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FKBP5 expression in human adipose tissue: Potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Klinisk diabetologi och metabolism, Clinical diabetology and metabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Klinisk diabetologi och metabolism, Clinical diabetology and metabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Klinisk diabetologi och metabolism, Clinical diabetology and metabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Klinisk diabetologi och metabolism, Clinical diabetology and metabolism)
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2017 (English)In: Article in journal (Refereed) Submitted
Abstract [en]

Background and aims

High levels of glucocorticoids can contribute to dyslipidemia, obesity, insulin resistance (IR) and the onset of diabetes with properties similar to type 2 diabetes (T2D). We recently showed that the FKBP5 is one of the genes with the greatest increase in human adipose tissue following exposure to the synthetic glucocorticoid dexamethasone. FKBP5 codes for FKBP51, a co-chaperone of the glucocorticoid receptor (GR) complex. Here, we explore the involvement of FKBP51 in glucocorticoid-induced IR in human subcutaneous adipose tissue (SAT), including its potential role in T2D. Moreover, we assess the metabolic effects of reducing the activity of FKBP51 by the use of the specific inhibitor SAFit1.

Materials and Methods

FKBP5 gene expression was assessed in fresh SAT explants in a separate cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 non-diabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (19F/9M) by needle biopsies of the lower abdominal region. SAT was incubated for 24 h with or without dexamethasone and the FKBP51-specific inhibitor SAFit1. Incubated SAT was used to measure the glucose uptake rate of isolated adipocytes (n=19) or to measure the expression levels of genes known to be regulated by the GR-complex (n=9).

Results

The FKBP5 gene expression levels in SAT showed a tendency of being about 10% higher in T2D subjects compared to non-diabetic subjects (p=0.088). In addition, FKBP5 gene expression levels positively correlated with several markers of IR, including glucose area under the curve during oral glucose tolerance test (r=0.33, p<0.05). FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. These included ATGL, PLIN3, DGAT2 PPARG and CEBPA (r=-0.50, r=-0.47, r=-0.44, r=-0.43, r=-0.50, respectively, p<0.01 for all). Dexamethasone was shown to up- or downregulate several genes known to be regulated by the GR-complex. Co-incubation with the FKBP51-selective inhibitor, SAFit1, had no effect on these gene expression levels. SAFit1 was partly able to prevent the inhibitory effects of dexamethasone on glucose uptake.

Place, publisher, year, edition, pages
2017.
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-334197OAI: oai:DiVA.org:uu-334197DiVA, id: diva2:1163420
Available from: 2017-12-06 Created: 2017-12-06 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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Supervisors
Available from: 2018-01-12 Created: 2017-12-06 Last updated: 2018-03-07

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