Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers
ObjectiveWhile variations in the first intron of the fat mass and obesity-associated gene (FTO, rs9939609 T/A variant) have long been identified as a major contributor to polygenic obesity, the mechanisms underlying weight gain in risk allele carriers still remain elusive. On a behavioral level, FTO...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1130203/full |
| _version_ | 1827952363709661184 |
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| author | Sharmili Edwin Thanarajah Sharmili Edwin Thanarajah Ruth Hanssen Ruth Hanssen Corina Melzer Marc Tittgemeyer Marc Tittgemeyer |
| author_facet | Sharmili Edwin Thanarajah Sharmili Edwin Thanarajah Ruth Hanssen Ruth Hanssen Corina Melzer Marc Tittgemeyer Marc Tittgemeyer |
| author_sort | Sharmili Edwin Thanarajah |
| collection | DOAJ |
| description | ObjectiveWhile variations in the first intron of the fat mass and obesity-associated gene (FTO, rs9939609 T/A variant) have long been identified as a major contributor to polygenic obesity, the mechanisms underlying weight gain in risk allele carriers still remain elusive. On a behavioral level, FTO variants have been robustly linked to trait impulsivity. The regulation of dopaminergic signaling in the meso-striatal neurocircuitry by these FTO variants might represent one mechanism for this behavioral alteration. Notably, recent evidence indicates that variants of FTO also modulate several genes involved in cell proliferation and neuronal development. Hence, FTO polymorphisms might establish a predisposition to heightened trait impulsivity during neurodevelopment by altering structural meso-striatal connectivity. We here explored whether the greater impulsivity of FTO variant carriers was mediated by structural differences in the connectivity between the dopaminergic midbrain and the ventral striatum.MethodsEighty-seven healthy normal-weight volunteers participated in the study; 42 FTO risk allele carriers (rs9939609 T/A variant, FTO+ group: AT, AA) and 39 non-carriers (FTO− group: TT) were matched for age, sex and body mass index (BMI). Trait impulsivity was assessed via the Barratt Impulsiveness Scale (BIS-11) and structural connectivity between the ventral tegmental area/substantia nigra (VTA/SN) and the nucleus accumbens (NAc) was measured via diffusion weighted MRI and probabilistic tractography.ResultsWe found that FTO risk allele carriers compared to non-carriers, demonstrated greater motor impulsivity (p = 0.04) and increased structural connectivity between VTA/SN and the NAc (p< 0.05). Increased connectivity partially mediated the effect of FTO genetic status on motor impulsivity.ConclusionWe report altered structural connectivity as one mechanism by which FTO variants contribute to increased impulsivity, indicating that FTO variants may exert their effect on obesity-promoting behavioral traits at least partially through neuroplastic alterations in humans. |
| first_indexed | 2024-04-09T13:57:17Z |
| format | Article |
| id | doaj.art-f13f627e8e664577b9da7e4381d40e99 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-09T13:57:17Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-f13f627e8e664577b9da7e4381d40e992023-05-08T04:33:00ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-05-011410.3389/fendo.2023.11302031130203Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriersSharmili Edwin Thanarajah0Sharmili Edwin Thanarajah1Ruth Hanssen2Ruth Hanssen3Corina Melzer4Marc Tittgemeyer5Marc Tittgemeyer6Max Planck Institute for Metabolism Research, Cologne, GermanyDepartment for Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyMax Planck Institute for Metabolism Research, Cologne, GermanyFaculty of Medicine and University Hospital Cologne, Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEPD), University of Cologne, Cologne, GermanyMax Planck Institute for Metabolism Research, Cologne, GermanyMax Planck Institute for Metabolism Research, Cologne, GermanyCluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, GermanyObjectiveWhile variations in the first intron of the fat mass and obesity-associated gene (FTO, rs9939609 T/A variant) have long been identified as a major contributor to polygenic obesity, the mechanisms underlying weight gain in risk allele carriers still remain elusive. On a behavioral level, FTO variants have been robustly linked to trait impulsivity. The regulation of dopaminergic signaling in the meso-striatal neurocircuitry by these FTO variants might represent one mechanism for this behavioral alteration. Notably, recent evidence indicates that variants of FTO also modulate several genes involved in cell proliferation and neuronal development. Hence, FTO polymorphisms might establish a predisposition to heightened trait impulsivity during neurodevelopment by altering structural meso-striatal connectivity. We here explored whether the greater impulsivity of FTO variant carriers was mediated by structural differences in the connectivity between the dopaminergic midbrain and the ventral striatum.MethodsEighty-seven healthy normal-weight volunteers participated in the study; 42 FTO risk allele carriers (rs9939609 T/A variant, FTO+ group: AT, AA) and 39 non-carriers (FTO− group: TT) were matched for age, sex and body mass index (BMI). Trait impulsivity was assessed via the Barratt Impulsiveness Scale (BIS-11) and structural connectivity between the ventral tegmental area/substantia nigra (VTA/SN) and the nucleus accumbens (NAc) was measured via diffusion weighted MRI and probabilistic tractography.ResultsWe found that FTO risk allele carriers compared to non-carriers, demonstrated greater motor impulsivity (p = 0.04) and increased structural connectivity between VTA/SN and the NAc (p< 0.05). Increased connectivity partially mediated the effect of FTO genetic status on motor impulsivity.ConclusionWe report altered structural connectivity as one mechanism by which FTO variants contribute to increased impulsivity, indicating that FTO variants may exert their effect on obesity-promoting behavioral traits at least partially through neuroplastic alterations in humans.https://www.frontiersin.org/articles/10.3389/fendo.2023.1130203/fullFTOdopamineconnectivityimpulsivitystructurenucleus accumbens |
| spellingShingle | Sharmili Edwin Thanarajah Sharmili Edwin Thanarajah Ruth Hanssen Ruth Hanssen Corina Melzer Marc Tittgemeyer Marc Tittgemeyer Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers Frontiers in Endocrinology FTO dopamine connectivity impulsivity structure nucleus accumbens |
| title | Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers |
| title_full | Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers |
| title_fullStr | Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers |
| title_full_unstemmed | Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers |
| title_short | Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers |
| title_sort | increased meso striatal connectivity mediates trait impulsivity in fto variant carriers |
| topic | FTO dopamine connectivity impulsivity structure nucleus accumbens |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1130203/full |
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