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Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue
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.
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.
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2016 (engelsk)Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 427, s. 124-132Artikkel i tidsskrift (Fagfellevurdert) Published
Resurstyp
Text
Abstract [en]

The adipokine lipocalin 2 is linked to obesity and metabolic disorders. However, its role in human adipose tissue glucose and lipid metabolism is not explored. Here we show that the synthetic glucocorticoid dexamethasone dose-dependently increased lipocalin 2 gene expression in subcutaneous and omental adipose tissue from pre-menopausal females, while it had no effect in post-menopausal females or in males. Subcutaneous adipose tissue from both genders treated with recombinant human lipocalin 2 showed a reduction in protein levels of GLUT1 and GLUT4 and in glucose uptake in isolated adipocytes. In subcutaneous adipose tissue, lipocalin 2 increased IL-6 gene expression whereas expression of PPAR gamma and adiponectin was reduced. Our findings suggest that lipocalin 2 can contribute to insulin resistance in human adipose tissue. In pre-menopausal females, it may partly mediate adverse metabolic effects exerted by glucocorticoid excess.

sted, utgiver, år, opplag, sider
2016. Vol. 427, s. 124-132
Emneord [en]
Glucocorticoids, Lipocalin 2, Human adipose tissue, Type 2 diabetes, Insulin resistance, PPAR gamma
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-297263DOI: 10.1016/j.mce.2016.03.011ISI: 000375335500013PubMedID: 26973291OAI: oai:DiVA.org:uu-297263DiVA, id: diva2:942078
Forskningsfinansiär
Swedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenAstraZenecaSwedish Society for Medical Research (SSMF)Tilgjengelig fra: 2016-06-23 Laget: 2016-06-22 Sist oppdatert: 2018-08-12bibliografisk kontrollert
Inngår i avhandling
1. Role of nuclear receptors in the regulation of human adipose tissue metabolism
Åpne denne publikasjonen i ny fane eller vindu >>Role of nuclear receptors in the regulation of human adipose tissue metabolism
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Nuclear receptors modulate expression of genes involved in adipose tissue (AT) metabolism. Their improved understanding may provide new treatment options for metabolic disorders such as obesity, insulin resistance (IR) and type 2 diabetes (T2D).

This thesis explored the role of nuclear receptors, mainly, glucocorticoid and estrogen receptors (GR and ER, respectively) and peroxisome proliferator-activated receptor gamma (PPARγ), and their interplay in the regulation of metabolic function and dysfunction in human AT.

In Paper I, the regulation of adipokine lipocalin 2 (LCN2) expression by synthetic glucocorticoid, dexamethasone and effect of LCN2 on glucose and lipid metabolism in AT were studied. In pre-menopausal but not post-menopausal women or men, dexamethasone upregulated LCN2 gene expression, which also correlated with markers of obesity and IR. LCN2 inhibited adipocyte glucose uptake.

In Paper II, the effect of estrogen (E2) and its interaction with GR in LCN2 regulation in AT from post-menopausal women were examined. E2 increased LCN2 expression, what seems to be mediated by ERβ. E2 and dexamethasone co-treatment increased LCN2 gene expression in presence of ERα but not ERβ antagonist. Dexamethasone decreased ERα, while increased ERβ gene expression.

In Paper III and IV, the feasibility of genotype-based recall (GBR), a participant recruitment approach, was tested by undertaking clinical and AT phenotyping of different PPARγ Pro12Ala carriers. The baseline characteristics were comparable between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro group also accompanied with a higher antilipolytic effect of insulin after oral glucose. Adipocyte glucose uptake and adipogenesis remained unchanged between genotypes.

Overall, LCN2 can induce IR in human AT and may mediate metabolic defects by excess glucocorticoids in pre-menopausal women. GR selectively interacts with ERα and ERβ, the latter two acts oppositely to control LCN2 expression in AT. PPARγ Pro12Ala had no major effect on clinical and adipose phenotype, likely due to a small sample size in relation to the modest effect the Ala variant or tissues other than adipose could be critical in conferring protection by Pro12Ala against T2D risk. Further, the GBR approach deemed feasible, however, would be more suitable in the characterization of rare genetic variants.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 77
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1489
Emneord
human adipose tissue, nuclear receptors, glucocorticoids, estrogen, PPARγ, lipocalin 2, glucose uptake, lipolysis, adipogenesis, genotype-based recall
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-357119 (URN)978-91-513-0401-4 (ISBN)
Disputas
2018-09-28, Rudbeckssalen, Rudbeck entréplan, C11, Rudbeck laboratory, Uppsala, 09:30 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-09-07 Laget: 2018-08-12 Sist oppdatert: 2018-10-02

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