Abstract
Obesity is associated with a wide range of metabolic disorders including inflammation and insulin-resistance. Sirtuin-1 (SIRT1) is an important regulator of metabolic homeostasis and stress response pathways in white adipose tissue. However, involvement of microRNAs (miRNAs) in regulating SIRT1 during obesity-induced inflammation and insulin-resistance remains unclear. Here, we found that miR-377 was upregulated in adipose tissue and showed a negative correlation with SIRT1 in chronic high fat diet (HFD)-fed mice. MiR-377 belongs to a large miRNA cluster and functions as an important tumor suppressor in several human malignancies. Recently, it has also gained considerable attention in oxidative stress and diabetic nephropathy. In our present study, we found that overexpression of miR-377 decreased SIRT1 protein abundance and caused inflammation and insulin-resistance in differentiated 3T3-L1 cells. Conversely, miR-377 inhibition increased SIRT1 mRNA and protein levels, ameliorated inflammation and improved insulin sensitivity. Furthermore, we demonstrated that miR-377 targets the 3′-UTR of SIRT1 mRNA directly, and downregulates SIRT1 protein abundance. Inhibition of SIRT1 by EX527 significantly eliminated the downregulation of the inflammation and insulin-resistance levels induced by the miR-377 inhibitor. Furthermore, SIRT1 deficiency intensified adipose tissue inflammation and insulin-resistance, resulting in hepatic steatosis in chronic-HFD-fed mice. In conclusion, our findings suggest that miR-377 promotes white adipose tissue inflammation and decreases insulin sensitivity in obesity, at least in part, through suppressing SIRT1.
Highlights
Obesity is a major global health issue [1]
We investigated the potential mechanism by which miR-377 mediated regulation of SIRT1 expression in adipocyte inflammation and insulin-resistance during obesity
Overexpression of miR-377 had no effect on the luciferase activity of the mutant reporter (Figure 1C); miR-132 and miR-146b, which have been demonstrated to target the 3ʹ-UTR of SIRT1 were used as positive controls [8, 15]
Summary
Low-grade chronic inflammation is an important cause of obesityinduced systemic insulin-resistance [2, 3]. Large numbers of macrophages and T cells are recruited to obese adipose tissue leading to active inflammation, which is thought to alter adipose tissue function, resulting in metabolic disorders and systemic insulin-resistance [4,5,6]. Several miRNAs, such as miR132 [15], miR-155 [16], miR-130 [17], miR-145 [18], www.impactjournals.com/oncotarget miR-146b [19], and miR-29 [20] have been indentified in obesity-associated inflammation and insulin-resistance in adipocytes. In HFD-induced obese mice, miR-146b knockdown ameliorated insulin-resistance [8]. These results suggest that miRNAs play important roles in regulating adipocyte inflammation and insulin-resistance
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