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.
Highlights
Insulin resistance (IR) is a key pathogenic factor behind type 2 diabetes (T2D) that often accompanies obesity [1]
We recently investigated gene expression in abdominal subcutaneous white adipose tissue (WAT) of non-obese and obese women in relation to systemic in vivo insulin sensitivity assessed after two hours hyperinsulinemic-euglycemic clamp [10].Surprisingly, systemic insulin resistance had a limited impact on the transcriptional response to insulin infusion and the difference between the insulin resistant and sensitive groups was much smaller than the overall effect of obesity per se on gene expression in WAT
By transcriptome profiling in a large human cohort including non-obese and obese with or without insulin resistance, combined with functional evaluation in adipocyte cultures of specific genes, this study identifies KLF15 and SLC25A10 as potential modulators of adipocyte insulin sensitivity
Summary
Insulin resistance (IR) is a key pathogenic factor behind type 2 diabetes (T2D) that often accompanies obesity [1]. The mechanisms linking obesity to T2D are not well understood, it is likely that alterations of adipose tissue function are involved [2]. Expansion of white adipose tissue (WAT) mass leads to increased adipocyte size, accelerated mobilization of fatty acids, increased local inflammation and altered release of adipocyte hormones (adipokines), which may contribute to overall IR [1,2,3]. A previous study, applying global transcriptome profiling on subcutaneous WAT from nondiabetic individuals in the fasted state, reported association between systemic insulin sensitivity and expression of genes related to lipid metabolism and inflammation [9]. About 100 transcribed genes responded differently to hyperinsulinemia in women with systemic insulin resistance compared to insulin sensitive women
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