Cudratricusxanthone A Inhibits Lipid Accumulation and Expression of Inducible Nitric Oxide Synthase in 3T3-L1 Preadipocytes.

Hyo-Shin Kwon,Gil-Saeng Jeong,Byeong-Churl Jang

doi:10.3390/ijms22020505

Hyo-Shin Kwon, Gil-Saeng Jeong + Show 1 more

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https://doi.org/10.3390/ijms22020505

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Abstract

Cudratricusxanthone A (CTXA) is a natural bioactive compound extracted from the roots of Cudrania tricuspidata Bureau and has been shown to possess anti-inflammatory, anti-proliferative, and hepatoprotective activities. However, at present, anti-adipogenic and anti-inflammatory effects of CTXA on adipocytes remain unclear. In this study, we investigated the effects of CTXA on lipid accumulation and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, two known inflammatory enzymes, in 3T3-L1 preadipocytes. Strikingly, CTXA at 10 µM markedly inhibited lipid accumulation and reduced triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. On mechanistic levels, CTXA at 10 µM suppressed not only expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A, but also phosphorylation levels of signal transducer and activator of transcription-3 (STAT-3) and STAT-5 during 3T3-L1 preadipocyte differentiation. In addition, CTXA at 10 µM up-regulated phosphorylation levels of cAMP-activated protein kinase (AMPK) while down-regulating expression and phosphorylation levels of acetyl-CoA carboxylase (ACC) during 3T3-L1 preadipocyte differentiation. Moreover, CTXA at 10 µM greatly attenuated tumor necrosis factor (TNF)-α-induced expression of iNOS, but not COX-2, in 3T3-L1 preadipocytes. These results collectively demonstrate that CTXA has strong anti-adipogenic and anti-inflammatory effects on 3T3-L1 cells through control of the expression and phosphorylation levels of C/EBP-α, PPAR-γ, FAS, ACC, perilipin A, STAT-3/5, AMPK, and iNOS.

Highlights

Obesity is a major health concern often deteriorating life expectancy and increasing risks of many human diseases, such as type 2 diabetes mellitus, cardiovascular diseases, hypertension, non-alcoholic fatty liver disease, osteoarthritis, and cancer [1]
Cudratricusxanthone A (CTXA) at 10 μM has strong anti-adipogenic and anti-inflammatory effects in 3T3-L1 cells, and these effects are mediated through modulation of the expression and phosphorylation levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), perilipin A, signal transducer and activator of transcription-3 (STAT-3)/5, AMPK, and inducible nitric oxide synthase (iNOS)
10 μM has strong anti-adipogenic and anti-inflammatory effects on 3T3-L1 preadipocytes, and these effects are mediated through modulation of the expression and phosphorylation level of CCAAT/enhancer-binding proteins (C/EBPs)-α, peroxisome proliferator-activated receptors (PPARs)-γ, FAS, ACC, perilipin A, signal transducer and activator of transcription (STAT)-3/5, AMPK, and iNOS

Summary

Introduction

Obesity is a major health concern often deteriorating life expectancy and increasing risks of many human diseases, such as type 2 diabetes mellitus, cardiovascular diseases, hypertension, non-alcoholic fatty liver disease, osteoarthritis, and cancer [1]. Preadipocyte differentiation, called adipogenesis, is a multi-step process that occurs in the form of cellular, morphological, genetic, and biochemical changes. Through this process, fibroblast-like preadipocytes are converted into mature adipocytes that are filled with lipid droplets (LDs) [6,7,8]. It has been shown that fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and perilipin A, which regulate lipogenesis and LDs maturation/stabilization are crucial for preadipocyte differentiation [11,12,13]. There is evidence pointing out the positive role of numerous signaling protein kinases, such as cAMP-activated protein kinase (AMPK), protein kinase A (PKA), extracellular signal-regulated protein kinase-1/2 (ERK-1/2), p38 mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in preadipocyte differentiation [14,15,16,17]

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