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Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover.
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, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.ORCID iD: 0000-0001-5894-0351
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
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2018 (English)In: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 7, no 4, p. 285-296Article in journal (Refereed) Published
Abstract [en]

Protective mechanisms of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala polymorphism in type 2 diabetes (T2D) are unclear. We obtained adipose tissue (AT) before and 3 h after oral glucose (OGTT) in carriers and non-carriers of the Ala allele (12 Pro/Pro, 15 Pro/Ala, and 13 Ala/Ala). Adipogenesis, adipocyte glucose uptake and lipolysis as well as PPARγ target genes expression were investigated and compared between the genotype groups. On fasting and post-OGTT, neither basal nor insulin-stimulated adipocyte glucose uptake differed between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro (p<0.05) also accompanied with a higher antilipolytic effect of insulin post-OGTT (p<0.01). The adipocyte size was similar across groups. Preadipocyte differentiation rates between Pro/Pro and Ala/Ala were unchanged. In conclusion, no major differences in AT differentiation, glucose uptake, lipolysis or expression of PPARγ target genes were observed between different PPARγ Pro12Ala genotypes. Albeit small, our study may suggest that other pathways in AT or effects exerted in other tissues might contribute to the Pro12Ala-mediated protection against T2D.

Place, publisher, year, edition, pages
2018. Vol. 7, no 4, p. 285-296
Keywords [en]
PPARG Pro12Ala, human adipose tissue, metabolism and adipogenesis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-357116DOI: 10.1080/21623945.2018.1503030ISI: 000450440700007PubMedID: 30064293OAI: oai:DiVA.org:uu-357116DiVA, id: diva2:1238084
Available from: 2018-08-12 Created: 2018-08-12 Last updated: 2019-01-23Bibliographically approved
In thesis
1. Role of nuclear receptors in the regulation of human adipose tissue metabolism
Open this publication in new window or tab >>Role of nuclear receptors in the regulation of human adipose tissue metabolism
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1489
Keywords
human adipose tissue, nuclear receptors, glucocorticoids, estrogen, PPARγ, lipocalin 2, glucose uptake, lipolysis, adipogenesis, genotype-based recall
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-357119 (URN)978-91-513-0401-4 (ISBN)
Public defence
2018-09-28, Rudbeckssalen, Rudbeck entréplan, C11, Rudbeck laboratory, Uppsala, 09:30 (English)
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Available from: 2018-09-07 Created: 2018-08-12 Last updated: 2018-10-02

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