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Novel mechanisms of glucocorticoid-induced insulin resistance in human adipose tissue
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Klinisk diabetologi och metabolism, Clinical diabetology and metabolism)
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 [en]
cannabinoid receptor type 1 fkbp51 dexamethasone type 2 diabetes adipocytes
National Category
Endocrinology and Diabetes
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-334192ISBN: 978-91-513-0180-8 (print)OAI: oai:DiVA.org:uu-334192DiVA, id: diva2:1163421
Public defence
2018-02-02, Enghoffsalen, Akademiska sjukhuset, Ingång 50 bv, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2018-01-12 Created: 2017-12-06 Last updated: 2018-03-07
List of papers
1. Impaired adipose tissue lipid storage, but not altered lipolysis, contributes to elevated levels of NEFA in type 2 diabetes. Degree of hyperglycemia and adiposity are important factors
Open this publication in new window or tab >>Impaired adipose tissue lipid storage, but not altered lipolysis, contributes to elevated levels of NEFA in type 2 diabetes. Degree of hyperglycemia and adiposity are important factors
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2016 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 65, no 12, p. 1768-1780Article in journal (Refereed) Published
Abstract [en]

Background. Elevated levels of circulating non-esterified fatty acids (NEFA) mediate many adverse metabolic effects. In this work we aim to determine the impact of type 2 diabetes (T2D), glycemic control and obesity on lipolysis regulation. Design and Participants. 20 control and 20 metformin-treated T2D subjects were matched for sex (10 M/10 F), age (58 +/- 11 vs 58 +/- 9 y) and BMI (30.8 +/- 4.6 vs 30.7 +/- 4.9 kg/m(2)). In vivo lipolysis was assessed during a 3 h-OGTT with plasma glycerol and NEFA levels. Subcutaneous adipose tissue (SAT) biopsies were obtained to measure mRNA and metabolite levels of factors related to lipolysis and lipid storage and to assess in vitro lipolysis in isolated subcutaneous adipocytes. Results. Plasma NEFA AUC during the OGTT where higher 30% (P = 0.005) in T2D than in control subjects, but plasma glycerol AUC and subcutaneous adipocyte lipolysis in vitro were similar, suggesting that adipose tissue lipolysis is not altered. Expression in SAT of genes involved in lipid storage (FABP4, DGAT1, FASN) were reduced in T2D subjects compared with controls, but no differences were seen for genes involved in lipolysis. T2D subjects had elevated markers of beta-oxidation, alpha-hydroxybutyrate (1.4-fold, P < 0.01) and p-hydroxybutyrate (1.7-fold, P < 0.05) in plasma. In multivariate analysis, HbA1c, visceral adipose tissue volume and sex (male) were significantly associated with NEFA AUC in T2D subjects. Conclusions. In T2D subjects, NEFA turnover is impaired, but not due to defects in lipolysis or lipid beta-oxidation. Impaired adipose NEFA re-esterification or de novo lipogenesis is likely to contribute to higher NEFA plasma levels in T2D. The data suggest that hyperglycemia and adiposity are important contributing factors for the regulation of plasma NEFA concentrations.

Keywords
Lipolysis, Type 2 diabetes, Adipose tissue, Metabolism, Lipid storage
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-311176 (URN)10.1016/j.metabol.2016.09.008 (DOI)000388158700007 ()27832864 (PubMedID)
Funder
AstraZenecaSwedish Diabetes Association
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2017-12-06Bibliographically approved
2. Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance
Open this publication in new window or tab >>Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance
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2017 (English)In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 55, no 3, p. 839-852Article in journal (Refereed) Published
Abstract [en]

We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone. CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity. Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue. Subcutaneous adipose tissue was obtained from well-controlled type 2 diabetes subjects and controls. Subcutaneous adipose tissue gene expression levels of CNR1 and endocannabinoid synthesizing and degrading enzymes were assessed. Furthermore, paired human subcutaneous adipose tissue and omental adipose tissue from non-diabetic volunteers undergoing kidney donation or bariatric surgery, was incubated with or without dexamethasone. Subcutaneous adipose tissue obtained from volunteers through needle biopsy was incubated with or without dexamethasone and in the presence or absence of the CNR1-specific antagonist AM281. CNR1 gene and protein expression, lipolysis and glucose uptake were evaluated. Subcutaneous adipose tissue CNR1 gene expression levels were 2-fold elevated in type 2 diabetes subjects compared with control subjects. Additionally, gene expression levels of CNR1 and endocannabinoid-regulating enzymes from both groups correlated with markers of insulin resistance. Dexamethasone increased CNR1 expression dose-dependently in subcutaneous adipose tissue and omental adipose tissue by up to 25-fold. Dexamethasone pre-treatment of subcutaneous adipose tissue increased lipolysis rate and reduced glucose uptake. Co-incubation with the CNR1 antagonist AM281 prevented the stimulatory effect on lipolysis, but had no effect on glucose uptake. CNR1 is upregulated in states of type 2 diabetes and insulin resistance. Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis. Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.

Place, publisher, year, edition, pages
SPRINGER, 2017
Keywords
Type 2 diabetes, Glucocorticoids, Insulin resistance, Adipose tissue, Endocannabinoid system
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-320351 (URN)10.1007/s12020-016-1172-6 (DOI)000394966900021 ()27858284 (PubMedID)
Funder
AstraZenecaSwedish Heart Lung Foundation, 20100648Swedish Diabetes Association
Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-12-06Bibliographically approved
3. FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance
Open this publication in new window or tab >>FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance
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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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-232423 (URN)10.1016/j.metabol.2014.05.015 (DOI)000340864400014 ()24997500 (PubMedID)
Available from: 2014-09-17 Created: 2014-09-17 Last updated: 2017-12-06
4. FKBP5 expression in human adipose tissue: Potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes
Open this publication in new window or tab >>FKBP5 expression in human adipose tissue: Potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes
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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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-334197 (URN)
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2017-12-06

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