uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.ORCID-id: 0000-0001-5498-3899
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
Visa övriga samt affilieringar
2017 (Engelska)Ingår i: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 55, nr 3, s. 839-852Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
SPRINGER , 2017. Vol. 55, nr 3, s. 839-852
Nyckelord [en]
Type 2 diabetes, Glucocorticoids, Insulin resistance, Adipose tissue, Endocannabinoid system
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
URN: urn:nbn:se:uu:diva-320351DOI: 10.1007/s12020-016-1172-6ISI: 000394966900021PubMedID: 27858284OAI: oai:DiVA.org:uu-320351DiVA, id: diva2:1089291
Forskningsfinansiär
AstraZenecaHjärt-Lungfonden, 20100648DiabetesförbundetTillgänglig från: 2017-04-19 Skapad: 2017-04-19 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Ingår i avhandling
1. Novel mechanisms of glucocorticoid-induced insulin resistance in human adipose tissue
Öppna denna publikation i ny flik eller fönster >>Novel mechanisms of glucocorticoid-induced insulin resistance in human adipose tissue
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 52
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1408
Nyckelord
cannabinoid receptor type 1 fkbp51 dexamethasone type 2 diabetes adipocytes
Nationell ämneskategori
Endokrinologi och diabetes
Forskningsämne
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-334192 (URN)978-91-513-0180-8 (ISBN)
Disputation
2018-02-02, Enghoffsalen, Akademiska sjukhuset, Ingång 50 bv, Uppsala, 09:30 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-01-12 Skapad: 2017-12-06 Senast uppdaterad: 2018-03-07

Open Access i DiVA

fulltext(1491 kB)124 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 1491 kBChecksumma SHA-512
776cf5eadeecc6d9c3a83f6da867c39dc08ce9db2fd95e4acabcaf974542ee741129f71be32abb5fc2e9fc13cc4a19c4874f874514143397cecbaf1f72dd1789
Typ fulltextMimetyp application/pdf

Övriga länkar

Förlagets fulltextPubMed

Personposter BETA

Sidibeh, Cherno O.Pereira, Maria J.Börjesson, Joey LauKamble, Prasad G.Katsogiannos, PetrosSundbom, MagnusSvensson, Maria K.Eriksson, Jan W.

Sök vidare i DiVA

Av författaren/redaktören
Sidibeh, Cherno O.Pereira, Maria J.Börjesson, Joey LauKamble, Prasad G.Katsogiannos, PetrosSundbom, MagnusSvensson, Maria K.Eriksson, Jan W.
Av organisationen
Klinisk diabetologi och metabolismGastrointestinalkirurgi
I samma tidskrift
Endocrine (Basingstoke)
Endokrinologi och diabetes

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 124 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 507 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf