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Whole Transcriptome Analysis of Obese Adipose Tissue Suggests u001kfc.1 as a Potential Regulator to Glucose Homeostasis

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Whole Transcriptome Analysis of Obese Adipose Tissue Suggests u001kfc.1 as a Potential Regulator to Glucose Homeostasis

Linlin Yang et al. Front Genet.

Abstract

Long non-coding RNA (LncRNAs) are newly highlighted key factors controlling brown adipogenesis and development, but their regulatory effect to white adipocyte is still merely understood. Deciphering their underlying mechanism could be a novel way to discovering potential targets of obesity. Therefore, we conducted a whole transcriptome analysis in white adipose tissue from obese patients for the first time. Six obese patients and five control subjects were selected for microarray assay. Differentially expressed coding genes (DEGs), targets of lncRNAs, and alternatively spliced genes in obesity group were systematically compared in a functional framework based on a global gene regulatory network. It was demonstrated that all the three kinds of transcripts were enriched in pathways related to glucose metabolism while only DEGs showed closer proximity to neuro-endocrine-immune system. Thus, a lncRNA-regulated core network was constructed by a stepwise strategy using DEGs as seed nodes. From the core network, we identified a decreased lncRNA, uc001kfc.1, as potential cis-regulator for phosphatase and tensin homolog (PTEN) to enhance insulin sensitivity of white adipocytes in obese patients. We further validated the down-regulation of uc001kfc.1 and PTEN in an independent testing sample set enrolling 22 subjects via qRT-PCR. Although whether the decreased uc001kfc.1 correlated with low risk of diabetes deserved to be examined in an expanded cohort with long-term follow-up visit, the present study highlighted the potential of lncRNA regulating glucose homeostasis in human adipose tissue from a global perspective. With further improvement, such network-based analyzing protocol proposed in this study could be applied to interpreting function of more lncRNAs from other whole transcriptome data.

Keywords: adipose tissue; glucose homeostasis; long non-coding ribonucleic acid; network; obesity.

Figures

Figure 1
Figure 1
Global view of altered transcripts in obese adipose tissue. (A) Principle component analysis of microarray samples. (B) Overlapping of differentially expressed transcripts. (C) Chromosome distribution of altered transcripts. The heatmap of outer ring denotes fold changes of all alternatively spliced genes (ASGs); the histogram of middle ring denotes fold changes of differentially expressed coding genes (DEGs), and the links in the center denotes interactions between differential expressed long non-coding RNAs [differentially expressed lncRNAs (DELRs)] and their targets. The symbols of connected DELRs, DEGs, and annotated ASGs are respectively labeled in red, blue, and green color. Links between DELRs and these transcripts are painted by the same color as targets’ labels.
Figure 2
Figure 2
Enriched pathways and proximities to neuro-endocrine-immune (NEI) system. (A) Enriched Kyoto Encyclopedia of Genes and Genomes pathways of differentially expressed transcripts. (B) Average distances between NEI genes and altered transcripts. (C) Average distances between NEI genes and altered transcripts. *The distance/connectivity from NEI genes to DETs is significantly different from those to non-DETs (P < 0.001, Kolmogorov-Smirnov test).
Figure 3
Figure 3
Core network of obese adipose tissue. (A) The most connected component in core network of obesity. Biological functions of connections within each module are classified according to the hierarchical sort of pathways in Kyoto Encyclopedia of Genes and Genomes pathway database. (B) The TOP20 genes with highest degree in the core network. The bars highlighted by red color denote genes related to PI3K pathway.
Figure 4
Figure 4
Quantitative real-time polymerase chain reaction validation for candidate genes. (A) Relative quantity of candidate genes. *A significant difference between obese and control group exists if p-value 0.05 (Student’s t test). (B) Receiver operating characteristic curve of candidate genes.

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