Adipose Tissue

Insulin resistance describes the failure of target tissues to respond adequately to circulating insulin, and several miRNAs have been found to regulate insulin signalling in these tissues. Adipose tissue in the context of T2DM and obesity is one of the main tissues experiencing acute insulin resistance. It is also an important contributor to the systemic chronic inflammatory state characteristic of diabetes, as macrophage infiltration results in adipocytes releasing pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-a) or interleukin-6 (IL-6), and adipokines including leptin and resistin (Jung and Choi 2014). Some miRNAs that are induced during adipogenesis are downregulated in obesity, and this is a potential mechanism for insulin resistance (Xie et al. 2009).

MiR-143 is downregulated in the adipocytes from ob/ob mice resulting in increased adipogenesis through the target ERK5, which promotes cell differentiation and proliferation (Xie et al. 2009; Esau et al. 2004). Similar roles in adipogenesis have been attributed to miR-103 and miR-107: they are repressed in adipocytes following TNF-a treatment, and their inhibition enhances insulin signalling, decreases adipocyte size and enhances insulin-stimulated glucose uptake (Xie et al. 2009). MiR-320 is upregulated in insulin-resistant adipocytes, where it decreases insulin sensitivity by targeting p85 (which normally contributes to cell growth by increasing Akt phosphorylation) (Ling et al. 2009). It is well known that the co-occurrence and feedback between inflammation and insulin resistance in the adipose tissue are crucial in the onset of T2DM. Interestingly, selected miRs may link these two main processes, highlighting their therapeutic potential for preventing insulin resistance. In this context, miR-132, which is upregulated in the omental fat of obese humans (Heneghan et al. 2011), was found to activate NF-kB and subsequently increase the transcription of interleukin-8 and monocyte chemoattractant protein 1 (MCP1) in human adipocytes in vitro (Strum et al. 2009). Conversely, some miRNAs are induced by cytokines, including miR-378, which is induced by TNF-a and IL-6 in matured human adipocytes (Xu et al. 2014), and both miR-221 and miR-222, which are positively correlated with TNF-a levels in the adipose tissue of high-fat diet-fed mice (Parra et al. 2010).

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