Abstract
Gomisin N (GN) is a physiological lignan derived from Schisandra chinensis. In the present study, we investigated the inhibitory effects of GN on differentiation of 3T3-L1 preadipocytes and the anti-obesity effects of GN in high-fat diet (HFD)-induced obese mice. Incubation with GN significantly inhibited the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner. This inhibitory effect primarily occurred at an early adipogenic stage through impairment of mitotic clonal expansion (MCE) caused by cell cycle arrest at the G1/S phase transition. GN inhibited the extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B signaling in the MCE process and activated AMP-activated protein kinase. Furthermore, GN downregulated CCAT/enhancer-binding protein β (C/EBPβ) and histone H3K9 demethylase JMJD2B during early stages of adipogenesis, and therefore repressed the expression of C/EBPβ-targeted cell cycle genes. In addition, GN also repressed the expression of histone H3K4 methyltransferase MLL4 and reduced PPARγ expression. Moreover, GN effectively lowered the final body weight, adipose tissue mass, and reduced the serum levels of glucose, total triglyceride, and cholesterol in the HFD-induced obese mice. GN also markedly reduced hepatic triglyceride level induced by HFD. Collectively, these findings suggest that GN has potential as a novel agent for the prevention and treatment of obesity.
Highlights
Obesity is a major global health problem because it is associated with an increased risk of metabolic disorders, including type 2 diabetes mellitus, hypertension, atherosclerosis, cancer, and cardiovascular disease[1]
Cytotoxicity was assessed by measurement of lactate dehydrogenase (LDH) released in medium. (B) Post-confluent 3T3-L1 preadipocytes were differentiated in MDI medium containing various concentrations of Gomisin N (GN), and adipocyte differentiation was examined on day 8 by Oil Red O (ORO) staining. (C) Intracellular triglyceride accumulation was measured on day 8 of differentiation. (D) Expression of PPARγ, C/EBPα, acid-binding protein 2 (aP2), and fatty acid synthase (FAS) was measured on day 8 by quantitative Polymerase chain reaction (PCR) (qPCR)
We investigated the inhibitory effects of GN on adipocyte differentiation. 3T3-L1 preadipocytes were differentiated in the MDI medium with the indicated concentrations of GN for eight days, and accumulation of intracellular lipid droplets was assessed by Oil Red O (ORO) staining
Summary
Obesity is a major global health problem because it is associated with an increased risk of metabolic disorders, including type 2 diabetes mellitus, hypertension, atherosclerosis, cancer, and cardiovascular disease[1]. Growth-arrested confluent preadipocytes re-enter the cell cycle in a differentiation medium cocktail, including insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IBMX) They increase in number, exit the cell cycle, and undergo terminal differentiation into mature adipocytes. Several early adipogenic transcription factors, including CCAT/enhancer-binding protein β(C/EBPβ), C/EBPδ, and Kruppel-like factors 4 and 5, are transcriptionally activated during the MCE process[10] These transcription factors stimulate master adipogenic transcription factors essential for terminal differentiation, such as peroxisome proliferator-activated receptor gamma (PPARγ) and C/EBPα. PPARγand C/EBPαcoordinately stimulate the expression of triglyceride synthesis genes, such as the genes for adipocyte fatty acid-binding protein 2 (aP2), fatty acid synthase (FAS), acetyl-coenzyme A carboxylase (ACC), lipin 1, and diacylglycerol acyltransferase These proteins, associated with lipogenesis and tracylglycerol synthesis, induce the formation of lipid droplets in mature adipocytes. We have reported that S. chinensis and GN show protective effects against the endoplasmic reticulum (ER) stress-induced hepatic steatosis[21,22]
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