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Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
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2017 (English)In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 55, no 3, 839-852 p.Article 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. Vol. 55, no 3, 839-852 p.
Keyword [en]
Type 2 diabetes, Glucocorticoids, Insulin resistance, Adipose tissue, Endocannabinoid system
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-320351DOI: 10.1007/s12020-016-1172-6ISI: 000394966900021PubMedID: 27858284OAI: oai:DiVA.org:uu-320351DiVA: diva2:1089291
Funder
AstraZenecaSwedish Heart Lung Foundation, 20100648Swedish Diabetes Association
Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-12-06Bibliographically approved
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. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1408
Keyword
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)
Opponent
Supervisors
Available from: 2018-01-12 Created: 2017-12-06 Last updated: 2018-01-12

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