Abstract
Long noncoding RNA(lncRNA)s are new regulators governing the metabolism in adipose tissue. In this study, we aimed to understand how lncRNAs respond to insulin signalling and explore whether lncRNAs have a functional role in insulin signalling pathway. We treated primary adipocyte cultures with insulin and collected RNA for RNA-sequencing to profile the non-coding transcriptome changes, through which we identified a top Adipose Specific Insulin Responsive LncRNA (LncASIR). To determine its biological function, we knocked down LncASIR using dcas9-KRAB, followed by RNA-seq to examine the effect on insulin-induced gene expression program. We identified a set of lncRNAs regulated by insulin signalling pathway. LncASIR is transcribed from a super enhancer region and responds robustly to insulin treatment. Silencing LncASIR resulted in an impaired global insulin-responsive gene program. LncASIR is a novel and integral component in the insulin signalling pathway in adipocytes.
Highlights
Insulin is an essential hormone in maintaining glucose homeostasis
LncRNAs located in cytosol could affect mRNA stability and translational efficiency[14] by acting as sponges for miRNAs26 or direct pairing with mRNA to modulate their stability or translational efficiency[27]; long noncoding RNAs (lncRNAs) located in the nucleus often affect chromosomal structure/conformation to regulate gene transcription[28,29,30]
RNA-seq data revealed a set of insulin-responding lncRNAs in adipocytes, including LncASIR
Summary
Insulin is an essential hormone in maintaining glucose homeostasis. While most mammalian cells express insulin receptors, essential targets for insulin are metabolic organs such as muscle, liver and adipose[1]. Insulin binds to insulin receptor to trigger insulin signalling cascade that leads to glucose uptake and gene program changes for altered lipid and carbohydrate metabolism. Response to insulin is often impaired in adipose tissue during obesity and Type 2 Diabetes(T2D)[6]. A detailed understanding of insulin signalling pathway is a prerequisite for developing new therapeutic strategies for obesity-related type 2 diabetes. There is a limited number of studies on the role of long noncoding RNAs (lncRNAs) in insulin signalling pathway. The expression of lncRNAs, in comparison with protein-coding mRNAs, is more tissue and developmental stage specific[19,20,21]. LncRNA Gm15290 sponges miR-27b to promote lipid accumulation in adipocytes by enhancing PPARγ mRNA stability[39]. The function of lncRNAs in insulin signalling pathway remains largely unexplored
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