The effect of body mass index on glucagon-like peptide receptor gene expression in the post mortem brain from individuals with mood and psychotic disorders

Mansur, Rodrigo B.; Fries, Gabriel R.; Trevizol, Alisson Paulino; Subramaniapillai, Mehala; Lovshin, Julie A.; Lin, Kangguang; Vinberg, Maj; Ho, Roger; Brietzke, Elisa; McIntyre, Roger S.

doi:10.1016/j.euroneuro.2018.10.007

Cited by 20 publications

(18 citation statements)

References 47 publications

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“…Multiple allostatic mediators function as part of a nonlinear network that contributes to the development of AL, including elevated levels of stress hormones (eg, cortisol, epinephrine), proinflammatory markers (eg, C‐reactive protein, Il‐6, TNF‐a), and oxidative stress 12,13 . These then contribute to damaging effects in the brain and other organs, including altered gene expression, 14 telomere shortening 15 and ultimately playing a role in cognitive, cardiovascular, and immune dysfunction as well as in obesity, bone demineralization and atrophy of cerebral nerve cells, whose association with BD is well established 16,17 …”

Section: Introductionmentioning

confidence: 99%

Allostatic load, emotional hyper‐reactivity, and functioning in individuals with bipolar disorder

et al. 2020

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Objectives Diagnosis and management of bipolar disorder (BD) are limited by the absence of available biomarkers. Allostatic load (AL) represents the strain that stress, including the effects of acute phases and inter‐episode chronic mood instability, exerts on interconnected biological systems. This study aimed to operationalize an AL index and explore whether it could be relevant to better characterize BD patients with and without emotional hyper‐reactivity particularly those at higher risk of immune‐cardiometabolic dysregulation and functional impairment. Methods Levels of biomarkers of chronic inflammation (hsCRP and albumin), cardiovascular (systolic/diastolic blood pressure) and metabolic functions (fasting glucose, glycosylated hemoglobin, total cholesterol, LDL, HDL, and triglycerides) were measured in 1072 adult BD outpatients. Patients were classified in two groups (with/without emotional hyper‐reactivity) assessed by the Multidimensional Assessment of Thymic States scale. An Allostatic Load Index for BD (BALLI), comprising six biomarkers, was constructed using data‐driven biomarker selection. Results BALLI showed 81.1% accuracy with good sensitivity (81%) and specificity (81.2%) for characterizing BD patients presenting emotional hyper‐reactivity, elevated risk of inflammation (increased hsCRP, hypoalbuminemia) and cardiometabolic disturbances (hypertension, hyperglycemia, and hypertriglyceridemia). Patients classified by the BALLI as presenting emotional hyper‐reactivity had significantly lower global and cognitive functioning than those without emotional hyper‐reactivity (P < .0001). Conclusions A multidimensional approach based on a simple AL score (eg, BALLI) and dimensions of behavior (eg, emotional hyper‐reactivity) alongside mood is clinically relevant. AL index could be a useful tool to detect multisystemic physiological dysregulations in BD patients with/without emotional hyper‐reactivity particularly those at higher risk of immune‐cardiometabolic disturbances and functional impairment.

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Section: Introductionmentioning

confidence: 99%

Allostatic load, emotional hyper‐reactivity, and functioning in individuals with bipolar disorder

et al. 2020

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“…Furthermore, a recent review suggested that 24 genes previously associated with cardiometabolic phenotypes are also associated with mood disorders (major depressive disorder (MDD) and BD) 26 . An overview of studies previously investigating the role of genes potentially involved in both BD and obesity or T2D 16,17,21,27–36 is reported in Table 1. The majority of these studies investigated variants already known to be associated with T2D or other metabolic phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI

et al. 2019

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Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E−04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E−05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E−24), five were located in the ETV5 gene (best SNP: rs1516725, p = 1E−24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E−09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E−08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.

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“…increased immobility in a tail-suspension test) [15]. In a human brain study, GLP2R was significantly decreased in the dorsolateral prefrontal cortex, but not dysregulated within the hippocampus (just a decreasing trend of GLP2R) [23]. In contrast, decreased GLP2R resulted in cognitive impairment in Sprague-Dawley rats subjected to chronic cerebral hypoperfusion [22].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice

Ang

Kim

Lee

et al. 2020

IJMS

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Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in the central nervous system. However, little is known about the biological effects of SREBP-1c in the brain. Our previous study uncovered that mice deficient in SREBP-1c exhibit schizophrenia-like behaviors. To investigate whether there are novel molecular mechanisms involved in the neurological aberrations caused by SREBP-1c deficiency, we analyzed the transcriptomes of the hippocampus of SREBP-1c knockout (KO) mice and wild-type mice. We found seven differentially expressed genes (three up-regulated and four down-regulated genes) in the hippocampus of SREBP-1c KO mice. For further verification, we selected the three most significantly changed genes: glucagon-like peptide 2 receptors (GLP2R) involved in hippocampal neurogenesis and neuroplasticity as well as in cognitive impairments; necdin (NDN) which is related to neuronal death and neurodevelopmental disorders; and Erb-B2 receptor tyrosine kinase 4 (ERBB4) which is a receptor for schizophrenia-linked protein, neuregulin-1. The protein levels of GLP2R and NDN were considerably decreased, but the level of ERBB4 was significantly increased in the hippocampus of SREBP-1c KO mice. However, further confirmation is warranted to establish the translatability of these findings from this rodent model into human patients. We suggest that these data provide novel molecular evidence for the modulatory role of SREBP-1c in the mouse hippocampus.

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The effect of body mass index on glucagon-like peptide receptor gene expression in the post mortem brain from individuals with mood and psychotic disorders

Cited by 20 publications

References 47 publications

Allostatic load, emotional hyper‐reactivity, and functioning in individuals with bipolar disorder

Allostatic load, emotional hyper‐reactivity, and functioning in individuals with bipolar disorder

Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI

Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice

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