Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women

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.

Cdkn2a deficiency promotes adipose tissue browning

“…Interestingly, using global transcriptome profiling of adipocytes from lean and obese subjects (GEO: GSE94752 ; Ref. [36] ) we observed a significant increase of CDKN2A mRNA expression levels in obese insulin-resistant adipocytes compared to lean controls ( Figure 5 A). We next wondered whether decreasing CDKN2A levels in human adipocytes could recapitulate some of the effects we observed in mice and induce browning in human cells.…”

“…Gene Expression Omnibus (GEO) analysis from the NCBI was performed using “adipocytes obese human” as keywords, filtered with “published in the last year” and sorted by the number of samples “high to low”. The dataset GSE94753 [36] was selected and analyzed using GEO2R. The platform GPL11532 was selected and groups were defined using the disease status (lean, WAT, control versus obese resistant, WAT OIR).…”

Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes

“…Representatives of this cluster included mitochondrial carrier Solute Carrier Family 25 Member 10 (Slc25a10) and Thyroid Hormone Responsive (Thrsp). Interestingly, Slc25a10 was previously found to be involved in fatty acid synthesis in adipocytes and insulin sensitivity [29,30]. On the contrary, cluster 4 consisted of genes whose expression was reduced by light in WT cells and maintained low levels of expression in the Opn3-KO cells.…”

Aquaglyceroporins: Drug Targets for Metabolic Diseases?

“…In addition, human Aqp7 and mouse Aqp7 transcriptional activity is upregulated by peroxisome proliferator-activated receptor gamma (PPARγ) ( Kishida et al, 2001 ; Lindgren et al, 2002 ). Finally, a very recent study showed that Aqp7 transcription is also controlled by the transcription factor Küppel-like factor 15 (KLF-15), known be involved in insulin-triggered lipogenesis ( Kulyté et al, 2017 ).…”