Abstract
This study aimed to establish a high-fat diet (HFD)-fed obese mouse model and a cell culture model of insulin resistance (IR) in mature 3T3-L1 adipocytes. A dual-luciferase reporter assay (DLRA) was confirmed interaction between miR-27a and the 3′-untranslated region (UTR) of Peroxisome proliferator-activated receptor (PPAR)-γ. The inhibition of PPAR-γ expression by microRNA (miR)-27a in IR cells at both the protein and mRNA levels was confirmed by a mechanistic investigation. Moreover, the 3′-UTR of PPAR-γ was found to be a direct target of miR-27a, based on the DLRA. Furthermore, antagomiR-27a upregulated the activation of PI3K/Akt signaling and glucose transporter type 4 (GLUT4) expression at the protein and mRNA levels. Additionally, the PPAR inhibitor T0070907 repressed the insulin sensitivity upregulated by antagomiR-27a, which was accompanied by the inhibition of PPAR-γ expression and increased levels of AKT phosphorylation and GLUT4. The PI3K inhibitor wortmannin reduced miR-27a-induced increases in AKT phosphorylation, glucose uptake, and GLUT4. miR-27a is considered to be involved in the PPAR-γ-PI3K/AKT-GLUT4 signaling axis, thus leading to increased glucose uptake and decreased IR in HFD-fed mice and 3T3-L1 adipocytes. Therefore, miR-27a is a novel target for the treatment of IR in obesity and diabetes.
Highlights
Type 2 diabetes mellitus (T2DM) is a major worldwide health problem affecting adults and children [1, 2]
An high-fat diet (HFD)-induced obese mouse model and insulin resistance (IR) cell model were established to study the role of miR-27a expression in glucose metabolism and IR
The mechanisms underlying the development of metabolic diseases, such as T2DM, are synergetic processes related to the transcription of various genes T2DM has been investigated in many previous studies; Figure 3. miR-27a targeted at the 3’-untranslated region (UTR) of Peroxisome proliferator-activated receptor (PPAR)-γ
Summary
Type 2 diabetes mellitus (T2DM) is a major worldwide health problem affecting adults and children [1, 2]. Over the past 30 years, the occurrence of T2DM has increased constantly, suggesting that an indepth understanding of its complex pathologic mechanism is urgently needed. The major widely accepted pathogenic factors of T2DM are genetic factors, obesity, lifestyle factors, and impaired glucose tolerance [3, 4]. Impaired glucose metabolism is commonly involved in insulin resistance (IR), which is a critical characteristic of metabolic syndrome [5]. IR contributes to impaired glycogen synthesis and the failure to repress glucose production in the liver. The current understanding of the underlying molecular mechanisms for hepatic IR is still lacking
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