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, 12 (6), e0178485
eCollection

Global Transcriptome Profiling Identifies KLF15 and SLC25A10 as Modifiers of Adipocytes Insulin Sensitivity in Obese Women

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Global Transcriptome Profiling Identifies KLF15 and SLC25A10 as Modifiers of Adipocytes Insulin Sensitivity in Obese Women

Agné Kulyté et al. PLoS One.

Abstract

Although the mechanisms linking obesity to insulin resistance (IR) and type 2 diabetes (T2D) are not entirely understood, it is likely that alterations of adipose tissue function are involved. The aim of this study was to identify new genes controlling insulin sensitivity in adipocytes from obese women with either insulin resistant (OIR) or sensitive (OIS) adipocytes. Insulin sensitivity was first determined by measuring lipogenesis in isolated adipocytes from abdominal subcutaneous white adipose tissue (WAT) in a large observational study. Lipogenesis was measured under conditions where glucose transport was the rate limiting step and reflects in vivo insulin sensitivity. We then performed microarray-based transcriptome profiling on subcutaneous WAT specimen from a subgroup of 9 lean, 21 OIS and 18 obese OIR women. We could identify 432 genes that were differentially expressed between the OIR and OIS group (FDR ≤5%). These genes are enriched in pathways related to glucose and amino acid metabolism, cellular respiration, and insulin signaling, and include genes such as SLC2A4, AKT2, as well as genes coding for enzymes in the mitochondria respiratory chain. Two IR-associated genes, KLF15 encoding a transcription factor and SLC25A10 encoding a dicarboxylate carrier, were selected for functional evaluation in adipocytes differentiated in vitro. Knockdown of KLF15 and SLC25A10 using siRNA inhibited insulin-stimulated lipogenesis in adipocytes. Transcriptome profiling of siRNA-treated cells suggested that KLF15 might control insulin sensitivity by influencing expression of PPARG, PXMP2, AQP7, LPL and genes in the mitochondrial respiratory chain. Knockdown of SLC25A10 had only modest impact on the transcriptome, suggesting that it might directly influence insulin sensitivity in adipocytes independently of transcription due to its important role in fatty acid synthesis. In summary, this study identifies novel genes associated with insulin sensitivity in adipocytes in women independently of obesity. KFL15 and SLC25A10 are inhibitors of insulin-stimulated lipogenesis under conditions when glucose transport is the rate limiting step.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flowchart describing the project.
Fig 2
Fig 2. Effects of KLF15 and SLC25A10 knockdownon lipogenesis in vitro.
A. KLF15 and SLC25A10 were knocked down using 40nM of siRNA in SVF-derived human adipocytes differentiated in vitro and expression of the genes evaluated using real-time PCR. Results were analyzed using Students t-test and are presented as relative fold change ± SD vs. negative control. B. SVF-derived adipocytes differentiated in vitro were transfected with 40 nM of siRNA against KLF15 and SLC25A10 for 48 hours followed by evaluation of basal and insulin-stimulated lipogenesis. Relative insulin-stimulated lipogenesis was calculated against non-targeting siRNA NegC at insulin-stimulated state. Induction of lipogenesis by insulin for NegC was minimum 3-fold in all experiments. Results are based on three to five biological/independent experiments.*p<0.05, **p<0.01 and ***p<0.001.
Fig 3
Fig 3. Ingenuity analysis of KLF15 target genes associated with insulin stimulated lipogenesis in vivo.

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Substances

Grant support

The funding sources for this project are: Swedish Research Council (www.vr.se, 2016-01376), Strategic research program in diabetes at Karolinska Institutet (http://ki.se/en/srp-diabetes/strategic-research-programme-in-diabetes), EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant number 115372), The Swedish Diabetes fund (https://www.diabetes.se/diabetesfonden/forskning/beviljade-projekt/), Stockholm county council (https://forskningsstod.vmi.se/Ansokan/start.asp, 20150011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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