Glucocorticoid receptor polymorphism in obesity and glucose homeostasis

Majer-Łobodzińska, Agnieszka; Adamiec-Mroczek, Joanna

doi:10.17219/acem/41231

Cited by 23 publications

(10 citation statements)

References 34 publications

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“…Furthermore, GR mRNA expression was downregulated in GSAT from our obese study population [ 19 ], and although its expression did not correlate with methylation levels (data not shown), it is now widely accepted that DNA methylation marks are functionally complex and may orchestrate other important regulatory events, including alternative splicing and even the promotion of gene transcription [ 8 ]. However, we cannot rule out the possibility of other genetic/epigenetic mechanisms underlying GR regulation in this study, such as the presence of SNPs or inhibition by non-coding RNAs and/or histone modifications [ 22 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

et al. 2020

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Background Disruption of the hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine system associated with the stress response, has been hypothesized to contribute to obesity development. This may be mediated through epigenetic modulation of HPA axis-regulatory genes in response to metabolic stressors. The aim of this study was to investigate adipose tissue depot-specific DNA methylation differences in the glucocorticoid receptor (GR) and its co-chaperone, FK506-binding protein 51 kDa (FKBP5), both key modulators of the HPA axis. Methods Abdominal subcutaneous adipose tissue (ASAT) and gluteal subcutaneous adipose tissue (GSAT) biopsies were obtained from a sample of 27 obese and 27 normal weight urban-dwelling South African women. DNA methylation and gene expression were measured by pyrosequencing and quantitative real-time PCR, respectively. Spearman’s correlation coefficients, orthogonal partial least-squares discriminant analysis and multivariable linear regression were performed to evaluate the associations between DNA methylation, messenger RNA (mRNA) expression and key indices of obesity and metabolic dysfunction. Results Two CpG dinucleotides within intron 7 of FKBP5 were hypermethylated in both ASAT and GSAT in obese compared to normal weight women, while no differences in GR methylation were observed. Higher percentage methylation of the two FKBP5 CpG sites correlated with adiposity (body mass index and waist circumference), insulin resistance (homeostasis model for insulin resistance, fasting insulin and plasma adipokines) and systemic inflammation (c-reactive protein) in both adipose depots. GR and FKBP5 mRNA levels were lower in GSAT, but not ASAT, of obese compared to normal weight women. Moreover, FKBP5 mRNA levels were inversely correlated with DNA methylation and positively associated with adiposity, metabolic and inflammatory parameters. Conclusions These findings associate dysregulated FKBP5 methylation and mRNA expression with obesity and insulin resistance in South African women. Additional studies are required to assess the longitudinal association of FKBP5 with obesity and associated co-morbidities in large population-based samples. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

et al. 2020

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“…NR3C1 encodes the GR. The binding of glucocorticoid to the GRs plays important roles in glucose homeostasis (135) and regulates the stress response through both genetic (136) and epigenetic mechanisms (137). Childhood trauma and early stress alter the methylation status of this gene and its expression.…”

Section: The Associations Between Genetic and Epigenetic And Childhoomentioning

confidence: 99%

Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma

et al. 2019

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Adverse childhood experiences (ACEs) may be referred to by other terms (e.g., early life adversity or stress and childhood trauma) and have a lifelong impact on mental and physical health. For example, childhood trauma has been associated with posttraumatic stress disorder (PTSD), anxiety, depression, bipolar disorder, diabetes, and cardiovascular disease. The heritability of ACE-related phenotypes such as PTSD, depression, and resilience is low to moderate, and, moreover, is very variable for a given phenotype, which implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Currently, there is increasing interest in the investigation of epigenetic contributions to ACE-induced differential health outcomes. Although there are a number of studies in this field, there are still research gaps. In this review, the basic concepts of epigenetic modifications (such as methylation) and the function of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response are outlined. Examples of specific genes undergoing methylation in association with ACE-induced differential health outcomes are provided. Limitations in this field, e.g., uncertain clinical diagnosis, conceptual inconsistencies, and technical drawbacks, are reviewed, with suggestions for advances using new technologies and novel research directions. We thereby provide a platform on which the field of ACE-induced phenotypes in mental health may build.

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“…It has been suggested that fatty acid synthase (FAS) is a potential therapeutic target for anti-obesity drugs with the highest level of enriched expression in human adipocytes (Liang et al, 2018). NR3C1, which is targeted by He Ye, is related to the etiology of obesity, the control of which will lead to an improvement in obesity-related disorders (Majer-Łobodzińska and Adamiec-Mroczek, 2017). Moreover, DDP4 (targeted by Zhi Qiao) and ACHE (targeted by Ling Zhi) play a significant role in obesity, and modulating their activity may be of great utility in obesity treatment (Valerio et al, 2017; Shenhar-Tsarfaty et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity

et al. 2019

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Obesity is a multi-factorial chronic disease that has become a serious, prevalent, and refractory public health challenge globally because of high rates of various complications. Traditional Chinese medicines (TCMs) as a functional food are considered to be a valuable and readily available resource for treating obesity because of their better therapeutic effects and reduced side effects. However, their “multi-compound” and “multi-target” features make it extremely difficult to interpret the potential mechanism underlying the anti-obesity effects of TCMs from a holistic perspective. An innovative systems-pharmacology approach was employed, which combined absorption, distribution, metabolism, and excretion screening and multiple target fishing, gene ontology enrichment analysis, network pharmacology, and pathway analysis to explore the potential therapeutic mechanism of weight-loss herbal intervention therapy in obesity and related diseases. The current study provides a promising approach to facilitate the development and discovery of new botanical drugs.

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Glucocorticoid receptor polymorphism in obesity and glucose homeostasis

Cited by 23 publications

References 34 publications

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma

Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity

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