Obesity gene NEGR1 associated with white matter integrity in healthy young adults

Dennis, Emily L.; Jahanshad, Neda; Braskie, Meredith N.; Warstadt, Nicholus M.; Hibar, Derrek P.; Kohannim, Omid; Nir, Talia M.; McMahon, Katie L.; Zubicaray, Greig I. de; Montgomery, Grant W.; Martin, Nicholas G.; Toga, Arthur W.; Wright, Margaret J.; Thompson, Paul M.

doi:10.1016/j.neuroimage.2014.07.041

Cited by 35 publications

(30 citation statements)

References 65 publications

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“…However, declines in nodal and paranodal axonal complexes observed in HFD mice indicate that axonal conduction could be impaired. Single nucleotide polymorphisms in the neuronal cell adhesion gene, Negr1, are associated with obesity (Willer et al, 2009) and reduce FA in white matter tracts (Dennis et al, 2014) suggesting that there may also be neuronal factors driving reduced axoglial signaling and myelination in obese white matter.…”

Section: The Structural Integrity Of White Matter Is Compromised By Omentioning

confidence: 99%

Obesity blocks oligodendrocyte precursor cell differentiation and impedes repair after white matter stroke

Xiao

Burguet

Kawaguchi

et al. 2018

Preprint

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Obesity is a growing public health problem that increases rates of white matter atrophy and increases the likelihood of ischemic lesions within white matter. However, the cellular and molecular mechanisms that regulate these changes are unknown. We hypothesized that obesity may alter oligodendrocytes and myelin priming white matter for worsening injury and repair responses after ischemia. C57Bl/6 mice fed a high fat diet (60% kcal from fat) show increased numbers of oligodendrocyte progenitor cells (OPCs), decreased myelin thickness with elevated g-ratios, and shorter paranodal axonal segments, indicating compromised myelination in high fat diet mice. Fate mapping of OPCs in PDGFR-Cre ERT ;Rpl22 tm1.1Psam mice demonstrated that OPC differentiation rates are enhanced by obesity. Gene expression analyses using a novel oligodendrocyte staging assay demonstrated that obesity restricts oligodendrocyte maturation in between the pre-myelinating and myelinating stages. Using a model of subcortical white matter stroke, the number of stroke-responsive OPCs in obese mice was increased after stroke. At early time points after ischemic white matter stroke, spatial mapping of stroke-responsive OPCs indicates that obesity leads to increased OPCs at the edge of ischemic white matter lesions. At later time points, obesity results in increased OPCs within the ischemic lesion while reducing the number of GST--positive mature oligodendrocytes in the lesion core. These data indicate that obesity disrupts normal white matter biology by impeding oligodendrocyte differentiation, leading to an exaggerated response of OPCs to white matter ischemia, and limited brain repair after stroke.All rights reserved. No reuse allowed without permission.

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Section: The Structural Integrity Of White Matter Is Compromised By Omentioning

confidence: 99%

Obesity blocks oligodendrocyte precursor cell differentiation and impedes repair after white matter stroke

Xiao

Burguet

Kawaguchi

et al. 2018

Preprint

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“…The corona radiata is an extensive WM structure with large fibres carrying information from and to the cerebral cortex. Interestingly, a recent study investigating the effect of 16 obesity‐related genes in mostly normal‐weight young adults showed the strongest association between the obesity‐risk gene neural growth regulator 1 ( NEGR1; rs2815752 ) and lower WM integrity (lower FA values), especially in the corona radiata . NEGR1 is important for neural development and the risk allele has been associated with a higher BMI .…”

Section: Dti Studies In Obesity Researchmentioning

confidence: 99%

Compromised white matter integrity in obesity

et al. 2015

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Obesity is associated with both structural and functional changes of the central nervous system. While gray matter alterations in obesity point to a consistent reduction with increasing body mass index (BMI), volumetric changes in white matter are more complex and less conclusive. Hence, more recently, diffusion tensor imaging (DTI) has been employed as a highly sensitive tool to investigate microstructural changes in white matter structure. Parameters of diffusivity and anisotropy are used to evaluate white matter and fibre integrity as well as axonal and myelin degeneration. Fractional anisotropy (FA) is the most commonly used parameter as it is the best estimate of fibre integrity. The focus of this review was on the relationship between obesity and brain alterations assessed by DTI. Altogether, these studies have shown a loss of white matter integrity with obesity-related factors, especially in tracts within the limbic system and those connecting the temporal and frontal lobe. More specifically, multiple studies found an inverse association between BMI and FA in the corpus callosum, fornix, cingulum and corona radiata in elderly and young adults as well as children. Furthermore, significant interactions were observed between BMI and age, pointing to accelerated ageing of white matter structure in obese.

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“…Overlap between genetic risk for obesity and white matter microstructural integrity (in the corpus callosum and superior fronto-occipital tract) has also been reported (Spieker et al, 2015). SNPs in a number of candidate genes, including FTO (Chuang et al, 2015), and NEGR1 (Dennis et al, 2014) have also been shown to contribute to both obesity and neural structure and/or function.…”

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confidence: 99%

Contributions of polygenic risk for obesity to PTSD-related metabolic syndrome and cortical thickness

Wolf

Miller

Logue

et al. 2017

Brain, Behavior, and Immunity

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Background Research suggests that posttraumatic stress disorder (PTSD) is associated with metabolic syndrome (MetS) and that PTSD-associated MetS is related to decreased cortical thickness. However, the role of genetic factors in these associations is unclear. This study evaluated contributions of polygenic obesity risk and PTSD to MetS and of MetS and polygenic obesity risk to cortical thickness. Methods 196 white, non-Hispanic veterans of the wars in Iraq and Afghanistan underwent clinical diagnostic interviews, physiological assessments, and genome-wide genotyping; 168 also completed magnetic resonance imaging scans. Polygenic risk scores (PRSs) for obesity were calculated from results of a prior genome-wide association study (Speliotes et al., 2010) and PTSD and MetS severity factor scores were obtained. Results Obesity PRS (β = .15, p = .009) and PTSD (β = .17, p = .005) predicted MetS and interacted such that the association between PTSD and MetS was stronger in individuals with greater polygenic obesity risk (β = .13, p = .02). Whole-brain vertex-wise analyses suggested that obesity PRS interacted with MetS to predict decreased cortical thickness in left rostral middle frontal gyrus (β = −.40, p < .001). Conclusions Results suggest that PTSD, genetic variability, and MetS are related in a transactional fashion wherein obesity genetic risk increases stress-related metabolic pathology, and compounds the ill health effects of MetS on the brain. Genetic proclivity towards MetS should be considered in PTSD patients when prescribing psychotropic medications with adverse metabolic profiles. Results are consistent with a growing literature suggestive of PTSD-related accelerated aging.

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Obesity gene NEGR1 associated with white matter integrity in healthy young adults

Cited by 35 publications

References 65 publications

Obesity blocks oligodendrocyte precursor cell differentiation and impedes repair after white matter stroke

Obesity blocks oligodendrocyte precursor cell differentiation and impedes repair after white matter stroke

Compromised white matter integrity in obesity

Contributions of polygenic risk for obesity to PTSD-related metabolic syndrome and cortical thickness

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