Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes

Mansur, Rodrigo B.; Fries, Gabriel R.; Subramaniapillai, Mehala; Frangou, Sophia; Felice, Fernanda G. De; Rasgon, Natalie; McEwen, Bruce S.; Brietzke, Elisa; McIntyre, Roger S.

doi:10.1016/j.jpsychires.2018.10.020

Cited by 20 publications

(11 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In autopsy results, decreased expression of insulin receptor‐associated signalling genes (ie, INSR, IRS1 and IRS2) resulted in genes that regulate dopamine neurotransmission in dlPFC and hippocampus (ie, DDC, TH, VMAT2, DRD1, DRD2, DRD5 and MAOB). The gene expression is reduced, which in turn leads to lower dopamine metabolism 152 . This result is basically consistent with relevant clinical data 150,153,154 …”

Section: Effect Of Insulin On Depressionsupporting

confidence: 88%

Potential role of insulin on the pathogenesis of depression

et al. 2020

View full text Add to dashboard Cite

| INTRODUC TI ONDiabetes is a metabolic disease characterized by hyperglycaemia due to the defect of insulin secretion or impaired insulin biological effect. A survey has shown that about 30% of people with diabetes also suffer from depression and 10% have severe depression, which suggests a close relationship between the two diseases. 1,2 The mechanism of depression as a complication of diabetes is not completely clear, but studies have found that insulin deficiency or insulin resistance is the symptom that can also be observed in major depression disorder. [3][4][5] Insulin is the only hormone in the human body that reduces the blood glucose level and promotes the synthesis of glycogen, fat and protein. Several studies found that insulin had the ability to affect the nervous system. 6-8 Insulin receptors were distributed in other parts of the brain, except for the parts related to food intake and energy. 9-11 Experiments have gradually revealed other functions of insulin in the brain, for instance promoting memory, protecting neurons, regulating synaptic plasticity and maintaining HPA axis homeostasis. [12][13][14] These effects of insulin may provide a background for its relationship with depression. 15,16 In this case, although there is no direct evidence supporting the link between insulin and treatment for depression, more and more researches support this hypothesis. Here, we review the relationship between insulin signalling and neurophysiological homeostasis, neurotrophic metabolism, cellular pathways and some survey statistics.The exploration of these links and the validation of more relevant mechanisms will develop a new impact on the way of the diagnosis and treatment of depression. | IN SULIN AND DEPRE SS I ONAs early as 1980s, many evidences proved that insulin influenced depression and functional insulin receptors were widely present in the brain. [17][18][19] Data from clinical and epidemiological studies demonstrate a two-way link between emotion and metabolic dysfunction. In young depression patients, insulin sensitivity is significantly decreased. 20,21 Compared with "low insulin" (1.5 mU/kg × min), "high insulin" (15 mU/kg × min) induces a more pronounced of the ability to remember word lists in human being. 22 Intranasal delivery of insulin in awake mice can transmit regulatory and metabolic AbstractThe regulation of insulin on depression and depression-like behaviour has been widely reported. Insulin and activation of its receptor can promote learning and memory, affect the hypothalamic-pituitary-adrenal axis (HPA) balance, regulate the secretion of neurotrophic factors and neurotransmitters, interact with gastrointestinal microbiome, exert neuroprotective effects and have an impact on depression. However, the role of insulin on depression remains largely unclear. Therefore, in this review, we summarized the potential role of insulin on depression. It may provide new insight for clarifying role of insulin on the pathogenesis of depression.

show abstract

Section: Effect Of Insulin On Depressionsupporting

confidence: 88%

Potential role of insulin on the pathogenesis of depression

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A recent study demonstrated that the knockdown of insulin receptors in astrocytes also generates anxiety and depressive-like behavior in mice, via decreased purinergic signaling and altered dopamine release (24). A recent post-mortem analysis in the brain of patients diagnosed with mental illness has observed a correlation between gene expression of proteins involved with both the dopaminergic system and the insulin signaling (25), supporting the idea that insulin could regulate the dopaminergic response. Oppositely, another report observed that deleting insulin receptors from dopaminergic neurons had no impact on anxiety or depressive-like behavior in young adult mice (26).…”

Section: Molecular Links Between Depression and Diabetesmentioning

confidence: 86%

Insulin Resistance as a Shared Pathogenic Mechanism Between Depression and Type 2 Diabetes

et al. 2019

Self Cite

View full text Add to dashboard Cite

Neuropsychiatric disorders and type 2 diabetes (T2D) are major public health concerns proposed to be intimately connected. T2D is associated with increased risk of dementia, neuropsychiatric and mood disorders. Evidences of the involvement of insulin signaling on brain mechanisms related to depression indicate that insulin resistance, a hallmark of type 2 diabetes, could develop in the brains of depressive patients. In this article, we briefly review possible molecular mechanisms associating defective brain insulin signaling with reward system, neurogenesis, synaptic plasticity and hypothalamic-pituitary-adrenal (HPA) stress axis in depression. We further discuss the involvement of tumor necrosis factor α (TNFα) promoting defective insulin signaling and depressive-like behavior in rodent models. Finally, due to the high resistant rate of anti-depressants, novel insights into the link between insulin resistance and depression may advance the development of alternative treatments for this disease.

show abstract

“…These results suggest a potential interplay between BMI and molecular targets involved in the mechanism of action of this mood stabilizer. Although a link between BD and BMI has been established, the molecular mechanisms underlying this comorbidity have only recently started to be investigated and are still largely unknown 16,17 . Increasing our scarce knowledge of the factors predisposing patients with BD to develop metabolic comorbidities such as obesity and T2D would be of great importance, eventually allowing us to identify patients that could benefit from early monitoring and/or intervention.…”

Section: Introductionmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes

Cited by 20 publications

References 73 publications

Potential role of insulin on the pathogenesis of depression

Potential role of insulin on the pathogenesis of depression

Insulin Resistance as a Shared Pathogenic Mechanism Between Depression and Type 2 Diabetes

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

Contact Info

Product

Resources

About