Impact of Serotonin Transporter Absence on Brain Insulin Receptor Expression, Plasma Metabolome Changes, and ADHD-like Behavior in Mice fed a Western Diet
Anthony D.C. Probert F. Gorlova A. Hebert J. Radford-Smith D. Nefedova Z. Umriukhin A. Nedorubov A. Cespuglio R. Shulgin B. Lyundup A. Lesch K.P. Strekalova T.
August 2024Multidisciplinary Digital Publishing Institute (MDPI)
Biomolecules
2024#14Issue 8
The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a “Western diet” (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.
ADHD , aging , glucose tolerance , insulin receptors , metabolomics , serotonin transporter , Sert-deficient mice , western diet
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Department of Pharmacology, Oxford University, Oxford, OX1 3QT, United Kingdom
Department of Chemistry, Oxford University, Oxford, OX1 2JD, United Kingdom
Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), Moscow, 117198, Russian Federation
Department of Normal Physiology, Sechenov First Moscow State Medical University, Moscow, 119991, Russian Federation
Laboratory of Engineering Profile Physical and Chemical Methods of Analysis, Korkyt Ata Kyzylorda University, Kyzylorda, 120014, Kazakhstan
Endocrinology Research Centre, Dmitry Ulyanov Str. 19, Moscow, 117036, Russian Federation
Division of Molecular Psychiatry, Center of Mental Health, University Hospital Würzburg, Würzburg, 97080, Germany
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, 97080, Germany
Department of Pharmacology
Department of Chemistry
Research and Education Resource Center
Department of Normal Physiology
Laboratory of Engineering Profile Physical and Chemical Methods of Analysis
Endocrinology Research Centre
Division of Molecular Psychiatry
Department of Child and Adolescent Psychiatry
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