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FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0001-5498-3899
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2014 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 63, no 9, p. 1198-1208Article in journal (Refereed) Published
Abstract [en]

Objective

To study effects of dexamethasone on gene expression in human adipose tissue aiming to identify potential novel mechanisms for glucocorticoid-induced insulin resistance.

Materials/methods

Subcutaneous and omental adipose tissue, obtained from non-diabetic donors (10 M/15 F; age: 28–60 years; BMI: 20.7–30.6 kg/m2), was incubated with or without dexamethasone (0.003–3 μmol/L) for 24 h. Gene expression was assessed by microarray and real time-PCR and protein expression by immunoblotting.

Results

FKBP5 (FK506-binding protein 5) and CNR1 (cannabinoid receptor 1) were the most responsive genes to dexamethasone in both subcutaneous and omental adipose tissue (~ 7-fold). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots. The gene product, FKBP51 protein, was 10-fold higher in the omental than in the subcutaneous depot, whereas the mRNA levels were similar. Higher FKBP5 gene expression in omental adipose tissue was associated with reduced insulin effects on glucose uptake in both depots. Furthermore, FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter and negatively with plasma HDL-cholesterol. FKBP5 SNPs were found to be associated with type 2 diabetes and diabetes-related phenotypes in large population-based samples.

Conclusions

Dexamethasone exposure promotes expression of FKBP5 in adipose tissue, a gene that may be implicated in glucocorticoid-induced insulin resistance.

Place, publisher, year, edition, pages
2014. Vol. 63, no 9, p. 1198-1208
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-232423DOI: 10.1016/j.metabol.2014.05.015ISI: 000340864400014PubMedID: 24997500OAI: oai:DiVA.org:uu-232423DiVA, id: diva2:747936
Available from: 2014-09-17 Created: 2014-09-17 Last updated: 2017-12-06
In thesis
1. Novel mechanisms of glucocorticoid-induced insulin resistance in human adipose tissue
Open this publication in new window or tab >>Novel mechanisms of glucocorticoid-induced insulin resistance in human adipose tissue
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The global prevalence of obesity and type 2 diabetes (T2D) is increasing. From a public health perspective, it is therefore of interest to identify common underlying mechanisms of these comorbidities. Glucocorticoids are steroid hormones that are important in stress regulation in mammals. Elevated glucocorticoid levels are associated with insulin resistance (IR) and T2D-like phenotypes. Here, glucocorticoids are used to model a state of IR in human adipose tissue to identify potential pharmacological targets.

In Paper I the impact of T2D on lipid turnover was examined in a cohort of 20 T2D subjects and 20 healthy controls. Plasma levels of non-esterified fatty acids (NEFA) were shown to be elevated in T2D subjects during oral glucose tolerance test (OGTT) compared to healthy controls. In vitro lipolysis and assessments of mRNA and metabolites in subcutaneous adipose tissue (SAT) were performed. Results showed that elevated NEFA levels in T2D subjects could be attributed to impaired lipid storage.

In Paper II we explored the role of cannabinoid receptor type 1 (CNR1) in glucocorticoid-induced IR. The CNR1 gene was upregulated after exposure to glucocorticoids in SAT. Moreover, CNR1 gene expression in SAT was associated with markers of IR and elevated in T2D subjects compared to healthy controls. Furthermore, using a CNR1-specific antagonist, we found that CNR1 may mediate lipolysis in SAT.

In Paper III-IV, we examined the role of FK506 protein 5 (FKBP51) in glucocorticoid-induced IR. Its corresponding gene, FKBP5, was found to be upregulated in SAT and omental adipose tissue (OAT) following glucocorticoid-exposure. In addition, FKBP5 gene expression in SAT was associated with markers of IR and tended to be elevated in T2D subjects compared to healthy controls. Furthermore, co-incubating an FKBP51-specific inhibitor with glucocorticoids in SAT partly prevented glucocorticoid-impaired adipocyte glucose uptake.

We identified CNR1 and FKBP51 as potential pharmacological targets in T2D and glucocorticoid-induced IR. Both were shown to be elevated in human adipose tissue after glucocorticoid-exposure. Their SAT gene expression levels were also associated with markers of IR and tended to be elevated in T2D. Both may be involved in perturbations of adipocyte metabolism, including glucose and lipid metabolism.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 52
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1408
Keywords
cannabinoid receptor type 1 fkbp51 dexamethasone type 2 diabetes adipocytes
National Category
Endocrinology and Diabetes
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-334192 (URN)978-91-513-0180-8 (ISBN)
Public defence
2018-02-02, Enghoffsalen, Akademiska sjukhuset, Ingång 50 bv, Uppsala, 09:30 (English)
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Available from: 2018-01-12 Created: 2017-12-06 Last updated: 2018-03-07

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Pereira, Maria JFall, ToveSidibeh, Cherno OEriksson, Jan W

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