Abstract
Obesity-related insulin resistance and high fatty acid concentrations occur during the development of type 2 diabetes mellitus. The role of high concentrations of plasma-free fatty acids is not fully understood. In this study, palmitic acid (PA, 0.8 mM for 24 h) induced the expression of miR-221 that bound to phosphoinositide 3-kinases (PI3K) mRNA to inhibit glucose uptake by HepG2 cells. Compared with controls, PA significantly decreased glucose uptake, increased insulin receptor substrate-2 (IRS-2) and miR-221 expression, and decreased phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter type 4 (GLUT4) mRNA expression. Luciferase reporter assay revealed that miR-221 binding inhibited PI3K expression. Transfection of HepG2 cells with an miR-221 mimic induced miR-221 expression and inhibited the PI3K/AKT pathway. PA decreased glucose uptake in HepG2 cells by inducing the expression of miR-221, which bound to PI3K mRNA and suppressed PI3K/AKT signaling. miR-221 may be a novel target for preventing and treating obesity-induced insulin resistance.
Highlights
Obesity is a serious global health problem [1, 2]
Palmitic acid (PA), a representative free fatty acids (FFAs), has been shown to directly impair insulin signaling in cultured hepatocytes and myotubes [14]
We found that PA induced miR-221 expression in HepG2 cells that impaired phosphoinositide 3-kinases (PI3K)/AKT signaling pathway and inhibited glucose uptake
Summary
Obesity is a serious global health problem [1, 2]. In the United States, the prevalence of youth and adult obesity is increasing, with an age-adjusted prevalence of 35% in men and 40.4% in women in 2013-2014 [3]. e prevalence of type 2 diabetes mellitus (T2DM) increases along with obesity and has an estimated prevalence of 18.5% in obese adults and 5.4% in normal-weight adults in the United States in 20132014 [4]. T2DM is a serious chronic metabolic disease triggered by impaired insulin signal pathways and systemic insulin resistance and the lack of response to insulin target cells such as hepatocytes, skeletal muscle cells, and adipocytes [5]. Activated insulin receptor substrate-2 (IRS-2) regulates glucose homeostasis [7]. It transduces insulin action by stimulating the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) pathway and promotes glucose uptake by insulin-sensitive glucose transporter type 4 (GLUT4) in the plasma membrane. A significant correlation has been reported between obesity and increased risk of insulin resistance and T2DM [11]. An excess of lipids increases circulating FFAs and evokes insulin resistance in muscle and liver tissues [13]. Palmitic acid (PA) is the most common saturated fatty acid found in animals and plants and is found in foods
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