AUTHOR=Edwin Thanarajah Sharmili , Hanssen Ruth , Melzer Corina , Tittgemeyer Marc 

TITLE=Increased meso-striatal connectivity mediates trait impulsivity in FTO variant carriers

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1130203

DOI=10.3389/fendo.2023.1130203

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p>While variations in the first intron of the <italic>fat mass and obesity-associated gene</italic> (<italic>FTO</italic>, 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, <italic>FTO</italic> variants have been robustly linked to trait impulsivity. The regulation of dopaminergic signaling in the meso-striatal neurocircuitry by these <italic>FTO</italic> variants might represent one mechanism for this behavioral alteration. Notably, recent evidence indicates that variants of <italic>FTO</italic> 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 <italic>FTO</italic> variant carriers was mediated by structural differences in the connectivity between the dopaminergic midbrain and the ventral striatum.</p></sec><sec><title>Methods</title><p>Eighty-seven healthy normal-weight volunteers participated in the study; 42 FTO risk allele carriers (rs9939609 T/A variant, <italic>FTO</italic><sup>+</sup> group: AT, AA) and 39 non-carriers (<italic>FTO</italic><sup>−</sup> 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.</p></sec><sec><title>Results</title><p>We found that <italic>FTO</italic> risk allele carriers compared to non-carriers, demonstrated greater motor impulsivity (<italic>p</italic> = 0.04) and increased structural connectivity between VTA/SN and the NAc (p&lt; 0.05). Increased connectivity partially mediated the effect of FTO genetic status on motor impulsivity.</p></sec><sec><title>Conclusion</title><p>We report altered structural connectivity as one mechanism by which <italic>FTO</italic> variants contribute to increased impulsivity, indicating that <italic>FTO</italic> variants may exert their effect on obesity-promoting behavioral traits at least partially through neuroplastic alterations in humans.</p></sec>