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Variation in glucocorticoid sensitivity and the relation with obesity.

ABSTRACT: Increasing evidence points to a relation between increased glucocorticoid (GC) exposure and weight gain. In support, long-term cortisol measurements using hair analysis revealed that many individuals with obesity appear to have cortisol values in the high physiological range. The mechanisms behind this relationship need to be determined in order to develop targeted therapy to reach sustainable weight loss in these subgroups. The effect of GCs is not only determined by the plasma concentration of GCs but also by individual differences in GC sensitivity and the target tissue, which can be analyzed by functional GC assays. GC sensitivity is influenced by multiple genetic and acquired (e.g., disease-related) factors, including intracellular GC availability, hormone binding affinity, and expression levels of the GC receptors and their isoforms, as well as factors involved in the modulation of gene transcription. Interindividual differences in GC sensitivity also play a role in the response to exogenous GCs, with respect to both therapeutic and adverse effects. Accordingly, in this review, we summarize current knowledge on mechanisms that influence GC sensitivity and their relationships with obesity and discuss personalized treatment options targeting the GC receptor.

SUBMITTER: Lengton R

PROVIDER: S-EPMC9285588 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Variation in glucocorticoid sensitivity and the relation with obesity.

Lengton Robin R Iyer Anand M AM van der Valk Eline S ES Hoogeveen Ellen K EK Meijer Onno C OC van der Voorn Bibian B van Rossum Elisabeth F C EFC

Obesity reviews : an official journal of the International Association for the Study of Obesity 20211127 3

Increasing evidence points to a relation between increased glucocorticoid (GC) exposure and weight gain. In support, long-term cortisol measurements using hair analysis revealed that many individuals with obesity appear to have cortisol values in the high physiological range. The mechanisms behind this relationship need to be determined in order to develop targeted therapy to reach sustainable weight loss in these subgroups. The effect of GCs is not only determined by the plasma concentration of ...[more]

PMID: 34837448

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Project description:IntroductionThe glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9β are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity.MethodsThe presence of GR polymorphisms was assessed in healthy controls (n = 5033), and in RA patients (n = 368). A second control group (n = 532) was used for confirmation of results. In RA patients, the relationship between GR polymorphisms and disease severity was examined.ResultsCarriers of the N363 S and BclI minor alleles had a lower risk of developing RA: odds ratio (OR) = 0.55 (95% confidence interval (CI) 0.32-0.96, P = 0.032) and OR = 0.73 (95% CI 0.58-0.91, P = 0.006), respectively. In contrast, 9β minor allele carriers had a higher risk of developing RA: OR = 1.26 (95% CI 1.00-1.60, P = 0.050). For ER22/23EK minor allele carriers a trend to an increased risk OR = 1.42 (95% CI 0.95-2.13, P = 0.086) was found. All ER22/23EK carriers (32/32) had erosive disease, while only 77% (259/336) of the non-carriers did (P = 0.008). In addition, ER22/23EK carriers were treated more frequently with anti-tumor necrosis factor-alpha (TNFα) therapy (P < 0.05).ConclusionsThe minor alleles of the 9β and ER22/23EK polymorphisms seem to be associated with increased predisposition to develop RA. Conversely, the minor alleles of the N363 S and BclI polymorphisms are associated with reduced susceptibility to develop RA. These opposite associations suggest that constitutionally determined GC resistance may predispose to development of auto-immunity, at least in RA, and vice versa.

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Variation in glucocorticoid sensitivity and the relation with obesity.

Publications

Variation in glucocorticoid sensitivity and the relation with obesity.

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