional","affiliation":[{"name":"Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boris","family":"Shulgin","sequence":"additional","affiliation":[{"name":"Laboratory of Engineering Profile Physical and Chemical Methods of Analysis, Korkyt Ata Kyzylorda University, Kyzylorda 120014, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksey","family":"Lyundup","sequence":"additional","affiliation":[{"name":"Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia"},{"name":"Endocrinology Research Centre, Dmitry Ulyanov Str. 19, 117036 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus Peter","family":"Lesch","sequence":"additional","affiliation":[{"name":"Division of Molecular Psychiatry, Center of Mental Health, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"},{"name":"Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatyana","family":"Strekalova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.2169\/internalmedicine.4975-20","article-title":"Impact of Metabolic Syndrome on the Mortality Rate among Participants in a Specific Health Check and Guidance Program in Japan","volume":"59","author":"Iseki","year":"2020","journal-title":"Intern. 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