Abstract
Tanshinone I (Tan I) is a diterpenoid isolated from Salvia miltiorrhiza Bunge and exhibits antitumor effects in several cancers. However, the anti-obesity properties of Tan I remain unexplored. Here, we evaluated the anti-obesity effects of Tan I in high-fat-diet (HFD)-induced obese mice and investigated the underlying molecular mechanisms in 3T3-L1 cells. HFD-induced obese mice were orally administrated Tan I for eight weeks, and body weight, weight gain, hematoxylin and eosin staining and serum biological parameters were examined. The adipogenesis of 3T3-L1 preadipocytes was assessed using Oil Red O staining and measurement of intracellular triglyceride (TG) levels, and mitotic clonal expansion (MCE) and its related signal molecules were analyzed during early adipogenesis of 3T3-L1 cells. The administration of Tan I significantly reduced body weight, weight gain, and white adipocyte size, and improved obesity-induced serum levels of glucose, free fatty acid, total TG, and total cholesterol in vivo in HFD-induced obese mice. Furthermore, Tan I-administered mice demonstrated improvement of glucose metabolism and insulin sensitivity. Treatment with Tan I inhibited the adipogenesis of 3T3-L1 preadipocytes in vitro, with this inhibition mainly occurring at an early phase of adipogenesis through the attenuation of MCE via cell cycle arrest at the G1/S phase transition. Tan I inhibited the phosphorylation of p38, extracellular signal-regulated kinase (ERK), and Akt during the process of MCE, while it stimulated the phosphorylation of AMP-activated protein kinase. Furthermore, Tan I repressed the expression of CCAAT-enhancer-binding protein β (C/EBPβ), histone H3K9 demethylase JMJD2B, and subsequently cell cycle genes. Moreover, Tan I regulated the expression of early adipogenic transcription factors including GATAs and Kruppel-like factor family factors. These results indicate that Tan I prevents HFD-induced obesity via the inhibition of early adipogenesis, and thus improves glucose metabolism and insulin sensitivity. This suggests that Tan I possesses therapeutic potential for the treatment of obesity and obesity-related diseases.
Highlights
Obesity causes a critical health problem because of an increase in the incidence of metabolic diseases including type 2 diabetes mellitus, atherosclerosis, and hypertension
We examined the expression of cell cycle inhibitors in Tan Ipreadipocytes with MDI decreased the cell population in the G0/G1 phase, and increased the cell treated 3T3-L1 cells
Western blotting revealed that Tanshinone I (Tan I) enhanced the protein levels of p21 and p27, inhibitory regulators of the cell cycle, 24 h after MDI treatment (Figure 4C). These results indicated that Tan I inhibited the mitotic clonal expansion (MCE) process through the downregulation of cyclin A, cyclin D, and Cdk2, and upregulation of p21 and p27, which may contribute to a delayed entry into the S and G2 phases of the cell cycle, and subsequent growth inhibition
Summary
Obesity causes a critical health problem because of an increase in the incidence of metabolic diseases including type 2 diabetes mellitus, atherosclerosis, and hypertension. The expansion of the adipose tissue results from hyperplasia and hypertrophy [1]. Adipogenesis is mediated by various regulators including transcriptional factors, signaling kinases, and lipid metabolic enzymes [2]. The adipogenesis of 3T3-L1 preadipocyte is composed of two stages, an early stage from 0 to 48 h after adding differentiation medium, and a late stage from day 2 to day 8. The mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase (ERK) and p38 MAPK, play a positive role in the MCE process during early adipogenesis [4]. The activated MCE proceeds to the late phase of adipogenesis, during which well-programmed transcription cascades stimulate the expression of terminal differentiation-related genes including fatty acid synthase (FAS), fatty acid binding protein 2
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