Abstract
MicroRNAs are emerging as new mediators in the regulation of adipose tissue biology and the development of obesity. An important role of microRNA-125a has been suggested in the pathogenesis of insulin resistance (IR). Here, we characterized the function of microRNA-125a in adipose tissue in a context of experimentally-induced IR and obesity in mice and in obese patients. We showed time dependent overexpression of the microRNA in adipose tissue of BALB/c and C57BL/6J mice in response to high fat diet (HFD) feeding. MicroRNA-125a expression was downregulated in vitro in insulin resistant 3T3-L1 adipocytes and ex vivo in adipose tissue of obese patients. In vitro modulation of microRNA-125a expression in 3T3-L1 adipocytes did not affect glucose uptake. Gene set enrichment analysis (GSEA) identified significantly altered expression patterns of predicted microRNA-125a gene targets in transcriptomic datasets of adipose tissue from HFD-fed mice and obese patients. Among genes that contributed to global enrichment of altered expression of microRNA-125a targets, Thyrotroph embryonic factor (Tef), Mannan-binding lectin serine peptidase 1, Reticulon 2 and Ubiquitin-conjugating enzyme E2L3 were significantly differentially expressed in adipose tissue in these groups. We showed that Tef expression is reduced in adipose tissue of obese patients following gastric bypass surgery. Our findings indicate that microRNA-125a expression in adipose tissue adapts to IR and may play a role in the development of obesity in mice and obese subjects through uncoupled regulation of the expression of microRNA-125a and its targets.
Highlights
Obesity and type 2 diabetes mellitus (T2DM) are major health issues caused by a complex interplay between genetic risk factors and environmental influences, including sedentary lifestyle and change in feeding behavior [1,2]
In C57BL/6J, miR-125a expression was unchanged in fat in response to 1 week high fat diet (HFD) feeding but significantly overexpressed when the dietary stimulus was applied for 15 weeks (Fig. 1B)
We report reactive expression of miR-125a and its predicted mRNA targets in adipose tissue from HFD-fed mice and obese patients
Summary
Obesity and type 2 diabetes mellitus (T2DM) are major health issues caused by a complex interplay between genetic risk factors and environmental influences, including sedentary lifestyle and change in feeding behavior [1,2]. Defining molecular signatures of the onset and progression of T2DM and obesity has become crucial to provide a deeper understanding of the mechanisms involved and uncover predictive and therapeutical targets. Owing to the complexity of molecular studies in humans and limitations in access to organ biopsies in patients and controls, animal models of obesity and T2DM represent powerful tools to identify etiological mechanisms of IR. Models of spontaneously-occurring T2DM, such as the Goto Kakizaki (GK) rat [4], and experimentally-induced obesity by high fat diet (HFD) feeding [5] are widely used to identify novel genes and gene pathways involved in IR. We have previously demonstrated contrasting pathophysiological responses to HFD in C57BL/6J and BALB/c mice [6,7]
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